Pediatric Dermatology [1, 4 ed.] 9780723435402

Table of contents 1 The Dermatological Diagnosis 2 The structure and function of normal skin 3 Eczema 4 Contact derma

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Pediatric Dermatology [1, 4 ed.]
 9780723435402

Table of contents :
Front cover
Title page
Copyright page
Table of contents
Preface
List of Contributors
Acknowledgments
Chapter 1: Structure and function of the skin
Skin Development
Embryogenesis of the Skin
Structural and Functional Properties of Skin of Infants, Children, and Adults
Basic Immunology
References
Chapter 2: Psychosocial development in children with cutaneous disease
Introduction
The Personal and Cultural Significance of the Skin
Psychological Responses to Dermatologic Disease
The Psychosocial Interview
Screening for Pediatric Psychosocial Dysfunction in the Dermatologist’s Office
Psychosocial Concerns and Psychiatric Illness
Conclusion
References
Chapter 3: Principles of diagnosis in pediatric dermatology
Introduction
Approach to the Pediatric Patient
The Particularities of Pediatric Dermatology
The Clinical History and Examinations
The Ages of Children and Their Dermatoses
Approach to Difficult Situations
History
Dermatological Examination
Simple Clinical Tests
References
Chapter 4: Principles of treatment in pediatric dermatology
Introduction
Topical Treatment
Systemic Treatment
Molecular Therapy in Dermatology
Cosmetic Treatment
Complementary and Alternative Treatments
References
Chapter 5: Surgical techniques
Introduction
The Surgical Consultation
Intraoperative Techniques for Painful Procedures in the Pediatric Patient
Anesthesia
Wound Closure Materials
Surgical Techniques
Dressings
Specialized Forms of Dermatologic Surgery in Children
Special Equipment
Special Dermatologic Surgery Problems
Summary
References
Chapter 6: Neonatal skin and skin disorders
Fetal and Neonatal Skin Development, Structure and Function
Transient Physiologic Changes and Cutaneous Lesions in the Newborn
Benign Oral Neonatal Lesions
Benign Self-Limiting Cutaneous Lesions
Birthmarks
Developmental Anomalies
Vesiculopustular, Bullous and Erosive Diseases of the Newborn
Infectious Diseases of the Newborn
Prenatal Injury, Birth Trauma and Injury in the Neonatal Period
Prenatal Diagnosis
Skin Care of Newborn Infants
References
Chapter 7: Genodermatoses
Ectodermal Dysplasia Syndromes
Genetic Disorders of Pigmentation
Genetic Disorders of the Immune System
Immunoglobulin Deficiencies
Photosensitivity Disorders
Photosensitivity Disorders Other than Porphyrias
Tuberous Sclerosis Complex and Neurofibromatosis
Tumor Syndromes
Hereditary Metabolic Disorders
Aging Disorders
Cutaneous Mosaicism
References
Chapter 8: Ichthyosis and disorders of other cornification
Introduction
Pathogenesis of Ichthyosis and Disorders of Cornification
Autosomal Recessive Congenital Ichthyoses
Palmoplantar Keratoderma
Other Keratoses
References
Chapter 9: Mucous membrane disorders
Introduction
Disorders of the Ocular Mucous Membranes
Disorders of the Genital Mucous Membranes
Disorders of the Oral Mucous Membranes
Disorders of Multiple Mucous Membranes
References
Chapter 10: Pigmentary abnormalities
Melanocytes and Melanogenesis
DISORDERS OF HYPERPIGMENTATION
Disorders of Hypopigmentation
Vitiligo
Neoplastic Disorders of Melanocytes
References
Chapter 11: Hair disorders
Congenital or Early Onset Alopecia
Hypertrichosis
Eruptive Vellus Hair Cysts
Abnormalities of Hair Color
Non-Scarring Alopecia
Scarring Alopecia
Hirsutism
References
Chapter 12: Nail and appendageal abnormalities
The Nail
Nail Biopsy and Surgery
Diseases of Eccrine Sweat Glands
Diseases of Apocrine Glands
References
Chapter 13: Acne
Introduction and Historical Note
Epidemiology
Presenting History
Physical Examination
Laboratory Findings
Pathophysiology and Histogenesis
Acne Variants
Disorders Associated with Acne
References
Chapter 14: Eczematous dermatitis
Introduction
Atopic Dermatitis
Diaper Dermatitis
Contact Dermatitis
Photodermatitis
Autosensitization Dermatitis
Perioral Dermatitis
Lichen Striatus
Lichen Simplex Chronicus (Localized Neurodermatitis)
Prurigo Nodularis
Papular Urticaria
References
Chapter 15: Papulosquamous diseases
Psoriasis Vulgaris
Pustular Psoriasis
Psoriatic Arthritis
Reiter Syndrome
Seborrheic Dermatitis
Sebopsoriasis
Lichen Planus
Lichen Planus-Like Eruptions
Lichen Nitidus
Lichen Aureus
Gianotti–Crosti Syndrome
Pityriasis Rosea
Pityriasis Lichenoides
Lymphomatoid Papulosis
Parapsoriasis
Pityriasis Rubra Pilaris
Exfoliative Erythroderma
Subcorneal Pustular Dermatosis
Papulosquamous Drug Reactions
References
Chapter 16: Vesiculobullous disease
Introduction
Inherited Vesiculobullous Disease
Autoimmune Vesiculobullous Disease
Infections
Reactive Blistering Disorders
Miscellaneous Blistering Disorders
References
Chapter 17: Diseases of the dermis and subcutaneous tissues
Nodular Diseases
Skin-Colored Cysts and Nodules
Skin Nodules with Color Change of the Overlying Skin
Amyloidosis
Myxedema
Lipoid Proteinosis
Granuloma Annulare
Granuloma Faciale
Cutaneous Lymphoid Hyperplasia (Pseudolymphoma)
Lymphocytic Infiltrate of Jessner
Sweet Syndrome
Angiolymphoid Hyperplasia with Eosinophilia and Kimura Disease
Foreign Body Reactions
Halogenodermas
Calcinosis Cutis
Cutaneous Ossification
Myositis Ossificans
Mastocytosis
Hyperlipidemias and Xanthomas
Sarcoidosis
Acknowledgments
References
Chapter 18: Sclerosing and atrophying conditions
Morphea
Progressive Facial Hemiatrophy
Scleredema
Sclerema Neonatorum (SN)
Stiff Skin Syndrome
Restrictive Dermopathy
Keloids and Hypertrophic Scars
Acne Keloidalis Nuchae
Ainhum and Pseudo-Ainhum
Striae
Lichen Sclerosus
Atrophodermas
Anetoderma
Focal Dermal Hypoplasia (Goltz Syndrome)
Aplasia Cutis Congenita
Fat Atrophy (Lipoatrophy)
Necrobiosis Lipoidica
References
Chapter 19: Vascular reactions
Introduction
Transient Erythemas
Persistent Erythemas
Vasospastic Reactions with Acral Erythema
Vasculitis and Inflammatory Purpuras
Non-Inflammatory Petechial and Ecchymotic Purpuras
Acknowledgments
References
Chapter 20: Vascular birthmarks:
Introduction
Vascular Tumors
Vascular Malformations
Acknowledgments
References
Chapter 21: Benign and malignant tumors
Introduction
Tumors and Tumor-like Lesions of Subcutaneous Fat
Tumors and Tumor-like Conditions of Fibroblasts and Myofibroblasts
Neural Tumors
Smooth Muscle Tumors
Skeletal Muscle Tumors
Epithelial Tumors
Adnexal Tumors
Lymphocytic Disorders
Lymphomas
Leukemias
Neuroblastoma
Ewing Family of Tumors
Metastases
Histiocytic Disorders
References
Chapter 22: Cutaneous manifestations of endocrine, metabolic, and nutritional disorders
Thyroid Disorders
Growth Hormone Disorders
Gonadal Dysgenesis
Adrenal Disorders
Disorders of Androgen Excess
Disorders of Insulin Resistance
Diabetes Mellitus
Disorders of G Protein Signal Transduction
Autoimmune Polyendocrine Syndromes
Multiple Endocrine Neoplasia (Men) Syndromes
Carney Complex
Vitamin D Resistance and Alopecia
Anorexia and Bulimia Nervosa
Disorders of Pregnancy
Disorders of Minerals and Co-Factors
Protein Energy Malnutrition
Vitamins
Acknowledgment
References
Chapter 23: Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations
Connective Tissue Diseases and Arthritides
Kawasaki Disease
Selected Systemic Diseases with Skin Manifestations
References
Chapter 24: Bacterial infections
Overview
Skin Infections Caused Predominantly by Staphylococcus Aureus
Skin Infections Caused Predominantly by Streptococci
Skin Infections Caused by Staphylococci, Streptococci and Other Bacteria
Infections Caused by Gram-Negative Bacteria
Rickettsial Infection
Infections Caused by Other Gram-Positive Bacteria
Infections Caused by Mycobacteria
Non-Tuberculosis Mycobacterial Infections
References
Chapter 25: Viral infections
Viral Exanthems
Epstein–Barr virus Infections
Eruptive Pseudoangiomatosis
Varicella-Zoster Infections
Milker’s Nodules (Pseudocowpox)
Human Papillomavirus
References
Chapter 26: Fungal, protozoal, and helminthic infections
Fungal Infections
Paronychia
Protozoal Infections
Helminthic Infections and Other Parasitic Eruptions
References
Chapter 27: Infestations
Lice
Scabies
Demodex: The Hair Follicle Mite
Dermanyssidae or Gamasidae (Bloodsucking Mites)
Pyemotes (Grain Mites)
Cheyletiellidae and/or Cheyletidae (Pet or Fur Mites)
Trombiculidae (Chiggers)
Thrips
Cimex Lectularius (Bedbugs)
References
Chapter 28: Sexually transmitted diseases
Syphilis
Diseases Caused by Neisseria Gonorrhoeae
Chancroid
Granuloma Inguinale (Donovanosis)
Infection Caused by Chlamydia Trachomatis
Lymphogranuloma Venereum (LGV)
External Genital and Anal Warts
Genital Herpes Simplex Infections
Molluscum Contagiosum
Human Immunodeficiency Virus (HIV) Infection, Including Acquired Immunodeficiency Syndrome (AIDS) In Children
Acknowledgment
References
Chapter 29: Physical injury and environmental hazards
Introduction
Adverse Reactions to Solar Radiation
Adverse Reactions to Cold
Adverse Reactions to Heat
Artefactual Skin Disease (Dermatitis Artefacta, Dermatitis Artifacta)
Cutaneous Manifestations of Child Abuse
Aquatic Hazards
Hazards of Selected Arthropods
Snakes
Selected Chemical Hazards
Hazards of Ionizing Radiation
References
Chapter 30: Drug reactions
Introduction
Approach to the Patient with a Suspected ADR
Exanthematous Eruptions
Urticarial Eruptions
Pustular Eruptions
Bullous Eruptions
Miscellaneous Drug Reactions
References
Index

Citation preview

PEDIATRIC DERMATOLOGY

Acquisitions Editors: Claire Bonnett/Russell Gabbedy Development Editor: Sharon Nash Editorial Assistant: Rachael Harrison Project Manager: Jess Thompson Design: Charles Gray Illustration Manager: Gillian Richards Illustrator: Marion Tasker Marketing Managers: Helena Mutak/Gaynor Jones

PEDIATRIC DERMATOLOGY F O UR T H E D I T I O N

Editors

Associate Editors

Lawrence A Schachner MD Harvey Blank Professor and Chairman Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, FL, USA

Bernice R Krafchik MB ChB FRCP(C) Professor Emeritus University of Toronto Toronto, Ontario, Canada

Ronald C Hansen MD Medical Staff Section Chief Phoenix Children’s Medical Group Division Chief Phoenix Children’s Hospital Phoenix, AZ, USA

Anne W Lucky MD Acting Director Division of Pediatric Dermatology, Cincinnati Children’s Hospital Volunteer Professor of Dermatology and Pediatrics The University of Cincinnati College of Medicine Cincinnati, OH, USA Amy S Paller MD Walter J Hamlin Professor and Chair of Dermatology Professor of Pediatrics Northwestern University Feinberg School of Medicine Attending Physician, Children’s Memorial Hospital Chicago, IL, USA Maureen Rogers MB BS FACD Emeritus Consultant Dermatologist Department of Dermatology The Children’s Hospital at Westmead Westmead, NSW, Australia Antonio Torrelo MD Chair, Department of Dermatology Hospital Infantil del Niño Jesús Madrid, Spain



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© 2011, Elsevier Ltd. All rights reserved. First edition 1988 Second edition 1995 Third edition 2003 The right of Lawrence A Schachner and Ronald C Hansen to be identified as authors of this work have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Dr Gabriele Richards retains copyright of all clinical, EM, and biological pictures provided by her to be used in this publication. Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing in Publication Data Mosby Pediatric dermatology. – 4th ed.   1.  Pediatric dermatology.   I.  Schachner, Lawrence A.  II.  Hansen, Ronald C.   618.9′25–dc22   ISBN-13: 9780723435402 Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress

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Contents Preface List of Contributors Acknowledgments

xi xiii xix

Molecular Therapy in Dermatology

VOLUME 1

Antonio Martorell and Antonio Torrelo

Cosmetic Treatment Zoe D. Draelos

SECTION I: BASIC SCIENCE AND PRINCIPLES OF DIAGNOSIS AND TREATMENT 1 Structure and function of the skin

Complementary and Alternative Treatments Howard B. Pride

5 Surgical techniques 1

SECTION II: NEONATAL AND INHERITED DISORDERS

Maria I. Morasso, David H. Chu and Thomas Schwarz

Embryogenesis of the Skin Maria I. Morasso

6 Neonatal skin and skin disorders

Structural and Functional Properties of Skin of Infants, Children, and Adults

Fetal and Neonatal Skin Development, Structure and Function

Basic Immunology Thomas Schwarz

Lawrence F. Eichenfield and Pristine W. Lee

51

Christine E. Wittmann, Paula K. Rauch and Michael S. Jellinek

3 Principles of diagnosis in pediatric dermatology

Mandi L. Maronn, Alanna F. Bree, Elaine C. Siegfried, Alex Zvulunov, Orith Waisbourd-Zinman, Dan Ben-Amitai, Ayelet Adir-Shani, Antonio Martorell, Antonio Torrelo, Zoe D. Draelos and Howard B. Pride

Introduction

Transient Physiologic Changes and Cutaneous Lesions in the Newborn Lawrence F. Eichenfield and Pristine W. Lee

69

Henning Hamm, Robert Johr, Sibel Ersoy-Evans and Angela Hernández-Martín

4 Principles of treatment in pediatric dermatology

Benign Oral Neonatal Lesions Margarita Larralde and Paula C. Luna

Benign Self-Limiting Cutaneous Lesions Margarita Larralde and Paula C. Luna

115

Birthmarks Margarita Larralde and Paula C. Luna

Developmental Anomalies Margarita Larralde and Paula C. Luna

Vesiculopustular, Bullous and Erosive Diseases of the Newborn

Mandi L. Marron, Alanna F. Bree and Elaine C. Siegfried

Margarita Larralde and Paula C. Luna

Topical Treatment

Infectious Diseases of the Newborn

Mandi L. Maronn, Alanna F. Bree and Elaine C. Siegfried

Lawrence F. Eichenfield and Pristine W. Lee

Systemic Treatment

Prenatal Injury, Birth Trauma and Injury in the Neonatal Period

Alex Zvulunov, Orith Waisbourd-Zinman, Dan Ben-Amitai and Ayelet Adir-Shani

299

Lawrence F. Eichenfield, Pristine W. Lee, Margarita Larralde and Paula C. Luna

David H. Chu

2 Psychosocial development in children with cutaneous disease

211

Bari Cunningham and Annette M. Wagner

Lawrence F. Eichenfield and Pristine W. Lee

v

Contents

Prenatal Diagnosis Lawrence F. Eichenfield and Pristine W. Lee

Congenital Ichthyosiform Erythroderma (CIE) and LI/CIE Intermediate Phenotypes

Skin Care of Newborn Infants

Gabriele Richard

Lawrence F. Eichenfield and Pristine W. Lee

Harlequin Ichthyosis

7 Genodermatoses

374

Alanna F. Bree, Peter Itin, Jon Dyer, Amy Paller, Sethuraman Gomathy, Carola Durán-McKinster, Julie Schaffer, Adrian-Martin Pierini, Bruce R. Korf, Susan J. Bayliss, Jan Izakovic, Patsy Lenane, Bernice Krafchik, Antonio Torrelo, Cristina López-Obregón and Alain Hovnanian

Gabriele Richard

Sjögren–Larsson Syndrome Gabriele Richard

Refsum Disease Gabriele Richard

Multiple Sulfatase Deficiency

Ectodermal Dysplasia Syndromes

Heiko Traupe

Alanna F. Bree

Neutral Lipid Storage Disease with Ichthyosis

Dyskeratosis Congenita

Gabriele Richard

Peter Itin

Conradi–Hünermann–Happle Syndrome

Incontinentia Pigmenti (Bloch–Sulzberger)

Heiko Traupe

Peter Itin

Child Syndrome

Pseudoxanthoma Elasticum

Arne König and Heiko Traupe

Jon Dyer and Amy Paller

Kid Syndrome

Genetic Disorders of Pigmentation

Peter Itin

Sethuraman Gomathy and Carola Durán-McKinster

Netherton Syndrome

Genetic Disorders of the Immune System

Peter Itin and Stephan Lautenschlager

Julie Schaffer and Amy Paller

Peeling Skin Syndrome

Photosensitivity Disorders

Alan Irvine

Adrian-Martin Pierini

Erythrokeratodermas

Tuberous Sclerosis Complex and Neurofibromatosis

Peter Itin

Palmoplantar Keratoderma

Bruce R. Korf

Daniel Hohl and Stephanie Christen-Zaech

Tumor Syndromes

Other Keratoses

Susan J. Bayliss

Peter Itin

Hereditary Metabolic Disorders Jan Izakovic

Antonio Torrelo

SECTION III: DISEASES OF MUCOUS MEMBRANES AND APPENDAGEAL STRUCTURES

Follicular Nevi

9 Mucous membrane disorders

Aging Disorders Patsy Lenane and Bernice Krafchik

Cutaneous Mosaicism

Antonio Torrelo and Cristina López-Obregón

10 Pigmentary abnormalities

Prenatal Diagnosis of Genetic Skin Diseases Alain Hovnanian

8 Ichthyosis and disorders of other cornification Gabriele Richard, Alan Irvine, Heiko Traupe, Arne König, Peter Itin, Stephan Lautenschlager, Daniel Hohl and Stephanie Christen-Zaech

Introduction

Melanocytes and Melanogenesis Danielle A. Marcoux and Carola Durán-McKinster

Disorders of Hyperpigmentation Danielle A. Marcoux and Carola Durán-McKinster

Disorders of Hypopigmentation

Pathogenesis of Ichthyosis and Disorders of Cornification

Vitiligo

Eulalia Baselga

Gabriele Richard

Joseph Morelli

Ichthyosis Vulgaris

Neoplastic Disorders of Melanocytes

Recessive X-Linked Ichthyosis

vi

567

700

Danielle A. Marcoux, Carola Durán-McKinster, Eulalia Baselga, Joseph Morelli, Khanh Thieu and Hensin Tsao

Gabriele Richard

Alan Irvine

644

Adelaide A. Hebert

Khanh Thieu and Hensin Tsao

11 Hair disorders

Heiko Traupe

Maureen Rogers, Yong-Kwang Tay and Li-Chuen Wong

Keratinopathic Ichthyoses: Epidermolytic Ichthyosis (EI) and Superficial Epidermolytic Ichthyosis (SEI)

Congenital or Early Onset Alopecia

Gabriele Richard

Li-Chuen Wong

Lamellar Ichthyosis

Eruptive Vellus Hair Cysts

Gabriele Richard

Li-Chuen Wong

Maureen Rogers

Hypertrichosis

747

Contents

21 Benign and malignant tumors

Abnormalities of Hair Colour Li-Chuen Wong

Non-scarring Alopecia

22 Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

Yong-Kwang Tay

Scarring Alopecia

Thyroid Disorders

Hirsutism

Anne W. Lucky

Yong-Kwang Tay

794

Robert Silverman and Robert Baran

13 Acne

1219

Anne W. Lucky, Julie Powell and Adelaide A. Herbert

Yong-Kwang Tay

12 Nail and appendageal abnormalities

1181

Walter H. C. Burgdorf, Pedram Gerami and Albert C. Yan

827

Daniel P. Krowchuk, Carlo Gelmetti and Anne W. Lucky

Disorders of Pregnancy Julie Powell

23 Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

1269

Nancy K. Barnett, William L. Weston, Alfons Krol, Michael Shishov, Kaleo Ede, Stanford T. Shulman, Elizabeth Swanson, Michelle Jeffries and Patricia A. Treadwell

VOLUME 2

Lupus Erythematosus Nancy K. Barnett

Neonatal Lupus Erythematosus

SECTION IV: REACTION PATTERNS 14 Eczematous dermatitis

William L. Weston

851

Bernice R. Krafchik, Sharon Jacob, Thomas Bieber, James G. H. Dinoulos and Eric Simpson

Juvenile Systemic Sclerosis (JSS) (Formerly Progressive Systemic Sclerosis, PSS; Scleroderma) Nancy K. Barnett

Juvenile Dermatomyositis

Atopic Dermatitis Bernice R. Krafchik

Alfons Krol

Pathophysiology of Atopic Dermatitis

Sjögren Syndrome

Thomas Bieber

Nancy K. Barnett

Therapeutics

Familial Mediterranean Fever

Eric Simpson

Nancy K. Barnett

Diaper Dermatitis

Cryoproteinemia

James G. H. Dinoulos

Nancy K. Barnett

Contact Dermatitis

Chronic Recurrent Multifocal Osteomyelitis and Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis Syndrome

Sharon Jacob

Autosensitization Dermatitis

Elizabeth Swanson

Bernice R. Krafchik

15 Papulosquamous diseases

901

Peter A. Hogan and Richard G.B. Langley

16 Vesiculobullous disease

952

Michael J. Tidman, Jemima E. Mellerio and Elena Pope

17 Diseases of the dermis and subcutaneous tissues

Deficiency of the Interleukin-1-Receptor Antagonist (DIRA) Michelle Jeffries

Kawasaki Disease Stanford T. Shulman

990

Selected Systemic Diseases with Skin Manifestations Patricia A. Treadwell

Julie S. Prendiville and Alfons L. Krol

Nodular Diseases

SECTION VI: INFECTIONS AND INFESTATIONS

Julie S. Prendiville

Amyloidosis Alfons L. Krol

18 Sclerosing and atrophying conditions

1057

Mary K. Spraker, Leslie P. Lawley and Elizabeth Alvarez Connelly

19 Vascular reactions

1096

David Orchard and David Burden

Sheilagh M. Maguiness and Ilona J. Frieden

1331

Yvonne Chiu, Sheila Galbraith, Wesley King Galen, Kristen Holland and Liborka Kos

Overview Liborka Kos and Sheila Galbraith

Skin Infections Caused Predominantly by Staphylococcus Aureus Liborka Kos

SECTION V: NEOPLASMS AND SYSTEMIC DISEASES 20 Vascular birthmarks: tumors and malformations

24 Bacterial infections

Skin Infections Caused Predominantly by Streptococci Sheila Galbraith

1135

Skin Infections Caused by Staphylococci, Streptococci and Other Bacteria Liborka Kos and Sheila Galbraith

vii

Contents

Enteric Fever

Orf (Sheeppox)

Yvonne Chiu

Anthony J. Mancini

Brucellosis

Human Papillomavirus

Yvonne Chiu

Orli Wargon

Tularemia

26 Fungal, protozoal, and helminthic infections

Yvonne Chiu

Rat-Bite Fever Yvonne Chiu

Fungal Infections

Bartonella

Joseph M. Lam and Sheila Fallon Friedlander

Kristen Holland

Deep Fungal Infections

Melioidosis

Joseph M. Lam and Hector W. Caceres-Rios

Yvonne Chiu

Protozoal Infections

Glanders

Joseph M. Lam and Hector W. Caceres-Rios

Yvonne Chiu

Helminthic Infections and Other Parasitic Eruptions

Pseudomonas aeruginosa

Joseph M. Lam and Sheila Fallon Friedlander

Kristen Holland

27 Infestations

Gram-Negative Folliculitis in Acne Vulgaris

28 Sexually transmitted diseases

Pasteurella multocida Yvonne Chiu

Bernard Cohen, Gail Todd and Gayle Fischer

Plague

Syphilis

Yvonne Chiu

Diseases Caused by Neisseria Gonorrhoeae

Yvonne Chiu

Bernard Cohen

Haemophilus influenzae

Chancroid

Yvonne Chiu

Bernard Cohen

Leptospirosis

Granular Inguinale (Donovanosis)

Kristen Holland

Bernard Cohen

Rickettsial Infection

Infections Caused by Chlamydia Trachomatis

Liborka Kos

External Genital and Anal Warts

Kristen Holland

Genital Herpes Simplex Infections

Infections Caused by Mycobacteria

Gayle Fischer

Wesley King Galen

Molluscum Contagiosum

Anthony J. Mancini

Epstein–Barr Virus Infections

Gayle Fischer

1425

Gayle Fischer

Human Immunodeficiency Virus (HIV) Infection, Including Acquired Immunodeficiency Syndrome (AIDS) in Children Gail Todd

Orli Wargon

SECTION VII: INJURY AND RESPONSES

Acquired Cytomegalovirus Infections

29 Physical injury and environmental hazards

Orli Wargon

Papular Acrodermatitis of Childhood Orli Wargon

viii

Bernard Cohen

Infections Caused by Other Gram-Positive Bacteria

Viral Exanthems

1584

Gail Todd

Neisseria meningitidis

Anthony J. Mancini and Orli Wargon

1535

Terri Meinking, David Taplin and Maureen Vicaria

Yvonne Chiu

25 Viral infections

1470

Joseph M. Lam, Hector W. Caceres-Rios and Sheila Fallon Friedlander

1642

Maureen Rogers, Catherine McCuaig, Chulabhorn Pruksachatkun, Michelle Jeffries, Ana M. Duarte, Giovanna Ciocca and Christine Norrie

Asymmetric Periflexural Exanthem of Childhood (Unilateral Laterothoracic Exanthem)

Adverse Reactions to Solar Radiation

Orli Wargon

Adverse Reactions to Cold

Eruptive Pseudoangiomatosis

Catherine McCuaig

Anthony J. Mancini

Adverse Reactions to Heat

Herpes Simplex Infection

Catherine McCuaig

Anthony J. Mancini

Varicella-Zoster Infections

Artefactual Skin Disease (Dermatitis Artefacta, Dermatitis Artifacta)

Orli Wargon

Maureen Rogers

Variola and Vaccinia

Cutaneous Manifestations of Child Abuse

Orli Wargon

Christine Norrie, Maureen Rogers

Milker’s Nodules (Pseudocowpox)

Aquatic Hazards

Anthony J. Mancini

Ana M. Duarte, Giovanna Ciocca

Catherine McCuaig

Contents

Hazards of Selected Arthropods Chulabhorn Pruksachatkun, Michelle Jeffries

30 Drug reactions

1698

Perla Lansang, Miriam Weinstein and Neil Shear

Snakes Michelle Jeffries

Selected Chemical Hazards Chulabhorn Pruksachatkun

Index

i1–75

Hazards of Ionizing Radiation Chulabhorn Pruksachatkun

ix

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Preface The fourth addition of pediatric dermatology represents a major advance in this series. We return to a 2-volume format to encourage usability, durability and longevity of the bindings. Each chapter has been extensively revised. The photographs have also been separately analyzed and revised. We continued to receive encouragement from colleagues throughout the world about continuing this series. We believe the fourth edition will meet the needs of worldwide readership. We continue to be indebted to the associated editors who, in fact, do the lion’s share of the editing. These include Drs. Bernice Krafchik, Anne Lucky, Amy Paller, Maureen Rogers and for the fourth edition we have added Dr. Antonio Torrelo. We should point out that Drs. Lucky and Torrelo have done the lion’s share of editing and augmenting the photographs for the fourth edition and we are very grateful for that input. The place of textbooks in medical education is becoming more controversial. Obviously electronic communications can be much quicker and up to date. However, if you are looking for the advantage of distilled wisdom, wherein multiple authors and multiple editors collaborate for a wise synthesis, we believe that textbooks fill that role. We especially believe that Pediatric Dermatology does, in fact, represent that synthesis. Our goal is to have each chapter approved by the lead chapter author, the

lead editor and the senior editor. Where this succeeds, the textbook succeeds. We continue to have inputs from most of the continents to include North and South America, Europe, Asia, Africa and Australia. Such international contributions have greatly enhanced the text. We continue to be pleased with the layout pioneered in the third edition. This includes having references at the bottom of each page, which eliminates much of the page flipping needed to identify references in other textbooks. We greatly appreciate the coordination of multiple people at Elsevier, including Sharon Nash, Rachael Harrison and Claire Bonnett. We trust that the fourth edition will be helpful to physicians interested in the skin problems of children. We thank our families and the office staff who have helped us so greatly in producing this textbook. We thank our patients, from whom we have learned most of what we know in pediatric dermatology. We trust that this effort will continue to positively influence the quality of care for them and for other children. Lawrence A Schachner MD Ronald C Hansen MD 2010

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List of Contributors Robert L. Baran

MD

Honorary Professor University of Franche-Comté Nail Disease Center Cannes, France

Nancy K. Barnett

MD

Courtesy Staff, Dermatology Tufts Medical Center Dermatology of Cape Cod North Falmouth, MA, USA

Eulalia Baselga

MD

Medical Director Pediatric Dermatology Unit and Hemangiomas and Vascular Anomalies Clinic Department of Dermatology Hospital de la Santa Creu i Sant Pau Barcelona, Spain

Susan J. Bayliss

MD

Professor of Internal Medicine and Pediatrics (Dermatology) Director of Pediatric Dermatology Washington University School of Medicine St Louis, MO, USA

Dan Ben-Amitai

MD

Head of Pediatric Dermatology Unit Schneider Children’s Medical Center of Israel Petach Tikvah Lecturer Sackler School of Medicine Tel-Aviv University Tel-Aviv, Israel

Thomas Bieber

MD PhD FAAD FAAAI

Professor of Dermatology and Allergy; Chairman and Director Department of Dermatology and Allergy University of Bonn Bonn, Germany

Alanna F. Bree

MD

Assistant Professor of Dermatology and Pediatrics Department of Dermatology Baylor College of Medicine Texas Houston, TX, USA

A. David Burden

MD FRCP

MD

MD

Professor of Pediatric Dermatology Peruvian University Cayetano Heredia Instituto de Salud del Niño Lima, Peru

Yvonne E. Chiu

MD

Instructor of Dermatology Medical College of Wisconsin Milwaukee, WI, USA

David H. Chu

MD PhD

Staff Physician Scripps Clinic Medical Group Division of Dermatology and Cutaneous Surgery La Jolla, CA, USA MD

Dermatologist Miami Children’s Hospital Miami, FL, USA

Clinical Lecturer in Dermatology Ludwig Maximillian University Munich, Germany

Hector W. Caceres-Rios

MD MSci

Attending Physician of Pediatric Dermatology Department of Dermatology and Venereology Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland

Giovanna Ciocca

Consultant Dermatologist Western Infirmary Glasgow, Scotland, UK

Walter Burgdorf

Stephanie Christen-Zaech

Bernard A. Cohen

MD

Director of Pediatric Dermatology Johns Hopkins Children’s Center Professor of Dermatology and Pediatrics Johns Hopkins University School of Medicine Baltimore, MD, USA

Elizabeth A. Connelly

MD

Voluntary Associate Professor of Dermatology University of Miami Miami, FL, USA

James G. H. Dinulos

MD

Section Chief Dermatology (Interim) Dartmouth-Hitchcock Clinic Lebanon, NH, USA xiii

List of contributors

Zoe D. Draelos

Ilona J. Frieden

MD

Consulting Professor Department of Dermatology Duke University School of Medicine Durham, NC, USA

Professor of Dermatology and Pediatrics Chief, Division of Pediatric Dermatology University of California at San Francisco San Francisco, CA, USA

Ana M. Duarte

Sheila Fallon Friedlander

MD

Pediatric Dermatologist Director, Division of Dermatology Miami Children’s Hospital Miami, FL, USA

Carola Durán-McKinster

MD

Pediatric Dermatologist Head of the Department of Dermatology National Institute of Pediatrics of Mexico Professor of Pediatric Dermatology Universidad Nacional Autonoma de Mexico Mexico

Jonathan A. Dyer

MD

Assistant Professor Departments of Dermatology and Child Health University of Missouri Columbia, MO, USA

Kaleo Ede

MD

Clinical Assistant Professor of Pediatrics University of Arizona College of Medicine Division of Pediatric Rheumatology Phoenix Children’s Hospital Phoenix, AZ, USA

Lawrence F. Eichenfield

MD

Professor of Medicine (Dermatology) and Pediatrics Division of Pediatric and Adolescent Dermatology Rady Children’s Hospital and UC San Diego San Diego, CA, USA

Sibel Ersoy-Evans

MD

Associate Professor of Dermatology Hacettepe University Faculty of Medicine Department of Dermatology Ankara, Turkey

Gayle Fischer

MBBS FACD

Senior Lecturer in Dermatology The University of Sydney Visiting Medical Officer The Royal North Shore Hospital Sydney, Australia xiv

Adelaide A. Hebert

MD

MD

MD

Professor of Dermatology and Pediatrics Department of Dermatology University of Texas Health Science Center – Houston Houston, TX, USA

Angela Hernández-Martín

Professor, Pediatrics and Dermatology UCSD School of Medicine Section Chief, Division of Dermatology Rady Children’s Hospital San Diego, CA, USA

Staff Dermatologist Dermatology Department Hospital Niño Jesús Madrid, Spain

Sheila S. Galbraith

Peter Hogan

MD

Assistant Professor of Dermatology Dept of Dermatology Medical College of Wisconsin Milwaukee, WI, USA

Wesley King Galen

MD FACD

Head Department of Dermatology Children’s Hospital at Westmead New South Wales, Australia

Daniel Hohl MD

MD

MD

Staff Dermatologist TC Thompson Children’s Hospital Chattanooga, TN, USA

Professor of Dermatology Service de Dermatologie du CHUV Hopital de Beaumont Lausanne, Switzerland

Carlo Gelmetti

Kristen E. Holland

MD

Vice-Direttore Dipartimento di Anestesiologia Terapia Intensiva e Scienze Dermatologiche Università degli Studi di Milano Fondazione IRCCS Ca’ Granda ‘Ospedale Maggiore Policlinico’ Milan, Italy

Pedram Gerami

MD

Assistant Professor of Dermatology Pathology and Pediatrics Northwestern University and the Feinberg School of Medicine Chicago, IL, USA

Sethuraman Gomathy

MD

Associate Professor Department of Dermatology All India Institute of Medical Sciences New Delhi, India

Henning Hamm

MD

Professor of Dermatology Department of Dermatology University of Würzburg Würzburg, Germany

MD

Assistant Professor of Dermatology Medical College of Wisconsin Milwaukee, WI, USA

Alain Hovnanian

MD PhD

Professor of Genetics Department of Medical Genetics and Dermatology Necker Hospital for Sick Children Université Paris 5 René Descartes Paris, France

Alan D. Irvine

MD FRCP FRCPI

Consultant Paediatric Dermatologist Associate Professor Trinity College Dublin Our Lady’s Children’s Hospital Dublin, Ireland

Peter Itin

MD

Professor of Dermatology Head of the Department of Dermatology University Hospital Basel, Switzerland

Jan Izakovic

MD

Associate Professor of Dermatology Co-Director, Division of Pediatric Dermatology Department of Dermatology University of Miami Miller School of Medicine Miami, FL, USA

List of contributors

Sharon E. Jacob

Joseph M. Lam

MD

Assistant Professor of Medicine and Pediatrics (Dermatology) University of California, San Diego – Rady San Diego, CA, USA

Michelle L. Jeffries

DO

Pediatric Dermatology Fellow Phoenix Children’s Hospital Department of Pediatric Dermatology Phoenix, AZ, USA

Michael S. Jellinek

MD

Professor of Psychiatry and of Pediatrics Harvard Medical School Department of Psychiatry Massachusetts General Hospital Boston, MA, USA

Robert Johr

MD

Clinical Professor of Dermatology Associate Clinical Professor of Pediatrics Pigmented Lesion Clinic University of Miami School of Medicine Boca Raton, FL, USA

Bruce R. Korf

MD PhD

Wayne H and Sara Crews Finley Chair in Medical Genetics Chair, Department of Genetics University of Alabama at Birmingham Birmingham, AL, USA

Liborka Kos

Assistant Clinical Professor of Dermatology Medical College of Wisconsin Milwaukee, WI, USA MB ChB FRCP(C)

Professor Emeritus University of Toronto Toronto, Ontario, Canada

Alfons Krol

Richard G.B. Langley

MD FRCPC

Professor of Dermatology and Director of Research Division of Dermatology, Department of Medicine Dalhousie University Halifax, Nova Scotia, Canada

Perla Lansang

MD FRCPC

Lecturer University of Toronto Division of Dermatology Sunnybrook Health Sciences Centre Toronto, ON, Canada

Margarita Larralde

Professor of Dermatology and Pediatrics Oregon Health and Sciences University Portland, OR, USA MD

Professor of Pediatrics and Dermatology Wake Forest University School of Medicine Winston-Salem, NC, USA

MD

Head of Dermatologic Outpatient Clinic Zürich, Switzerland

Leslie P. Lawley

MD

Assistant Professor of Dermatology and Pediatrics Emory University School of Medicine Department of Dermatology Atlanta, GA, USA MD

Divisions of Dermatology and Pediatric Dermatology University of California, San Diego Rady Children’s Hospital San Diego, CA, USA

Patsy Lenane

MB BCH BAO MRCPI

Consultant Dermatologist The Children’s University and The Mater Misericordiae Hospitals Dublin, Ireland

MD

Dermatologist Department of Dermatology Hospital del Niño Jesús Madrid, Spain

Anne W. Lucky

MD

Acting Director Division of Pediatric Dermatology, Cincinnati Children’s Hospital Volunteer Professor of Dermatology and Pediatrics The University of Cincinnati College of Medicine Cincinnati, OH, USA

Paula C. Luna

MD

Dermatologist Dermatology Department Hospital Alemán Pediatric Dermatology Department Hospital Ramos Mejía Buenos Aires, Argentina

Sheilagh M. Maguinness PhD MD

Associate Professor of Dermatology Head, Division of Dermatology Hospital Aleman Head, Department of Pediatric Dermatology Ramos Mejía Hospital Buenos Aires, Argentina

Pristine W. Lee

MD FRCPC

Daniel P. Krowchuk

Clinical Assistant Professor Department of Pediatrics, Division of General Pediatrics Associate Member Department of Dermatology and Skin Sciences University of British Columbia Vancouver, BC, Canada

Stephan Lautenschlager

MD

Bernice R. Krafchik

Cristina López-Obregón

MD

MD FRCPC

Associate Physician Kaiser Permanente Assistant Clinical Professor University of California San Francisco, CA, USA

Anthony J. Mancini

MD FAAP FAAD

Professor of Pediatrics and Dermatology Northwestern University’s Feinberg School of Medicine Head, Division of Pediatric Dermatology Children’s Memorial Hospital Chicago, IL, USA

Danielle A. Marcoux

MD FRCPC

Clinical Associate Professor of Paediatrics Dermatology CHU Sainte-Justine University of Montreal Montreal, Quebec, Canada

Mandi L. Maronn

MD

Pediatric Dermatology Fellow Department of Dermatology Baylor College of Medicine Texas Houston, TX, USA

Antonio Martorell

MD

Dermatologist Department of Dermatology Hospital Infantil del Niño Jesús Madrid, Spain xv

List of contributors

Catherine C. McCuaig

MD FRCPC

Gabriele Richard

MD

Professor of Dermatology University of Buenos Aires Head, Department of Dermatology Hospital for Pediatrics ‘Prof Juan P Garrahan’ Buenos Aires, Argentina

Terri L. Meinking

Elena Pope

PhD

President, International Research Team Global Health Associates of Miami Miami, FL, USA

Jemima Mellerio

BSc MD FRCP

Consultant Dermatologist St John’s Institute of Dermatology Guy’s and St Thomas’ NHS Foundation Trust London, UK

Maria I. Morasso

PhD

Principal Investigator Developmental Skin Biology Section National Institute of Arthritis and Musculoskeletal and Skin Diseases Bethesda, MD, USA

Joseph Morelli

MD

Professor of Dermatology and Pediatrics; Section Head, Pediatric Dermatology The Children’s Hospital Aurora, Colorado, USA

Christine Norrie

MB BS MForMed FACLM

Consultant Forensic Physician The Children’s Hospital at Westmead Westmead, NSW, Australia

David Orchard

MBBS FACD

Paediatric Dermatologist Royal Children’s Hospital Melbourne, Victoria, Australia

Amy S. Paller

MD

Walter J Hamlin Professor and Chair of Dermatology Professor of Pediatrics Northwestern University Feinberg School of Medicine Attending Physician, Children’s Memorial Hospital Chicago, IL, USA

xvi

Adrián-Martín Pierini

Associate Professor University of Montreal Dermatology Service, Pediatrics CHU Sainte-Justine Montréal, Québec, Canada

DABD

MD MSc FRCPC

Medical Director GeneDx Gaithersburg, MD Adjunct Associate Professor of Dermatology Thomas Jefferson University Philadelphia, PA, USA

Maureen Rogers

Associate Professor of Paediatrics University of Toronto Head, Section of Dermatology Division of Paediatric Medicine Hospital for Sick Children Toronto, Ontario, Canada

Julie Powell

Julie V. Schaffer

Thomas Schwarz

MB FRCPC

Clinical Professor Department of Pediatrics University of British Columbia British Columbia’s Children’s Hospital Vancouver, BC, Canada MD

Associate Departments of Dermatology and Pediatrics Geisinger Medical Center Danville, PA, USA

Chulabhorn Pruksachatkun

MD

Professor of Pediatric Dermatology Chiang Mai University Chiang Mai, Thailand

Paula K. Rauch

MD

Assistant Professor of Dermatology and Pediatrics and Director of Pediatric Dermatology Department of Dermatology New York University School of Medicine New York, NY, USA

Clinical Associate Professor of Pediatrics/Dermatology Director, Division of Pediatric Dermatology CHU Sainte-Justine University of Montreal Montreal, Quebec, Canada

Howard B. Pride

MB BS FACD

Emeritus Consultant Dermatologist Department of Dermatology The Children’s Hospital at Westmead Westmead, NSW, Australia

MD FRCPC ABD

Julie S. Prendiville

MD FACMG

MD

Founding Director Marjorie E. Korff PACT Program Chief, Child Psychiatry Consultation Service to Pediatrics Massachusetts General Hospital Boston, MA, USA

MD

Professor and Chairman Department of Dermatology and Allergology University Hospital Schleswig Holstein Kiel, Germany

Ayelet Shani-Adir

MD

Attending Physician Pediatric Dermatology Service Department of Dermatology Haemek Medical Center Afula, Israel Lecturer Faculty of Medicine Technion Israeli Institute of Technology Haifa, Israel

Neil H. Shear

BASc MD FRCPC FACP

Professor of Medicine (Dermatology, Clinical Pharmacology, Pediatrics) Chief of the Division of Dermatology University of Toronto Medical School Toronto, ON, Canada

Michael Shishov

MD MPH

Clinical Assistant Professor of Pediatrics University of Arizona College of Medicine Division Chief, Pediatric Rheumatology Phoenix Children’s Hospital Phoenix, AZ, USA

List of contributors

Stanford T. Shulman

MD

Virginia H Rogers Professor of Pediatric Infectious Diseases Northwestern University The Feinberg School of Medicine Chief, Division of Infectious Diseases The Children’s Memorial Hospital Chicago, IL, USA

Elaine C. Siegfried

MD

Professor of Pediatrics and Dermatology Department of Dermatology St. Louis University Medical School St. Louis, MO, USA

Robert A. Silverman

MD

Clinical Associate Professor of Pediatrics Georgetown University Hospital Clinical Associate Professor of Pediatrics University of Virginia, Charlottesville INOVA Fairfax Hospital for Children Fairfax, VA, USA

Eric L. Simpson

MD MCR

Associate Professor Department of Dermatology Oregon Health and Science University Portland, OR, USA

Mary Spraker

MD

Chief of Pediatric Dermatology, Children’s Healthcare of Atlanta at Egleston Department of Dermatology The Emory Clinic Atlanta, GA, USA

David Taplin Professor Emeritus University of Miami Miller School of Medicine Department of Dermatology and Cutaneous Surgery Miami, FL, USA

Yong-Kwang Tay

MD FRCP(Lond)

Associate Professor Senior Consultant and Chief Department of Dermatology Changi General Hospital Singapore

Khanh Thieu

MD

Dermatology Resident Department of Dermatology Columbia University Medical Center New York Presbyterian Hospital New York, NY, USA

Michael Tidman

MD FRCP(Edin) FRCP(Lond)

Consultant Dermatologist Department of Dermatology The Royal Infirmary of Edinburgh Edinburgh, UK

Gail Todd

FFDerm(SA) MBChB PhD BSc

Associate Director and Head Department of Dermatology University of Cape Town South Africa

Antonio Torrelo

MD

MD

Associate Professor of Dermatology University of Münster Medical School Münster, Germany

Patricia Treadwell

MD FAAP

Professor of Pediatrics Indianapolis, IN, USA

Hensin Tsao

MD PhD

MA MPH

Senior Research Associate Global Health Associates of Miami Miami, FL, USA

Annette M. Wagner

Associate Professor School of Women’s and Children’s Health University of NSW Senior Staff Specialist Department of Paediatric Dermatology Sydney Children’s Hospital Australia BSc MD FRCPC

Assistant Professor (Pediatrics and Dermatology) University of Toronto Staff Physician and Fellowship Director Hospital for Sick Children Toronto, ON, Canada

William L. Weston

MD

Professor Emeritus of Dermatology and Pediatrics University of Colorado School of Medicine Aurora, CO, USA

Christine E. Wittmann

Associate Professor of Dermatology Harvard Medical School Department of Dermatology Massachusetts General Hospital Boston, MA, USA

Maureen Vicaria

MBBS MClin Ed FACD

Miriam Weinstein

Chair, Department of Dermatology Hospital Infantil del Niño Jesús Madrid, Spain

Heiko Traupe

Orli Wargon

MD

Assistant Professor of Pediatrics and Dermatology Northwestern Feinberg School of Medicine Attending Physician Pediatric Dermatology Children’s Memorial Hospital Chicago, IL, USA

Orith Waisbourd-Zinman

MD

Resident Department of Pediatrics Schneider Children’s Medical Center Petah-Tiqva, Israel

MB BS FACD

Clinical Instructor in Psychiatry Harvard Medical School Cambridge Hospital Cambridge, MA, USA

Li-Chuen Wong

MB BS FACD

Consultant Dermatologist The Children’s Hospital at Westmead Westmead, NSW, Australia

Albert C. Yan

MD

Section Chief of Pediatric Dermatology Associate Professor Pediatrics and Dermatology Department of Pediatrics and Dermatology Children’s Hospital of Philadelphia University of Pennsylvania School of Medicine Philadelphia, PA, USA

Alex Zvulunov

MD MHA

Senior Dermatologist and Pediatrician Pediatric Dermatology Unit Schneider Children’s Medical Center of Israel Petach Tikvah Senior Lecturer in Dermatology Faculty of Health Sciences Medical School for International Health Ben-Gurion University of the Negev Beer-Sheva, Israel xvii

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Acknowledgments Twenty-three years ago, when we published the first edition of Pediatric Dermatology, our acknowledgement began ‘more than any one person, this project owes its existence to the Society for Pediatric Dermatology.’ This remains the case. Now in its 34th year of existence, the Society for Pediatric Dermatology remains the major force in shaping the field of pediatric dermatology, giving it substance and credibility. We continue to thank the generous contributions of expertise and energy, selflessly provided by many esteemed members of this society, as well as many international colleagues in pediatrics, dermatology, and pediatric dermatology. The editors humbly acknowledge our enormous debt of gratitude to all of our contributors. We too are indebted to the Departments of Dermatology and Pediatrics at the University of Miami, Leonard M. Miller School of Medicine, and the Phoenix Children’s Hospital. We are especially grateful to Dean Pascal J. Goldschmidt and President Donna Shalala at the University of Miami for providing us the academic milieu essential for the development of projects such as this book. We also gratefully acknowledge our administrators at Phoenix Children’s Hospital, our CEO Robert Meyer, and CMO Murray Pollack, for their encouraging the project. We are equally indebted to our muses Irit Spierer Schachner and Kay Pinckard Hansen for providing the love and support that helped us complete the project. We express enormous respect and gratitude to Drs Bernice Krafchik, Anne Lucky, Amy Paller, Maureen Rogers, and Antonio Torrelo. for their incredible work and dedication as associate editors of this fourth edition. We wish to express our gratitude for the dedication shown by our assistants, Maria Enamorado and Camilla Mendell, for the many hours of work which they contributed to the preparation of this book. We further acknowledge with gratitude the assistance of the editorial and production staff of Mosby-Elsevier Books. Lawrence A Schachner and Ronald C Hansen, 2010 Acknowledgements to previous edition authors This book would not exist without the excellent contributions to the first, second and third editions made by the following authors:

Michelle A Bene-Bain Joel H Berg Carl Bigler Christine Bodemer Lesley Boyer Raymond V Caputo Bernard A Cohen Irwin Cohen Gary L Darmstadt Odile Enjolras Nancy Esterly Jo-David Fine Joan Guitart Anne Halbert Rudi Happle Sidney Hurwitz Tomisaku Kawasaki Walter Krause Alfred T Lane Moise L Levy Giuseppe Micali Neal S Penneys Neil Prose Thomas T Provost Linda G Rabinowitz Ben G Raimer Sharon S Raimer Steven D Resnick Ramon Ruiz-Maldonado Findlay E Russell Rikako Sasaki Tor A Schwayder Edward M Sills Margaret H D Smith Lawrence M Solomon David H Stein Virginia P Sybert Ronald G Wheeland Mary L Williams Kazuya Yamamoto

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SECTION

i

BASIC SCIENCE AND PRINCIPLES OF DIAGNOSIS AND TREATMENT

Maria I. Morasso, David H. Chu and Thomas Schwarz



PROPERTIES OF THE SKIN

SKIN DEVELOPMENT The skin is the largest constantly renewable organ in the body. It is a complex tissue from which specialized structures such as hair, glands and nails develop during embryogenesis. Several of the structures renew throughout life and recapitulate morphological processes, and molecular and cellular events that are established during embryogenesis. The formation of the skin during human embryonic and fetal development will constitute the initial section of this chapter. Skin structure, composition, and function in the adult comprise the second section. Little is known about the development of skin or alterations in function between the first months of life and adult life.

EMBRYOGENESIS OF THE SKIN Maria I. Morasso

INTRODUCTION Early during embryogenesis the conceptus undergoes gastrulation, a process that leads to the establishment of the three primary embryonic layers, the ectoderm, mesoderm and endoderm. Ectoderm and endoderm are formed at 10–12 days estimated gestational age (EGA) and the mesoderm (origin of the dermis) forms around 18–19 days EGA. It is shortly after that the epidermis originates from the ectodermal cells covering the embryo. It starts as a one-cell layer epithelium, which differentiates and stratifies during development to ultimately form the skin, a water-impermeable structure that protects us from dehydration and infection. The gestational period can be divided into distinct embryonic/fetal developmental stages: the embryonic period (0–60 days), the early fetal period (2–5 months) and the late fetal period (5–9 months) (Fig. 1.1). In epidermal cells, each of these stages is characterized by specific biochemical and immunohistochemical markers for morphogenetic and differentiation processes.1 1.

1

UNIQUE PROPERTIES OF PRENATAL SKIN

Structure and function of the skin

Holbrook KA. Structure and function of the developing human skin. In: Goldsmith LE, ed. Physiology, Biochemistry and molecular biology of the skin. 2nd ed., Vol. 1. New York: Oxford University Press; 1991:63.

The skin is composed of the underlying dermis of mesodermal embryonic origin that is separated from the multilayered overlaying epidermis of ectodermal origin by a basement membrane. The epidermis is primarily composed of cells termed keratinocytes, due to the presence of the epidermal characteristic intermediate filaments, the keratins. Other cell types present in the skin are the Langerhans cells, melanocytes, and the sensory Merkel cells. The epidermis is organized into layers that correlate with stages of keratinocyte differentiation. During the process, the proliferative keratinocytes of the basal layer divide and move upward, differentiating to spinous cells. These cells then differentiate to granular cells and ultimately culminate in a cornified anucleated non-viable cell of the stratum corneum. Stratification is concurrent with the layer-specific expression of structural and enzymatic markers. This cornified cell is the product of covalent cross-links of cornified envelope precursors by Ca++-dependent transglutaminases and attachment of lipid molecules. The cornified layer provides the protective and water barrier functions between the body and the environment.2,3 The end point of epidermal differentiation in both the fetus and the adult is keratinization, but there are differences in how this is accomplished. In the adult, keratinization requires a relatively short time. A cell that leaves the basal layer moves into the lowest cornified cell layer in about 14 days. The fetal epidermis requires 22–24 weeks to keratinize. Thus, the fetal epidermis acquires the pattern of the adult tissue concurrent with stratification and differentiation. Some of the properties of adult skin are established during embryogenesis and are maintained throughout life. Other characteristics of fetal skin are unique.

UNIQUE PROPERTIES OF PRENATAL SKIN THE PERIDERM The periderm is a transient epidermal layer characteristic of the developing skin. It is the outermost layer of the embryonic and 2. 3.

Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005;6(4):328–340. Kalinin A, Marekov LN, Steinert PM. Assembly of the epidermal cornifies cell envelope. J Cell Sci. 2001;114:3069–3070.

1

i

Basic Science and Principles of Diagnosis and Treatment

Epidermal stratification Chorionic villous sampling

0

1

3

Interfollicular keratinization

Fetal biopsy

Amniocentesis

2

Embyonic stage 0-8 weeks

Follicular keratinization

4

Early fetal stage 2-5 months

5

6

7

Late fetal stage 5-9 months

8

9

Figure 1.1  Schematic summary of embryonic and fetal developmental stages UNIQUE PROPERTIES OF PRENATAL SKIN

and timing through gestation. The initiation of specific landmarks of epidermal differentiation is indicated (epidermal stratification, follicular keratinization and interfollicular keratinization). Timing of different techniques utilized for prenatal testing is highlighted.

fetal epidermis (Fig. 1.2). Periderm is ectodermal in origin and contains a single population of cells. Similarities in the cytoplasmic keratins, cell surface morphology, and antigens of the periderm support the hypothesis that it is the first layer of the skin, which divides and gives rise to the single layer of the epidermis.4–7 The periderm persists as a single layer of cells that remains on the surface of the developing skin until keratinization of cells in the underlying epidermal layers is complete.8 At that point, the periderm is sloughed in sheets and as individual cells from the skin surface into the amniotic fluid. Loss of a certain number of periderm cells occurs throughout the second trimester, as determined from the composition of cells in the amniotic fluid. The periderm cells cease to divide during the first trimester and do not appear to undergo any further steps in differentiation, but they continue to expand markedly in size and volume as the embryo/fetus grows. Characteristic changes in morphology (e.g., blebbing) and expression of markers characteristic of apoptotic cells (e.g., transglutaminases and DNA fragmentation) suggest that the periderm undergoes a sequence of programmed cell death.9 The shape and surface characteristics of periderm cells are used to define stages of epidermal development.8 Monoclonal antibodies have been made that recognize only the periderm cells among the epidermal cell populations10,11; some of them recognize stage-specific periderm cells. The function of the periderm is unknown, but it has been suggested that in early stages of development it protects the basal epidermal layer. The extensive microvilli and blebbing of the

5. 6. 7. 8. 9.

2

Embryonic/ fetal transition

Early fetal stage

Late fetal stage

Birth

Birth

Embyonic/fetal transition 9-10 weeks

4.

Embryonic

Dale BA, Holbrook KA, Kimball JR, et al. Expression of the epidermal keratins and filaggrin during fetal human development. J Cell Biol. 1985;101(4):1257–1269. Moll R, Moll I, Wiest W. Changes in the pattern of cytokeratin polypeptides in epidermis and hair follicles during skin development in human fetuses. Differentiation. 1982;23(2):170–178. Sanes JR, Rubenstein JLR, Nicolas J-F. Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos. EMBO J. 1986; 5(12):3133–3142. M’Boneko V, Merker H-J. Development and morphology of the periderm of mouse embryos (days 9–12 of gestation). Acta Anat. 1988;133(4): 325–336. Holbrook KA, Odland GF. The fine structure of developing human epidermis: light, scanning and transmission electron microscopy of the periderm. J Invest Dermatol. 1975;65(1):16–38. Polakowska RR, Piacentini M, Bartlett R, et al. Apoptosis in human skin development: morphogenesis, periderm and stem cells. Dev Dynam. 1994; 199(3):176–188.

Ectoderm basal cell Peridermal cell Intermediate cell

Spinous cell Granular cell Cornified cell

Figure 1.2  Schematic diagram of the distinct stages of epidermal development during gestation. Epidermis develops from a single layer of undifferentiated ectoderm (embryonic stage) to form a multilayered differentiated epidermis (late fetal stage). The gestation-specific periderm layer appears in the embryonic stage, with blebbing and final shedding occurring before birth. The intermediate epidermal layer appears at the onset of epidermal stratification and differentiation in the embryonic/fetal transition stage. From the early fetal stage onwards, the epidermis continues to undergo proliferation and differentiation programs that ultimately culminate in the formation of the cornified layer. The protective stratum corneum functions as a protective barrier against infection and dehydration by the time of birth.

periderm cell surfaces that face the amniotic cavity suggest that these cells play a role in some type of exchange between the fetus and the amniotic fluid. Evidence for this function includes: (1) the observation that periderm cells share antigens in common with other absorptive fetal and adult epithelial cells; (2) the demonstration that periderm in the sheep fetus is involved in the uptake of substances from the amniotic fluid12; and (3) the observation that the plasma membrane of human periderm cells has the morphologic characteristics of epithelia involved in water transport.13,14 The periderm may also be a secretory epithelium, contributing material to the amniotic fluid.15

DEVELOPMENT OF EPIDERMAL APPENDAGES In the mammalian embryo, the surface ectoderm envelopes the embryo during gastrulation and neurulation, forming a simple epithelium comprised of a single cell layer. During embryonic development and organ formation, a series of signals between epithelial ectodermal cells and underlying mesenchymal cells are the basis for the formation of the epidermal appendages.16 Skin 10. Lane AT, Negi M, Goldsmith LA. Human periderm: a monoclonal antibody marker. Curr Probl Dermatol. 1987;16:83–93. 11. Schofield OMV, McDonald JN, Fredj-Reygrobellet D, et al. Common antigen expression between human periderm and other tissues identified by GB1-monoclonal antibody. Arch Dermatol Res. 1990;282(3):143–148. 12. Mears GJ, Van Petten GR. Fetal absorption of drugs from the amniotic fluid. Proc West Pharmacol Soc. 1977;20:109–114. 13. Parmely TH, Seeds AE. Fetal skin permeability to isotopic water (THO) in early pregnancy. Am J Obstet Gynecol. 1970;108(1):128–131. 14. Riddle CV. Intramembranous response to cAMP in fetal epidermis. Cell Tissue Res. 1985;241(3):687–689. 15. Lind T, Kendal A, Hytten FE. The role of the fetus in the formation of amniotic fluid. J Obstet Gynaecol Br Commonw. 1972;79(4):289–298. 16. Pispa J, Thesleff I. Mechanisms of ectodermal organogenesis. Dev Biol. 2003;262(2):195–205.

Structure and function of the skin

SPECIALIZED NON-KERATINOCYTE CELLS WITHIN THE SKIN The epidermis has contributions from cells derived not only from the surface ectoderm but from other embryological origins such as neural crest. The three major non-keratinocyte cell types present in the skin are Langerhans cells, melanocytes and Merkel cells. All three cell types are detected within the epidermis by the end of the embryonic stage and can be easily distinguished by their nuclear morphology, cytoplasmic density, orientation in the tissue and antigenic properties. Langerhans cells, which arise from precursors in the bone marrow, function as antigen-presenting dendritic cells and are evident in embryonic epidermis as early as 43 days EGA. The appearance of Langerhans cells before the onset of bone marrow function suggests that the first Langerhans cells in the embryonic epidermis are derived from the yolk sac or fetal liver. The density of these cells is low (65 cells/mm2) in the epidermis during the first two trimesters of pregnancy, after which their numbers increase severalfold in the third trimester and after birth.22,23 Langerhans cells are recognized by the same surface markers

17. Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol. 2002;118(2):216–225. 18. Hardy MH. The secret life of the hair follicle. Trends Genet. 1992;8(2): 55–61. 19. Mikkola ML. Genetic basis of skin appendage development. Semin Cell Dev Biol. 2007;18(2):225–236. 20. Priolo M, Lagana C. Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet. 2001;38(9):579–585. 21. Morasso MI, Radoja N. Dlx genes, p63 and ectodermal dysplasias. Birth Defects Res C Embryo Today. 2005;75(3):163–171. 22. Drijkoningen M, DeWolf-Peeters C, VanDerSteen K, et al. Epidermal Langerhans cells and dermal dendritic cells in human fetal and neonatal skin: an immunohistochemical study. Pediatr Dermatol. 1987;4(1):11–17. 23. Foster CA, Holbrook KA. Ontogeny of Langerhans cells in human embryonic and fetal skin: expression of HLA-DR and OKT6 determinants. Am J Anat. 1989;184(2):157–164. 24. Holbrook KA, Underwood RA, Vogel AM, et al. The appearance, density and distribution of melanocytes in human embryonic and fetal skin revealed by the anti-melanoma monoclonal antibody, HMB-45. Anat Embryol. 1989;180(5):443–455. 25. Becker SW, Zimmerman AA. Further studies on melanocytes and melanogenesis in human fetus and newborn. J Invest Dermatol. 1955;25(2):103–112.

expressed in embryonic epidermis and by CD1a expression, which appears rather abruptly around 80 days EGA.22,23 At this time, Langerhans cell granules are evident in the cytoplasm, suggesting that the cells already may be involved in antigen procession and presentation. The neural crest-derived melanocytes, responsible for pigmentation, migrate into the embryonic epidermis around 50 days EGA. Although they do not contain melanosomes or produce distinguishable quantities of pigment until mid-pregnancy, they are easily detected using the HMB-45 monoclonal antibody that recognizes an antigen common to melanoblasts and melanomas. Even at this early age, melanocytes are dendritic, high in density (~1000 cells/mm2), and distributed uniformly throughout the epidermal tissue.24 Melanocytes reach a remarkably high density (~3000 cells/mm2) in the fetal epidermis of about 80 days EGA.24 Melanosomes first appear in the cytoplasm of melanocytes around 65 days EGA depending on the region of the body and the race of the fetus. The eyelids, external auditory meatus, and labial mucosa appear to have melanin-producing melanocytes before they are evident in the skin in other regions,25,26 but the cells are present only transiently in these structures. Melanocytes begin to transfer melanosomes to keratinocytes in the fifth month of gestation. Studies of HMB-45 immunostained epidermal sheets have revealed that the density of immunopositive cells decreases toward birth, probably reflecting the growth of the fetus. The total cutaneous numbers at this time appear to be similar to the total numbers of the melanocytes in newborn epidermis.27 The third cell type, the mechanoreceptor Merkel cells, have an epidermal origin.28–33 Adult Merkel cells are easily recognized by characteristic neuropeptides, but in the fetal epidermis, detection of these cells relies on the presence of keratins specific to Merkel cells (K8, K18, and K20). Merkel cells are known to be plentiful in adult palmar skin. Merkel cells have been demonstrated at 8 weeks EGA in fetal palmar and plantar skin,29,32 although the density of cells at this stage was low and quite variable.32 No other morphologic markers (e.g., dense-core granules) are apparent at this stage. By 80–90 days EGA, the density is as great as 1400 cells/mm,5,32 and by 22–24 weeks EGA increases to 1700 cells/mm.4,29 At both ages, the cells are organized specifically along the primary epidermal ridges. This is the expected location because Merkel cells in adult skin are

SPECIALIZED NON-KERATINOCYTE CELLS WITHIN THE SKIN

appendages in mammals include hair, nail, and sweat, sebaceous and mammary glands. The first morphologically distinguishable event is the thickening of the surface ectoderm, to form a placode or anlage that subsequently invaginates to form a bud. Similar sets of intersecting signaling pathways are involved in patterning the epithelium for placode formation and controlling bud invagination. Despite initial similarities, subsequent events in appendageal development are different. The best-studied epidermal appendage is the hair follicle.17,18 Findings in the last decade have helped elucidate the molecular and cellular mechanisms controlling early steps in the development of these organs and human genetic diseases that affect appendage morphogenesis.19 Disruption in the signal­ ing that leads to anomalies in epithelial/mesenchymal derived organs are features of a group of human pathological conditions defined as ectodermal dysplasias (EDs).20 Two transcription factors effectors of signaling pathways through developmental organogenesis and in which mutations have been linked to specific EDs are Dlx3 and p63 proteins.21

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26. Barla-Szabo L. Ejection of melanocytes and melanin from fetuses and newborn mammalian animals. Acta Morphol Acad Sci Hung. 1970;18(3):213–225. 27. Hamada H. Age changes in melanocyte distribution of the normal, human epidermis. Jpn J Dermatol. 1970;82:223–232. 28. Moll I, Moll R, Franke W. Formation of epidermal and dermal Merkel cells during human fetal skin development. J Invest Dermatol. 1986;87(6): 779–787. 29. Moll R, Moll I, Franke W. Identification of Merkel cells in human skin by specific cytokeratin antibodies: changes in cell density and distribution in fetal and adult plantar epidermis. Differentiation. 1984;28(2):136–154. 30. Moll I, Lane A, Franke W, et al. Intraepidermal formation of Merkel cells in xenografts of human fetal skin. J Invest Dermatol. 1990;94(3):359–364. 31. Moll I, Moll R. Early development of human Merkel cells. Exp Dermatol. 1992;1(4):180–184. 32. Kim DK, Holbrook KA. The appearance, density and distribution of Merkel cells in human embryonic and fetal skin: their relation to sweat gland and hair follicle development. J Invest Dermatol. 1995;104(3):411–416. 33. Narisawa Y, Hashimoto K. Immunohistochemical distribution of nerve-Merkel cell complex in fetal human skin. J Dermatol Sci. 1991; 2:361–370.

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Basic Science and Principles of Diagnosis and Treatment

P B

B

C STAGES OF HUMAN SKIN DEVELOPMENT

A

Figure 1.3  Light, transmission and scanning electron micrographs of the human embryonic skin. (A) Histology of the two-layered embryonic epidermis consists of glycogen-filed basal and periderm cells, where large vascular channels are detected. (B) Transmission electron micrograph of human embryonic skin. (C) Scanning electron micrograph of the periderm of human embryonic 70-day EGA; note the microvilli present in the surface. (B) ×3500; (C) ×2500. B, basal; P, periderm. (Panel A, courtesy of Karen Holbrook.)

A single-layered epithelium covers the human embryo from gastrulation and a cuboidal ectoderm overlying undifferentiated mesenchyme is recorded by 5 weeks of development. By 40 days’ gestation, the skin consists of an epidermis, dermal–epidermal junction (DEJ), dermis, and subcutaneous connective tissue (Fig. 1.3). The epidermis includes basal and periderm layers. The periderm is a simple pavement epithelium composed of hexagonally shaped, microvilli-covered cells. In sectioned specimens, periderm and basal cells are similar morphologically;

both contain large amounts of glycogen, few organelles, and small quantities of keratin filaments that are organized into fine networks and associated with desmosomes (Fig. 1.3). The species of keratins in periderm and basal cells are characteristic of simple and glandular epithelia K19, K18, and K8.4,5,36 Basal cells also contain the keratins K5 and K14 that are markers of the basal layer keratinocytes of adult epidermis.4,5,37 K18 is found in periderm cells and in Merkel cells. A planar, microfilamentous network is present internal to the plasma membrane of basal cells adjacent to the basement membrane. This assembly may promote adhesion and reinforce the cell before hemidesmosomes are organized in sufficient numbers to maintain the structural integrity of the dermal–epidermal interface. The epidermis is associated with a basement membrane at the DEJ at all embryonic and fetal ages. Ultrastructural images of this region show the basal keratinocytes physically separated from the lamina densa by a clear zone known as the lamina lucida. Several molecules that are characteristic of all basement membranes (e.g., type IV collagen, laminin, heparan sulfate proteoglycan), regardless of the epithelia with which they are associated, are also present in the embryonic DEJ. Skin-specific antigens are added to various regions of the DEJ coincident with epidermal stratification at the embryonic-fetal transition of development. Early stages of hemidesmosome formation are evident morphologically but these structures are sparse and incomplete in structure.38 Occasional strands of fine filamentous material (anchoring filaments) can be seen crossing the lamina lucida.38 The embryonic dermis is a loose network of mesenchymal cells with little intervening fibrous connective tissue matrix.39,40

34. Narisawa Y, Hashimoto K, Nakamura Y, et al. A high concentration of Merkel cells in the bulge prior to the attachment of the arrector pili muscle and the formation of the perifollicular nerve plexus in human fetal skin. Arch Dermatol Res. 1993;285(5):261–268. 35. Sharp F. A quantitative study of the glycogen content of human fetal skin in the first trimester. J Obstet Gynaecol Br Commonw. 1971; 78(11):981–986. 36. Moll R, Franke WW, Schiller DL. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982;31(1):11–24.

37. Tseng SCG, Jarvinen M, Nelson WG, et al. Correlation of specific keratins with different types of epithelial differentiation: monoclonal antibody studies. Cell. 1982;30(2):361–372. 38. McMillan JR, Eady RAJ. Hemidesmosome ontogeny in human fetal skin. Arch Dermatol Res. 1996;288:91–97. 39. Smith LT, Holbrook KA, Madri JM. Collagen types I, III and V in human embryonic and fetal skin. Am J Anat. 1986;175(4):507–521. 40. Smith LT. Patterns of type VI collagen compared to types I, III and V collagen in human embryonic and fetal skin and in fetal-skin derived cell cultures. Matrix Biol. 1994;14(2):159–170.

commonly found in association with hair follicles and sweat glands and both of these appendages are beginning to form during this stage of fetal development. Merkel cells are first seen in hairy skin at 75 days EGA where they are located in the infundibulum and bulge regions of the developing hair pegs and bulbous hair pegs.32,34 Cytochemical evidence suggests that Merkel cells may also function as neuroendocrine cells and may serve as target structures for the ingrowth of nerve fibers, possibly through the synthesis and use of nerve growth factor, or they may attract other cells such as the smooth muscle cells of the arrector pili muscle that are associated with nerve fibers in the skin.34,35

STAGES OF HUMAN SKIN DEVELOPMENT SKIN DEVELOPMENT DURING THE EMBRYONIC PERIOD

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Structure and function of the skin

SKIN DEVELOPMENT AT THE EARLY FETAL STAGE By the end of the second month of gestation, hematopoiesis has switched from the extraembryonic sac to the bone marrow and remarkable changes in the structure and biochemistry of the skin occur during the embryo/fetal transition period (Fig. 1.1). From this time to the end of the first trimester all regions of the skin acquire features that establish a template of adult skin. The first obvious change in the structure of the skin in this transition stage is the stratification of the epidermis to basal, intermediate, and periderm cell layers (Figs 1.2, 1.4). The cells of the intermediate layer show little difference in morphology from the basal cells; they have a high glycogen content (Fig. 1.4) and the few organelles are positioned around the nucleus and at the cell borders. There are larger and more densely staining

41. Breen M, Weinstein HG, Johnson RL, et al. Acid glycosaminoglycans in human skin during fetal development and in adult life. Biochim Biophys Acta. 1970;201(1):54–60. 42. Johnson CL, Holbrook KA. Development of human embryonic and fetal dermal vasculature. J Invest Dermatol. 1989;93(2):10S–17S. 43. Bickenbach JR, Holbrook KA. Proliferation of human embryonic and fetal epidermis in organ culture. Am J Anat. 1986;177(1):97–106. 44. Bickenbach JR, Holbrook KA. Label-retaining cells in human embryonic and fetal epidermis. J Invest Dermatol. 1987;88(1):42–46. 45. Gipson IK, Spurr-Michaud SJ, Tisdale AS. Hemidesmosomes and anchoring fibril collagen appear synchronously during development and wound healing. Dev Biol. 1988;126(2):253–262. 46. Tidman MJ, Eady RAJ. Hemidesmosome heterogeneity in junctional epidermolysis bullosa revealed by morphometric analysis. J Invest Dermatol. 1986;86:51–56.

bundles of keratin filaments located in the peripheral cytoplasm where they are associated with desmosomes (Fig. 1.4). Intermediate cells stain with antibodies that recognize the differentiation-specific keratins K1 and K10, of the adult stratified keratinized epidermis.4,5 This indicates that as soon as the basal keratinocytes divide and a layer of intermediate cells is added, the tissue is ‘differentiated’ in terms of the expression of adult epidermal keratins. Other markers of differentiation present in the intermediate layer cells are involucrin and loricrin.1 Once the intermediate layer is formed, the basal layer begins to lose some of its glycogen content and thus appears to begin to acquire more of the adult features. Glycogen is common in cells of fetal tissues where it may serve as an energy source; it occupies a significant volume of fetal keratinocytes and fibroblasts through the first and second trimester but diminishes in later stages of development toward birth. The epidermis continues to stratify by additional intermediate cell layers during the second trimester of development (Fig. 1.4). All cells of the fetal epidermis, including the periderm, can divide during the first trimester, but around the end of the third month, this ability appears to become restricted primarily to basal keratinocytes.43,44 Periderm cells at this stage have a large volume of cytoplasm and appear rounded. At later ages within the same period, one or more blebs project from the surfaces of periderm cells (Figs 1.2, 1.4) and remain densely covered by microvilli. Changes in the structure and composition of the DEJ parallel epidermal stratification. The basal keratinocytes synthesize the components of the hemidesmosomes, anchoring filaments, and anchoring fibrils. Fibroblasts of the papillary dermis contribute collagens and components of elastic fibrils to the connective tissue matrix of the sublamina densa.1 Hemidesmosomes are now complete in structure and anchoring filaments and anchoring fibrils organize in relation to these sites (Fig. 1.4).38 It has been suggested from studies of chick cornea that there may be an interdependent relationship between hemidesmosomes and anchoring fibrils during morphogenesis.45 If this is correct, it cannot be a dependent relationship because patients with junctional epidermolysis bullosa (EB) who lack hemidesmosomes do not lack anchoring fibrils,46 and vice versa in the case of individuals with recessive dystrophic EB who do not have anchoring fibrils but whose hemidesmosomes assemble normally.47 Several of the antigens that correlate with these structures are expressed in the DEJ at the time of the embryonic fetal transition.48,49 During the remainder of the first trimester, the mesenchymal cells differentiate into fibroblastic cells and the dermis becomes

STAGES OF HUMAN SKIN DEVELOPMENT

The high water content and hyaluronic-acid rich environment promote cell migration during all phases of active tissue morphogenesis.41 Types I, III, V, and VI interstitial collagens are detected in the earliest embryonic skin samples obtainable, but the fiber bundles contain few fibrils and are associated primarily with the surfaces of fibroblastic cells and in the zone subjacent to the DEJ.36,39,40 The latter zone, sometimes called the compact mesenchyme, is also a site that contains sulfated proteoglycans and is rich in growth factors. At later stages the collagens become distributed in accord with the adult pattern of deposition.39 Elastic fibers are not present in embryonic dermis, while microfibrillar structures are seen by electron microscopy.1 Small capillary-like vessels are evident in the embryonic dermis.42 They are sparse and do not appear to be organized as yet into patterns. Nerve fibers are recognized by immunostaining embryonic skin with antibodies to the p75 low-affinity nerve growth factor receptor. Fine fibers in the dermis connect with large nerve trunks located at the dermal–subcutaneous junction. It is difficult to distinguish subcutaneous tissue from dermis in the embryonic skin because the cells are quite similar and adipose tissue is synthesized considerably later in development. There is frequently, however, a difference in the density and/or orientation of the mesenchymal cells in the two regions, and, large, dilated channels, organized in the plane of the skin form an arbitrary boundary (Fig. 1.3). In some regions of the body there is also a greater density of fibrous connective tissue in the subcutaneous tissue compared with the dermis. There is no morphologic evidence that epidermal appendages have begun to form in embryonic skin.

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47. Tidman MJ, Eady RAJ. Evaluation of anchoring fibrils and other components of the dermal-epidermal junction in dystrophic epidermolysis bullosa by a quantitative ultrastructural technique. J Invest Dermatol. 1985;84:374–377. 48. Fine J-D, Horiguchi Y, Couchman JR. 19-DEJ-1, a hemidesmosomalanchoring filament complex associated monoclonal antibody: definition of a new skin basement membrane antigenic defect in junctional and dystrophic epidermolysis bullosa. Arch Dermatol. 1989;125(4):520–523. 49. Smith LT, Sakai LY, Burgeson RE, et al. Ontogeny of structural components at the dermal-epidermal junction in human embryonic and fetal skin: the appearance of anchoring fibrils and type VII collagen. J Invest Dermatol. 1988;90(4):480–485.

5

A

B

D

Figure 1.4  Light,

C

F

E

G

transmission and scanning electron micrographs of early fetal human skin. (A,B) Histology of normal human skin at the embryonic fetal transition stage 76-day EGA (A) and at the early fetal stage 107-day EGA (B), with identification of the intermediate layer after stratification starts. (C) The intermediate layer cells contain abundant glycogen (arrows) and keratin filaments are evident at the periphery of the cell. (D) Note the presence of complete hemidesmosomes and anchoring fibril-like structures (arrows in the dermal epidermal junction of skin from a 70-day EGA fetus. (E,F) Hair follicle bud and peg at 87-day and 101-day EGA development, respectively. (G) Scanning electron micrograph of the surface periderm at 112-day EGA. Note the microvilli and blebs. ×2500. (Panels A, B, E and F courtesy of Karen Holbrook.)

Structure and function of the skin

50. Smith LT, Holbrook KA, Byers PH. Structure of the dermal matrix during development and in the adult. J Invest Dermatol. 1982;79(1):93S–104S. 51. Holbrook KA, Minami SA. Hair follicle morphogenesis in the human: characterization of events in vivo and in vitro. NY Acad Sci. 1991;642:167–196. 52. Pinkus H. Embryology of hair. In: Montagna W, Ellis RA, eds. The hair growth. New York: Academic Press; 1958:1. 53. Akiyama M, Dale BA, Sun TT, et al. Characterization of hair follicle bulge in human fetal skin: the human fetal bulge is a pool of undifferentiated keratinocytes. J Invest Dermatol. 1995;105:844–850.

nisms for establishing these precisely positioned structures are unknown. The terminus of the bulbous hair peg has a concavity within which cells of the dermal papilla are sequestered.

SKIN DEVELOPMENT DURING THE LATE FETAL STAGE By 15 weeks’ gestation, the interfollicular epidermis is stratified further with one or two additional layers of intermediate cells, but until the end of the second trimester there is no evidence of keratinization (Fig. 1.1). The adult pattern of keratin polypeptides is maintained in the basal cells (K5 and K14) and the suprabasal keratinocytes of all intermediate layers express K1 and K10. Keratin filaments have continued to increase in quantity in the intermediate layers. Glycogen remains a significant component. The surface of the skin is still covered by a complete layer of periderm. The non-dividing, periderm cells have attained a peak stage of structural modification in which one or more simple or complex blebs project from the surface; all portions of the periderm cells facing the amniotic cavity are covered with microvilli.54 The internal morphology of the cells, however, is variable. Some of the cells contain the organelles associated with active metabolic processes (e.g., mitochondria, rough endoplasmic reticulum, Golgi); others have few organelles and are filled with filaments. The latter cells also have a thickened cell envelope, which is morphologically and biochemically equivalent to the cornified cell envelope. Involucrin, keratolinin, and loricrin have been identified at the boundary of the periderm cell55 and an active epidermal transglutaminase is present that appears able to crosslink the envelope proteins.2,55 At later stages of this period (~18 weeks) the periderm cells flatten, the blebs regress to small, button-like protrusions,2 and the subcellular morphology is indicative of a non-functional, perhaps non-viable, apoptotic remnant of this tissue.9 Between 22 and 24 weeks EGA the interfollicular epidermis begins to keratinize; the exact timing depends on the region of the body.8 Early evidence for keratinization is the appearance of lamellar granules and small keratohyalin granules in the uppermost intermediate cell layer (Fig. 1.5). This is the first age at which filaggrin is expressed in the fetal interfollicular epidermis,4 thus the onset of filaggrin synthesis appears to correlate precisely with the morphologic appearance of keratohyalin granules. The first few layers of cells that keratinize are a combination of ‘regressed’ periderm cells that contain primarily filaments and have a cornified cell envelope, and incompletely keratinized keratinocytes; the latter cells are characterized by a condensed nucleus, dense organelles, cornified cell envelope, and flattened

STAGES OF HUMAN SKIN DEVELOPMENT

less cellular and watery as more fibrous connective tissue accumulates in the interstitial spaces. By the end of this period, papillary and reticular regions can be distinguished on the basis of differences in cell density and orientation, fibril diameter, and fiber bundle size.39,50 Approximate boundaries between the two regions are also created by the organization of the subpapillary, horizontal vascular plane. A decrease in hyaluronic acid parallels the transition of the dermis from a cellular to a fibrous tissue; the water content of the dermis still remains >80%. Like adult dermis, the proteoglycan is composed largely of sulfated molecules. Around 70 days EGA the basic pattern of the adult vasculature is evident in fetal dermis.42 Horizontal plexuses are present within the dermis (subpapillary plexus) and separate the dermis from the subcutaneous tissue. The structure of the vessel wall is simple, making identification of vascular segments difficult. Nerve patterns are also well developed by the mid- to later first trimester and generally follow the vascular pattern, although the nerve fibers appear to be a little more ‘aggressive’ in their ascent toward the epidermis. Thus, the beginning of the fetal period is characterized by epidermal stratification and the histogenesis of various tissues of the skin. Epidermal stratification coincides with the onset of tooth, nail, and follicle morphogenesis, the addition of antigens and adhesive structures at the DEJ, regionalization of the dermis via the organization of fibrous extracellular matrix and patterns of nerves and vessels, and the expression of surface and cytoplasmic markers by melanocytes and Langerhans cells. Merkel cells are established in both hairy and glabrous skin. There can be a hiatus of as much as 10 weeks between keratinization of structures of the epidermal appendages and keratinization of the interfollicular epidermis. Keratinization of the follicle begins around 15 weeks EGA. At the beginning of the second trimester, the follicle is an elongated cord of cells consisting of a cellular core and an outer cellular layer. In general, the core cells are similar to intermediate layer epidermal cells and the cells of the external layer are more like cells of the basal epidermal layer. The hair peg grows and differentiates to become the bulbous hair peg (a structure named for the terminal bulb of the follicle), around 12–14 weeks EGA when primordia of the sebaceous gland, bulge, and the apocrine gland are recognized.51,52 Lipid is synthesized in the sebaceous gland around 15 weeks EGA. Simultaneously smooth muscle cells of the arrector pili muscle grow toward and attach to the follicle in the region of the bulge.53 The bulge is an exceptionally large structure in the developing and lanugo follicle and thus potentially available for extirpation and analysis of the cells in vitro. The apocrine gland grows as a short cord of cells that originates from the infundibular portion of the follicle; apocrine glands persist and continue to develop only in specialized regions of the body. The mecha-

1

54. Nanbu Y, Fujii S, Konishi I, et al. CA 125 in the epithelium closely related to the embryonic ectoderm: the periderm and the amnion. Am J Obstet Gynecol. 1989;161(2):462–467. 55. Holbrook KA, Underwood RA, Dale BA, et al. Cornified cell envelope (CCE) in human fetal skin: involucrin, keratolinin, loricrin and transglutaminase expression and activity, abstracted. J Invest Dermatol. 1991;96:542.

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STAGES OF HUMAN SKIN DEVELOPMENT

A B

Figure 1.5  Light, transmission and scanning electron micrographs of late

C

8

fetal human skin. (A,B) Histology of normal human skin at the late fetal stage 143-day EGA (A) and 189-day EGA (B). Note the stratification and the keratinization of the epidermis as well as the complex structural organization of the dermis. (C) Scanning electron micrograph of the periderm of human skin 160-day EGA; note the periderm sheet sloughed from the skin surface.

shape of the stratum corneum cell. The numbers of layers of keratinized cells and the size of keratohyalin granules gradually increase so that the epidermis of the third-trimester fetus appears similar to that of the neonate and adult with the exception that glycogen remains in the cytoplasm of the keratinocytes. Coincident with keratinization, the periderm is sloughed from most of the skin surface revealing the underlying keratinized epidermis (Figs 1.2, 1.5). The surface of the skin is coated with the lipid-rich material of the vernix caseosa, a combination of sebum secreted from the sebaceous gland of the follicle, epidermal lipids, desquamated cells, hair and other tissue debris.56,57 Like sebum, the vernix contains a significant level of triglycerides and wax esters, and like cornified cells it has a high proportion of sterols. Other lipids that are not characteristic of either of these sources contribute to the unique content of this material.56 Vernix caseosa

is often apparent on the skin at birth. It is not clear if there is a benefit from this substance to the fetal skin in its late stages of development or to the neonatal skin. The second-trimester dermis contains an extensive amount of fibrous connective tissue, including elastic fibers. The elastic microfibrils are synthesized early in development but, based on studies in which fetal skin fibroblasts of this age were assayed for elastin mRNA expression,58 the elastin gene does not appear to be expressed until approximately 15 weeks EGA. Elastic fiber networks are seen in the skin by histochemical and immunohistochemical methods around 20 weeks EGA.50,59 These fibers are immature in structure, more similar to adult elaunin fibers, and thus it is unrealistic to consider using the structure of the elastic fibers to identify a fetus at risk of a genetic disorder of elastic connective tissue such as cutis laxa. Even at birth the amount of elastin associated with elastic fibers is minimal.

56. Kurkkainen J, Nikkari T, Ruponen S, et al. Lipids of the vernix caseosa. J Invest Dermatol. 1965;44:333–338. 57. Nazarro-Porro M, Possi S, Boniforti L, et al. Effects of aging on fatty acids in skin surface lipids. J Invest Dermatol. 1979;73(1): 112–117.

58. Sephel GC, Buckley A, Davidson JM. Developmental initiation and elastin gene expression by human fetal skin fibroblasts. J Invest Dermatol. 1987;88(6):732–735. 59. Deutsch TA, Esterly NB. Elastic fibers in fetal dermis. J Invest Dermatol. 1975;65(3):320–323.

Structure and function of the skin

Coarse fiber bundles of the deep dermis clearly distinguish it from the fine connective tissue of the hypodermis. This pattern is reversed from the situation in younger skin where the density of matrix in the subcutaneous tissue is greater than that of the dermis. The organization of the hypodermis is readily apparent at 15 weeks EGA, and by 18 weeks EGA there is a small accumulation of subcutaneous fat. By late fetal stage, the hair follicles morphogenesis has proceeded and the hair canals can be seen as elongated ridges visible at the epidermal surface. The integrity of the periderm is disrupted along the tops of the ridges where the hair canal will rupture and open to the surface. The length of the canals, the time of hair release, and the density of the hair are dependent on the region of the body.60 The position of eyebrow and scalp hairs can be recognized as early as 15 weeks EGA by the presence of short, closely positioned, periderm-covered hair canals. At 21 weeks the hair canals on the trunk begin to rupture, interrupting the continuity of the periderm over the body surface and releasing a fully elongated hair.60

The eccrine sweat glands develop on the body late in the second trimester, more than 2 months after they were initiated on the palms and soles. Assuming that epithelial–mesenchymal interactions are responsible for induction of such structures, one must surmise that the signals to initiate sweat glands on the body are different from those at earlier stages of gestation when the skin composition was significantly different. This aspect of development has not been investigated. By birth, the skin has the final structure that it will maintain through life (Fig. 1.6). The detailed characterization of the skin structure, composition, and function, as well as the epidermal appendages, will be the focus of the next section of this chapter.

SKIN DEVELOPMENT IN IMMATURE/ PREMATURE SKIN

STAGES OF HUMAN SKIN DEVELOPMENT

A

1

The skin of the premature infant is that of the third-trimester fetus. During this period the skin increases in bulk, primarily by

INFUNDIBULUM

B

C G LC

HS

Sebaceous gland

S

ISTHMUS Bulge

SG B

BU

M

LOWER FOLLICLE

Dermal papillae

BULB 15 week

Figure 1.6  Architecture of normal human skin at birth. (A) Schematic representation of normal human skin at birth. Magnification delineates the distinct layers of the epidermis, cellular components and hair morphology. B, stratum basalis; S, stratum spinosum; G, stratum granulosum; C, stratum corneum; LC, Langerhans cell; M, melanocyte; HS, hair shaft; Bu, bulge; SG, sebaceous gland; DP, dermal papilla. (B) Light micrograph of a developing hair follicle at 15-week EGA. The regions of the follicle, sebaceous gland and bulge are indicated. Note the keratinization of the developing hair and of the lining of the hair canal in the region of the infundibulum and within the epidermis. ×400.

60. Holbrook KA, Odland GF. Structure of the hair canal and the initial eruption of hair in the human fetus. J Invest Dermatol. 1978;71(6):385–390.

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the addition of connective tissue to the dermis, the epidermis is keratinized, all of the epidermal appendages are formed, and the dermis contains all of the matrix proteins characteristic of the newborn and adult. Nonetheless, the skin is still immature in both structural and physiologic properties. The epidermis has all of the layers of the adult epidermis, but it is thinner. The cells retain a substantial amount of glycogen, and the stratum corneum forms a less formidable barrier. The relatively poor barrier properties of the preterm infant are of great importance when considering topical application of various pharmacologic and cleansing compounds.61,62 In some cases, failure to consider the enhanced permeability of the premature skin has led to systemic poisoning. The uptake of pharmacologic compounds applied topically to the skin is much more rapid in the 28- to 34-week premature newborn than in older newborns and the loss of water through the skin and evaporative water loss from the surface decreases exponentially with increasing gestational age.63,64 The amount of trans­ epidermal water loss through the skin of a 25- to 30-week EGA infant can be so substantial that death can result from dehydration. In the premature infant, it is suggested that the vernix caseosa functions to augment the as yet poorly established barrier properties of the epidermis or to serve as a natural emollient. The skin of the premature infant is more resistant to desquamation than that of the term newborn and has a more gelatinous quality. Both of these properties may be a consequence of the vernix. The structure of the DEJ of the premature infant correlates with gestational age. As the age increases, the contours (rete ridges and dermal papillae) become more prominent. In the youngest (26–34 weeks EGA) premature infants, the DEJ is relatively flat, although the structural components of the DEJ that anneal the epidermis and dermis are well established. The papillary dermis immediately underlying the DEJ is edematous and the bundles of collagen fibrils are smaller and more widely spaced than those of the term newborn or adult, and thus the epidermal–dermal integrity might be expected to be more easily compromised than in the term newborn.65 The dermis of the premature infant is approximately threequarters of the thickness of adult dermis and comparable in connective tissue organization. Fine collagen fibrils and the small-sized collagen fiber bundles give the dermis a highly cellular and delicate appearance. The water content of the dermis remains high in premature babies, but this, like many properties of the premature and newborn skin, depends on the nutritional status of the fetus in additional to gestational age. All of the adult epidermal appendages are established in premature skin. The fully formed, hair-synthesizing lanugo follicles of fetal skin are equivalent to those of the term newborn or adult; however, the eccrine sweat glands have formed only a few coils of the glandular segment and the light and dark cells are not

easily distinguishable.65 Sweat ducts are partially occluded until the end of the 7th month. The sweating response is limited or absent in premature infants66 and appears to have a strong correlation with gestational age; there is a tendency toward total anhidrosis in the premature neonate,67 although this dysfunction rapidly resolves after a few days of extrauterine life.

61. Nachman RL, Esterly NB. Increased skin permeability in preterm infants. J Pediatr. 1971;79(4):628–632. 62. West DP, Worobec S, Solomon LM. Pharmacology and toxicology of infant skin. J Invest Dermatol. 1981;76(3):147–150. 63. Hammarlund K, Sedin G. Transepidermal water loss in newborn infants. Acta Paediatr Scand. 1979;68(6):795–801. 64. Faranoff AA, Wald M, Gruber HS, et al. Insensible water loss in low birth weight infants. Pediatrics. 1972;50(2):236–245.

65. Holbrook KA. A histologic comparison of infant and adult skin. In: Maibach HI, Boisits EK, eds. Neonatal skin. New York: Marcel Dekker; 1981:3. 66. Sinclair JC. Thermal control in premature infants. Annu Rev Med. 1972;23:129–148. 67. Green M. Comparison of adult and neonatal skin eccrine sweating. In: Maibach HI, Boisits EK, eds. Neonatal skin. New York: Marcel Dekker; 1981:35. 68. Ashton GH, Eady RA, McGrath JA. Prenatal diagnosis for inherited skin diseases. Clin Derm. 2000;18:643–648.

PRENATAL TESTING A number of techniques have been developed to perform prenatal testing and diagnose fetuses for severe genodermatoses. This has been possible by the identification of structural and regulatory genes directly involved with epidermal developmental processes and for which mutations have been directly linked to specific diseases.68 The role of many key proteins in cutaneous development has been determined by direct genetic approaches utilizing genetic linkage on DNA from patients and extended kindreds, while the relevance of other factors has come to light with results obtained in experiments with animal models. As presented in Figure 1.1, chorionic villous sampling can be performed between 8 and 11 weeks EGA; amniocentesis, from 14 to 16 weeks EGA and fetal biopsy, between 22 and 24 weeks EGA (see Ch. 7).

SUMMARY OF EVENTS OCCURRING DURING EPIDERMAL DEVELOPMENT A summary of all the major morphological events that occur through the embryogenesis of the human skin is presented in Table 1.1.

STRUCTURAL AND FUNCTIONAL PROPERTIES OF SKIN OF INFANTS, CHILDREN, AND ADULTS David H. Chu

INTRODUCTION Skin is a complex organ that both provides protection and allows interaction with its host’s environment. Much more than a static, impenetrable shield against external insults, skin is a dynamic, complex, integrated arrangement of cells, tissues, and matrix elements that mediates a diverse array of functions: serving as a physical permeability barrier, offering protection from infectious agents, regulating body temperature, enabling sensation, providing UV protection, orchestrating wound repair and regeneration,

Structure and function of the skin

EMBRYONIC Periderm   Shedding of periderm Epidermis   Basal layer   Intermediate layer   Granular layer   Cornified layer Cell junctions   Desmosomes   Tight junctions   Hemidesmosomes

LATE FETAL

X X X X X X X X X

Appearance of specialized non-keratinocyte cells   Langerhans cells   Melanocytes   Merkel cells

X X X

Epidermal appendages   Hair follicle   Sebaceous gland   Apocrine gland   Sweat glands   Nails Dermis   Structural organization   Dermal papillae   Connective tissue

EARLY FETAL

X X X X X X X X

(Adapted from: Chu DH, Haake AR, Holbrook K, et al. The structure and development of the skin. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s dermatology in general medicine. 6th edn, Vol. 1. New York: McGraw-Hill; 2003.)

synthesizing essential nutrients, and defining outward physical appearance (Fig. 1.7). These various functions of skin are mediated by one or more of its major regions, the epidermis, dermis, and hypodermis (Fig. 1.7). These divisions are interdependent, functional units; each region of skin relies upon and is connected with its surrounding tissue for regulation and modulation of normal structure and function at molecular, cellular, and tissue levels of organization. This section of the text is subdivided according to these major histologic subdivisions of the skin, with consideration of each skin region at the tissue, cellular and molecular levels.

OVERALL SKIN STRUCTURE AND FUNCTION (Fig. 1.7) TISSUES Whereas the epidermis and its outer stratum corneum provide a large part of the physical barrier provided by skin, the structural integrity of the skin as a whole is provided primarily by the

dermis and hypodermis. The epidermis is a highly cellular layer atop the relatively acellular dermis, which is rich in secreted extracellular molecules. The functioning of the skin is dependent on these two tissues, which contain a variety of epidermal appendages and the blood vessels and nerves, which support the nutrition, and integration of these tissues. The epidermis has a very effective strategy to make a continually regenerating living barrier, which can continuously respond to the numerous diverse external and internal stimuli that bombard the skin daily. The skin starts to be organized during embryogenesis, where intercellular and intracellular signals, as well as reciprocal crosstalk between different tissue layers, are instrumental in regulating the eventual maturation of the different components of skin. Antimicrobial activities are provided by the innate immune system and antigen-presenting dendritic cells of the epidermis, circulating immune cells that migrate from the dermis, and antigen-presenting cells of the dermis. Protection from UV irradiation is provided in great measure by the most superficial cells of the epidermis. UV damage to DNA of skin cells can result in a variety of malignancies, including basal cell carcinoma, squamous cell carcinoma, and melanoma. Inflammation begins with the keratinocytes of the epidermis or immune cells of the dermis, and sensory apparatus emanates from nerves that initially traverse the hypodermis to the dermis and epidermis, ending in specialized receptive organs or free nerve endings. The largest blood vessels of the skin are found in the hypodermis, which serve to transport nutrients and immigrant cells. The cutaneous lymphatics course through the dermis and hypodermis, serving to filter debris and regulate tissue hydration. Epidermal appendages provide special protective or sensory functions. Skin also determines a person’s physical appearance, influenced by pigmentation provided by melanocytes, with body contours, appearance of age, and actinic damage influenced by the epidermis, dermis, and hypodermis. Highlighted in this section are illustrative cutaneous diseases that manifest when any of these skin functions is defective. Understanding the genetic and molecular basis of skin disease has confirmed, and in some cases revealed, the many factors and regulatory elements that play critical roles in skin function.

OVERALL SKIN STRUCTURE AND FUNCTION

Table 1.1  Summary of timing of major morphological events occurring during epidermal development

1

CELLS Cell types in the epidermis consist of keratinocytes, including stem cells and cells at various stages of differentiation, Merkel cells, melanocytes and two cells of the immune system, Langerhans cells (antigen presentation) and γ-δ T cells (immunoregulation). The DEJ is a complex acellular structure with multiple secreted macromolecules, which support the epidermal structure and the transmittal of cells and molecules in a bidirectional fashion between the epidermis and the dermis. The dermis has a complex structure: fibroblasts in the two portions of the dermis, the papillary and the reticular dermis; mast cells; blood and lymphatic vessels; hairs; eccrine sweat glands; sebaceous glands; apocrine sweat glands; and the hairassociated arrector pili muscles. The vascular system has a number of modifications within the skin for thermoregulation; in addition, the skin is richly innervated, and has nerve endings 11

Epidermal barrier to diffusion Early cell envelope Antigen processing Bulk of keratins synthesize Vitamin D synthesis

UV light protection mechanoreceptor Site of keratinocyte stem cells Synthesis of dermal-epidermal junction molecules Attaches epidermis to rest of body Differential barrier to molecular diffusion and cell migration

Cell envelope assembly extracellular lipids

Filaggrin synthesis and degradation Urocanic acid synthesis

Site for Langerhans cells, keratin 1 and 10 synthesis

Site for melanocytes and Merkel cells Keratin 5 and 14 synthesis

Site for laminin 5, collagen IV, V, and VII, proteoglycans

Stratum corneum

Granular layer

Spinous layer

Basal layer

Dermal–epidermal layer

Figure 1.7  Schematic diagram of the overall organization of the epidermis and dermal–epidermal junction.

Function

Cellular and molecular characteristics

Melanocyte

OVERALL SKIN STRUCTURE AND FUNCTION

12

Layer

Langerhans cell

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Structure and function of the skin

secreting sympathetic and the parasympathetic mediators as well as other neurotransmitters.

EPIDERMAL STRUCTURE AND FUNCTION (Figs 1.8, 1.9)

1

(e.g., palmoplantar skin versus truncal skin); other differences are microscopic. The keratinocyte is an ectodermally derived cell and is the primary cell type in the epidermis, accounting for at least 80%

TISSUES

Stratum corneum

EPIDERMAL STRUCTURE AND FUNCTION

One of the most fundamental and visible features of skin is the stratified, cornified epidermis (Fig. 1.8). The epidermis is a continually renewing structure that gives rise to derivative structures called appendages (pilosebaceous units, nails, and sweat glands). The epidermis ranges in thickness from 0.4 to 1.5 mm, as compared with the 1.5 to 4 mm full-thickness skin. The majority of cells in the epidermis are keratinocytes that are organized into four layers, named for either their position or a structural property of the cells. These cells progressively differentiate from proliferative basal cells, attached to the epidermal basement membrane, to the terminally differentiated, keratinized stratum corneum, the outermost layer and barrier of skin. Intercalated among the keratinocytes at various levels are the immigrant resident cells – melanocytes, Langerhans cells, and Merkel cells. Other cells, such as lymphocytes, are transient inhabitants of the epidermis and are extremely sparse in normal skin. There are many regional differences in the epidermis and its appendages. Some of these differences are apparent grossly, such as thickness

Spinous layer Basal layer

Figure 1.8  The epidermis is organized in functional units best visualized in monkey palm and mouse general body epidermis. Columns of proliferating and differentiating cells are capped by closely interdigitated layers of stratum corneum cells. (Modified from Freedberg IM, Eisen AZ, Wolff K et al., eds. Fitzpatrick’s dermatology in general medicine, New York: McGraw-Hill; 1999, with permission.)

Figure 1.9  Light micrographs of melanocytes in adult epidermis. Note their position among cells of the basal layer (arrows), their pale cytoplasm compared with the keratinocytes, and in (B) the presence of individual melanosomes (compared with melanosome complexes in keratinocytes) in the cytoplasm (arrows). (A) ×400; (B) ×6000. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

A

B

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of the total cells. The ultimate fate of these cells is to contribute the components for the epidermal barrier as the stratum corneum. Therefore, keratinocytes regulate solute, water, and gas interchange across the epidermis. They also synthesize previtamin D, the precursor of active vitamin D intermediates, and this process occurs in the basal and spinous layer. Thus, much of the function of the epidermis can be gleaned from the study of the structure and development of the keratinocyte. Keratinocyte differentiation (keratinization) is a genetically programmed, carefully regulated, complex series of morphologic changes and metabolic events whose endpoint is a terminally differentiated keratinocyte (corneocyte) that contains keratin filaments, matrix protein, and a protein-reinforced plasma membrane with surface-associated lipids. Pathologic changes in the epidermis can occur as a result of a number of different stimuli: repetitive mechanical trauma (as in lichen simplex chronicus), inflammation (as in atopic dermatitis and lichen planus), infection (as in verruca vulgaris), immune system activity and cytokine abnormalities (as in psoriasis), autoantibodies (as in pemphigus vulgaris and bullous pemphigoid), or genetic defects that influence differentiation or structural proteins (as in epidermolysis bullosa simplex, epidermolytic ichthyosis, other ichthyoses and Darier disease).

BASAL KERATINOCYTE STRUCTURE AND FUNCTION

spinous layers of epidermal keratinocytes. Note the extensive network of keratin filaments, desmosomes, and vacuoles containing melanosomes in these cells. The dermal–epidermal junction is indicated (arrows) (×6000). (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

The basal layer (stratum germinativum) contains mitotically active, columnar-shaped keratinocytes that attach via keratin filaments (K5 and K14) to the basement membrane zone at hemidesmosomes, to other surrounding cells through desmosomes, and give rise to cells of the more superficial, differentiated epidermal layers (Fig. 1.10). Ultrastructural analysis reveals the presence of membrane-bound vacuoles that contain pigmented melanosomes transferred from melanocytes by phagocytosis.69 The pigment within melanosomes contributes to the overall skin pigmentation perceived macroscopically.70 The basal layer is the primary location of mitotically active cells of the epidermis. Cell kinetic studies suggest that the basal layer cells exhibit different proliferative potentials (stem cells, transit amplifying cells, and

postmitotic cells), and in vivo and in vitro studies suggest that there exist long-lived epidermal stem cells.71,72 Because basal cells can be expanded in tissue culture and used to reconstitute sufficient epidermis to cover the entire skin surface of burn patients,73,74 such a starting population is presumed to contain long-lived stem cells with extensive proliferative potential. The tissue localization of putative epidermal stem cells has been based in part on stem cell characteristics defined in other self-renewing systems, such as the bone marrow and fetal liver. Under stable conditions, stem cells cycle slowly; only under conditions requiring more extensive proliferative activity, such as during wound healing or after exposure to exogenous growth factors, do stem cells undergo multiple, rapid cell divisions. A large amount of data supports the existence of multipotent epidermal stem cells within the bulge region of the hair follicle based on these traits.75–83 Recent advances in molecular analysis

69. Haass NK, Herlyn M. Normal human melanocyte homeostasis as a paradigm for understanding melanoma. J Invest Dermatol Symp Proc. 2005;10(2):153–163. 70. Grimes P, Nordlund JJ, Pandya AG, et al. Increasing our understanding of pigmentary disorders. J Am Acad Dermatol. 2006;54(5 suppl 2): S255–S261. 71. Kaur P. Interfollicular epidermal stem cells: identification, challenges, potential. J Invest Dermatol. 2006;126(7):1450–1458. 72. Blanpain C, Fuchs E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat Rev Mol Cell Biol. 2009;10(3):207–217. 73. Gallico GG, 3rd, O’Connor NE, et al. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med. 1984;311(7):448–451. 74. Pellegrini G, Ranno R, Stracuzzi G, et al. The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. Transplantation. 1999;68(6):868–879. 75. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61(7):1329–1337.

76. Kobayashi K, Rochat A, Barrandon Y. Segregation of keratinocyte colony-forming cells in the bulge of the rat vibrissa. Proc Natl Acad Sci USA. 1993;90(15):7391–7395. 77. Rochat A, Kobayashi K, Barrandon Y. Location of stem cells of human hair follicles by clonal analysis. Cell. 1994;76(6):1063–1073. 78. Taylor G, Lehrer MS, Jensen PJ, et al. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell. 2000;102(4):451–461. 79. Oshima H, Rochat A, Kedzia C, et al. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell. 2001;104(2):233–245. 80. Tumbar T, Guasch G, Greco V, et al. Defining the epithelial stem cell niche in skin. Science. 2004;303(5656):359–363. 81. Blanpain C, Lowry WE, Geoghegan A, et al. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004;118(5):635–648. 82. Morris RJ, Liu Y, Marles L, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol. 2004;22(4):411–417. 83. Ito M, Liu Y, Yang Z, et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005;11(12):1351–1354.

CELLS

14

Figure 1.10  Transmission electron micrograph of basal and suprabasal

Structure and function of the skin

84. Trempus CS, Morris RJ, Bortner CD, et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol. 2003;120(4):501–511. 85. Ohyama M, Terunuma A, Tock CL, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest. 2006;116(1):249–260. 86. Jaks V, Barker N, Kasper M, et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet. 2008;40(11):1291–1299. 87. Morasso MI, Tomic-Canic M. Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol Cell. 2005;97(3):173–183. 88. Mackenzie IC. Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis. Nature. 1970;226(5246):653–655. 89. Potten CS. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet. 1974;7(1):77–88. 90. Allen TD, Potten CS. Fine-structural identification and organization of the epidermal proliferative unit. J Cell Sci. 1974;15(2):291–319. 91. Potten CS. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int Rev Cytol. 1981;69:271–318. 92. Ghazizadeh S, Taichman LB. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. Embo J. 2001;20(6):1215–1222. 93. Kolodka TM, Garlick JA, Taichman LB. Evidence for keratinocyte stem cells in vitro: long term engraftment and persistence of transgene expression from retrovirus-transduced keratinocytes. Proc Natl Acad Sci USA. 1998;95(8):4356–4361.

the infrequent division of stem cells. These cells provide the bulk of the cell divisions needed for stable self-renewal and are the most common cells in the basal compartment. After undergoing several cell divisions, these cells give rise to the third class of epidermal basal cells, the postmitotic cells that undergo terminal differentiation. Although long believed to detach from the basal lamina to migrate to a more superficial (suprabasal) position in the epidermis, recent evidence has suggested that asymmetrical division of basal cells relative to the basement membrane can directly give rise to a suprabasal differentiating daughter cell.100 In humans, the normal transit time for a basal cell, from the time it loses contact with the basal layer to the time it enters the stratum corneum, is at least 14 days. Transit through the stratum corneum and subsequent desquamation require another 14 days. These periods of time can be altered in hyperproliferative or growth-arrested states.

BASAL KERATINOCYTE STRUCTURE AND FUNCTION

of stem cell populations has also revealed molecular markers that can identify epidermal stem cell populations.80–82,84–86 Cells from this region are able to contribute to the formation not only of the entire pilosebaceous unit, but to the interfollicular epidermis as well.80–83 The existence of an additional progenitor population of cells, within the surface epidermal basal layer, is also supported by a number of lines of evidence, both in vitro and in vivo.71,87 These putative basal stem cells appear to be clonogenic, progress rapidly through S-phase of the cell cycle, and divide infrequently during stable self-renewal (retaining radiolabeled nucleotide label over long periods). Additionally, they are capable of cell division in response to exogenous and endogenous agents. Early lineage tracing experiments in the epidermis identified that keratinocytes are organized into vertical columns of progressively differentiating cells, termed epidermal proliferating units.88–91 Subsequent experiments using retrovirally labeled grafts and dermabraded epidermis supported the existence of these functional subunits and demonstrated that they can exist separately for extended periods of time.92–94 Ultrastructural and kinetic evidence has also suggested that infrequently cycling cell exist at the deepest regions of the rete ridges in thicker palmoplantar skin.95 Elevated β1 integrin expression is found in a pattern that overlaps with the observed slow-cycling cells in palmoplantar skin, but is expressed in other clusters of basal cells as well.96–98 In vitro properties of isolated basal cells also appear to correlate with stem cell character. When plated at low cell density, cultured keratinocytes can form highly proliferative colonies of undifferentiated morphology (holoclones) that can be passaged long-term and can reconstitute epidermis in vitro.77,99 Two other types of colonies can form: the paraclone, which displays a large, flat morphology characteristic of terminally differentiated cells, and the meroclone, likened to a transit amplifying population, which is composed of a relatively heterogeneous mixture of cell types that become senescent after a few rounds of passaging.99 The second type of cell, the transit amplifying cells of the basal layer, arise as a subset of daughter cells produced by

1

MOLECULAR Keratins are members of the large family of the intermediate filaments that includes vimentin, desmin and neurofilaments and are the hallmark of all epithelial cells, including keratino­ cytes.101,102 They serve a predominantly structural role in the cells. Some 54 different functional keratin genes have been identified in humans, 37 epithelial keratins and 17 hair keratins.103 Traditional nomenclature of the keratin genes and gene products has separated them into two subfamilies, the acidic (type I, K9–19) and basic-to-neutral (type II, K1–8) subfamilies based on their isoelectric points, immunoreactivity, and sequence homologies with type I and type II wool keratins. They have also been divided into categories depending on their tissue of origin (e.g., hair keratins versus epithelial keratins). A recent consensus statement has proposed a more uniform and consistent system of naming and categorizing the keratins, to accommodate the discovery of newer keratin genes.103 All keratins assemble into filaments both within cells and when reconstituted in vitro, forming ‘obligate heteropolymers’, that is, containing a member of each family (acidic and basic),

94. Mackenzie IC. Retroviral transduction of murine epidermal stem cells demonstrates clonal units of epidermal structure. J Invest Dermatol. 1997;109(3):377–383. 95. Lavker RM, Sun TT. Heterogeneity in epidermal basal keratinocytes: morphological and functional correlations. Science. 1982;215(4537):1239–1241. 96. Jones PH, Watt FM. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell. 1993;73(4):713–724. 97. Jones PH, Harper S, Watt FM. Stem cell patterning and fate in human epidermis. Cell. 1995;80(1):83–93. 98. Legg J, Jensen UB, Broad S, et al. Role of melanoma chondroitin sulphate proteoglycan in patterning stem cells in human interfollicular epidermis. Development. 2003;130(24):6049–6063. 99. Barrandon Y, Green H. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci USA. 1987;84(8):2302–2306. 100. Lechler T, Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature. 2005;437(7056):275–280. 101. Freedberg IM, Tomic-Canic M, Komine M, et al. Keratins and the keratinocyte activation cycle. J Invest Dermatol. 2001;116(5):633–640. 102. Fuchs E. Keratins and the skin. Annu Rev Cell Dev Biol. 1995;11: 123–153. 103. Schweizer J, Bowden PE, Coulombe PA, et al. New consensus nomenclature for mammalian keratins. J Cell Biol. 2006;174(2): 169–174.

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in order to form the filament structure. These 8–10-nm diameter molecules are arranged in regions: An N-terminal random region, a central helical region, and a C-terminal random region. The helical regions allow interactions within the keratin filaments and the formation of larger intracellular aggregates of molecules; the N- and C-terminal portions of the molecules allow interactions with other intracellular macromolecules, including molecules forming cell attachments within cells to the nuclear envelope and between cells and the basement membrane zone. The basal border of the keratinocyte has sugar molecules that are not present on the apical or lateral borders and has hemidesmosomes, which connect the cell to the basement membrane. The hemidesmosome contains plectin, integrin α6β4, and two bullous pemphigoid antigens, BP 230, and BP180 (collagen XVII). Microfilaments (containing actin, α-actinin, and myosin) associate with the integrin receptor at the basal border. The keratinocyte also has cytoskeletal components, such as F-actin, α-actinin, tubulins, and others, which are found in many other cell types. The coexpression of specific keratin pairs is dependent on cell type, tissue type, developmental stage, differentiation stage, and disease condition.104 Furthermore, the critical role of these molecules is underscored by the numerous manifestations of disease that arise because of mutations in these genes.104,105 Thus,

knowledge of keratin expression, regulation, and structure provides insight into epidermal differentiation and structure.

SPINOUS KERATINOCYTE STRUCTURE AND FUNCTION CELLS The shape, structure, and subcellular properties of spinous cells correlate with their position within the mid-epidermis (Fig. 1.11). They are named for the spine-like appearance of the cell margins in histologic sections. Suprabasal spinous cells are polyhedral in shape, with a rounded nucleus. As these cells differentiate and move upward through the epidermis, they become progressively flatter and develop organelles known as lamellar granules. Spinous cells also contain large bundles of keratin filaments, organized around the nucleus and inserted into desmosomes peripherally.

MOLECULAR Spinous cells retain the stable K5/K14 keratins that are produced in the basal layer but do not synthesize new mRNA for these

B

A

Figure 1.11  Transmission electron micrographs of the upper spinous and granular layer cells of the epidermis. (A) Note the three layers of cells that contain keratohyalin granules. (B) Lamellar granules are evident within the cytoplasm and at the boundaries of the granular cells. Note the abrupt change in morphology between the upper granular layer cell and the first cornified cell layer. The cornified cell envelope in the first cornified cell is marked (arrows). (A) ×13 000; (B) ×36 000. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

104. Uitto J, Richard G. Progress in epidermolysis bullosa: from eponyms to molecular genetic classification. Clin Dermatol. 2005;23(1):33–40.

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105. Uitto J, Richard G, McGrath JA. Diseases of epidermal keratins and their linker proteins. Exp Cell Res. 2007;313(10):1995–2009.

Structure and function of the skin

proteins, except in hyperproliferative disorders. Instead, new synthesis of the K1/K10 keratin pair occurs in this epidermal layer. These keratins are characteristic of an epidermal pattern of differentiation and thus are referred to as the differentiationspecific or keratinization-specific keratins. This normal pattern of differentiation is switched to an alternative pathway in hyperproliferative states, however. In conditions such as psoriasis, actinic keratoses, and wound healing, synthesis of K1 and K10 mRNA and protein is downregulated and the synthesis and translation of messages for K6 and K16 are favored. Correlated with this change in keratin expression is a disruption of normal differentiation in the subsequent granular and cornified epidermal layers (see below). mRNA for K6 and K16 are present throughout the epidermis normally, but the message is only translated upon stimulation of proliferation. In palmar and plantar epidermis K9 predominates. K2e, which is related to K1 and pairs with K10, is expressed in the upper half of the epidermis. The ‘spines’ of spinous cells are abundant desmosomes, calcium-dependent cell surface modifications that promote adhesion of epidermal cells and resistance to mechanical stress.106 Within each cell is a desmosomal plaque, which contains the polypeptides plakoglobin, desmoplakins I and II, keratocalmin, desmoyokin, and plakophilin. Transmembrane glycoproteins, desmoglein 1 and 3 and desmocollins I and II, members of the cadherin family, provide the adhesive properties of the extracellular portion of the desmosomes, known as the core. Whereas the extracellular domains of the cadherins form part of the core, the intracellular domains insert into the plaque, linking them to the intermediate filament (keratin) cytoskeleton. Although desmosomes are related to adherens junctions, the latter associate with actin microfilaments at cell–cell interfaces, via a distinct set of cadherins (e.g., E-cadherin) and intracellular catenin adapter molecules. That the desmosomes are integral mediators of intercellular adhesion is clearly demonstrated in diseases in which these structures are disrupted (Fig. 1.10).107 The autoimmune bullous diseases pemphigus vulgaris and pemphigus foliaceus are caused by antibodies that target the desmoglein proteins within the desmosomes. Loss of desmosomal adhesion results in the characteristic rounding and separation of keratinocytes (acantholysis), ultimately forming a blister within the epidermis. Strikingly, the clinical presentation of these diseases reflects the relative expression in the tissue of the desmoglein 1 and 3 proteins. Pemphigus vulgaris results from autoantibodies directed against desmoglein 3 and results in disruption of the epidermis between the basal and suprabasal layers.108 On the other hand,

Named for the basophilic keratohyalin granules (Figs 1.11, 1.12) that are prominent within cells at this level of the epidermis, the granular layer is the site of generation of a number of the structural components that will form the epidermal barrier, as well as a number of proteins that process these components.114,115 Transitional cells are a rarely recognized component of the epidermis and are at the border between the uppermost granular cells and the first stratum corneum cell (Fig. 1.12). They have the heavily convoluted nucleus characteristic of a cell in the early stages of apoptosis.

106. Yin T, Green KJ. Regulation of desmosome assembly and adhesion. Semin Cell Dev Biol. 2004;15(6):665–677. 107. Kottke MD, Delva E, Kowalczyk AP. The desmosome: cell science lessons from human diseases. J Cell Sci. 2006;119(Pt 5):797–806. 108. Payne AS, Hanakawa Y, Amagai M, et al. Desmosomes and disease: pemphigus and bullous impetigo. Curr Opin Cell Biol. 2004;16(5):536–543. 109. Amagai M, Matsuyoshi N, Wang ZH, et al. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat Med. 2000;6(11):1275–1277. 110. Sakuntabhai A, Ruiz-Perez V, Carter S, et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet. 1999;21(3):271–277.

111. Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000;24(1): 61–65. 112. Herman GE. X-Linked dominant disorders of cholesterol biosynthesis in man and mouse. Biochim Biophys Acta. 2000;1529(1–3):357–373. 113. Hernandez-Martin A, Gonzalez-Sarmiento R, De Unamuno P. X-linked ichthyosis: an update. Br J Dermatol. 1999;141(4):617–627. 114. Segre JA. Epidermal barrier formation and recovery in skin disorders. J Clin Invest. 2006;116(5):1150–1158. 115. Kimyai-Asadi A, Kotcher LB, Jih MH. The molecular basis of hereditary palmoplantar keratodermas. J Am Acad Dermatol. 2002;47(3):327–343; quiz 344–346.

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GRANULAR CELLS

desmoglein 1 is expressed in the upper epidermal layers, and antibodies to this protein in patients with pemphigus foliaceus result in blisters in the more superficial granular layer. Other diseases that target the same desmoglein 1 protein but by a different mechanism are staphylococcal scalded skin syndrome and bullous impetigo, in which a bacterial protease cleaves and inactivates desmoglein 1, resulting in the same superficial blistering seen in pemphigus foliaceus.109 Genetic mutations in other desmosomal components also reveal a role for these proteins in adhesion as well as cell signaling.107 The importance of calcium as a mediator of adhesion is well illustrated in the cases of two conditions that exhibit characteristic epidermal dyscohesion, Darier disease (keratosis follicularis) and Hailey-Hailey disease (benign chronic pemphigus) (see Ch. 8, p. 639).110,111 Both of these diseases are caused by mutations in genes that regulate calcium transport, SERCA2 (sarco/ endoplasmic reticulum Ca(2+)-ATPase type 2 isoform) in the case of Darier disease, and ATP2C1 (a regulator of cytoplasmic calcium concentration) in the case of Hailey-Hailey disease. Lamellar granules are also formed in this layer of epidermal cells. These secretory organelles deliver precursors of stratum corneum lipids into the intercellular space. Lamellar granules contain glycoproteins, glycolipids, phospholipids, free sterols, and a number of acid hydrolases, including lipases, proteases, acid phosphatases, and glycosidases. Glucosylceramides, the precursors to ceramides and the dominant component of the stratum corneum lipids, are also found within these structures. Genetic diseases demonstrate the importance of steroid and lipid metabolism for sloughing of cornified cells; in recessive X-linked ichthyosis, for example, mutation of steroid sulfatase results in a retention hyperkeratosis (see Ch. 8).112,113

GRANULAR CELLS CELLS

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B

A GRANULAR CELLS

Figure 1.12  Electron micrograph of transitional cells that show morphology intermediate between that of granular and cornified cells. (A) The nucleus is retained, and (B) some of the organelles (ribosomes and keratohyalin granules) are evident. (A) ×12 000; (B) ×13 000. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

MOLECULAR

Stratum corneum cell

Cell envelope Lipids

Plasma membrane

Fusion and cytosis Lamellar granule

Granular cell

Figure 1.13  Schematic diagram of extracellular lipid deposition for barrier function and enzyme deposition for desquamation in the stratum corneum. (Modified from Freedberg IM, Eisen AZ, Wolff K et al., eds. Fitzpatrick’s dermatology in general medicine, New York: McGraw-Hill; 1999, with permission.)

In the cells of the granular layer, lamellar granules are extruded, apoptosis is initiated, the nucleus and other cellular contents susceptible to proteolysis are destroyed, and the potential for protein synthesis is lost (Fig. 1.13). The final stage of granular cell differentiation involves the cell’s own programmed destruction. During this process, in which the granular cell becomes a terminally differentiated corneocyte, an apoptotic mechanism results in the destruction of the nucleus and almost all cellular contents, with the exception of the keratin filaments and filaggrin matrix.

116. Huber M, Rettler I, Bernasconi K, et al. Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science. 1995;267(5197): 525–528. 117. Russell LJ, DiGiovanna JJ, Rogers GR, et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat Genet. 1995;9(3):279–283. 118. Sandilands A, O’Regan GM, Liao H, et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol. 2006;126(8): 1770–1775. 119. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006;38(3):337–342.

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Keratohyalin granules are composed primarily of profilaggrin, keratin filaments, and loricrin. It is in this layer that the cornified cell envelope begins to form. Release of profilaggrin from keratohyalin granules results in the calcium-dependent cleavage of the profilaggrin polymeric protein into filaggrin monomers. These filaggrin monomers aggregate with keratin to form macrofilaments. Eventually, filaggrin is degraded into molecules including urocanic acid and pyrrolidone carboxylic acid, which contribute to hydration of the stratum corneum and help filter ultraviolet radiation. Loricrin is a cysteine-rich protein that forms the major protein component of the cornified envelope, accounting for more than 70% of its mass. Upon its release from keratohyalin granules, loricrin binds to desmosomal structures. Loricrin, along with involucrin, cystatin A, small proline-rich proteins (SPR1, SPR2, and cornifin), elafin, and envoplakin are all subsequently cross-linked to the plasma membrane by tissue transglutaminases (TGases, primarily TGases 3 and 1), forming the cornified cell envelope (Fig. 1.14). Mutations in the TGM1 gene have been shown to be the basis of some cases of lamellar ichthyosis, an autosomal recessive condition characterized by large scales and a disruption in the uppermost differentiating layers of the epidermis.116,117 Another form of ichthyosis, ichthyosis vulgaris, is caused by mutations in the gene encoding filaggrin.118,119 Furthermore, filaggrin mutations have also been linked to increased risk for development of atopic dermatitis.120 Loricrin abnormalities result in a form of Vohwinkel’s syndrome with ichthyosis and pseudoainhum, as well as the disease progressive symmetric keratodermia.121–123

120. Jung T, Stingl G. Atopic dermatitis: therapeutic concepts evolving from new pathophysiologic insights. J Allergy Clin Immunol. 2008;122(6):1074–1081. 121. Maestrini E, Monaco AP, McGrath JA, et al. A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel’s syndrome. Nat Genet. 1996;13(1):70–77. 122. Korge BP, Ishida-Yamamoto A, Punter C, et al. Loricrin mutation in Vohwinkel’s keratoderma is unique to the variant with ichthyosis. J Invest Dermatol. 1997;109(4):604–610. 123. Ishida-Yamamoto A, Takahashi H, Iizuka H. Loricrin and human skin diseases: molecular basis of loricrin keratodermas. Histol Histopathol. 1998;13(3):819–826.

Structure and function of the skin

1

Cytoplasmic surface

Keratin filaments Loricrin SPR1/SPR2 Other proteins

A

Transglutaminase Envoplakin Periplakin Involucrin

STRATUM CORNEUM

Ceramides Exterior surface of cornified cell

Figure 1.14  The cell envelope is formed by sequential incorporation of several structural proteins and extracellular lipids across the plasma membrane. (From Steinert PM. The complexity and redundancy of epithelial barrier function. J Cell Biol 2000; 151(2):F5–F8, reproduced with permission.)

These findings emphasize the importance of proper formation of the cornified envelope in normal epidermal keratinization. Profilaggrin is a histidine-rich, very basic protein, which is highly phosphorylated and forms a large (≈400 kDa) polymer. Filaggrin forms in the granular layer, aggregates with keratin, and may have a role in forming keratin filaments in upper layers of the epidermis. With proteolysis filaggrin releases histidine, which then is deaminated by a histidase present in the stratum corneum and forms trans-urocanic acid. Trans-urocanic acid is converted to cis-urocanic acid by UVB. Glutamic acid released from filaggrin is converted to pyroglutamic acid and may function as a natural moisturizing agent in the epidermis. Keratins are both phosphorylated and subject to proteolytic degradation in this layer. Predesquamin in the transitional layer may facilitate apoptosis.

STRATUM CORNEUM CELLS B

Complete differentiation of granular cells results in stacked layers of anucleate, flattened cornified cells that form the stratum corneum. It is this layer that provides mechanical protection to the skin and a barrier to water loss and permeation of soluble substances from the environment.114,124,125 There is a large difference in the number of cell layers of the so-called dead epidermis. It is about 15 layers thick on the general body skin, and hundreds of layers thick on the palms and soles. Stratum corneum thickness is similar in children and in adults (Fig. 1.15). Within a thinned plasma membrane (with a 5 nm lipid layer) is a very highly cross-linked structure, the cell envelope, which is 7–15 nm in thickness. Epidermal ceramides are cross-linked across the cell

membrane to the envelope, which may stabilize the extracellular lipid layer. Regulation of permeability, desquamation, antimicrobial peptide activity, toxin exclusion, and selective chemical absorp-

124. Elias PM. Stratum corneum defensive functions: an integrated view. J Invest Dermatol. 2005;125(2):183–200.

125. Proksch E, Brandner JM, Jensen JM. The skin: an indispensable barrier. Exp Dermatol, 2008.

Figure 1.15  Scanning electron micrographs comparing the thickness of the

stratum corneum from (A) the arm and (B) the palm of an adult. (A) ×200; (B) ×200. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

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tion are all primarily functions of the extracellular lipid matrix. On the other hand, mechanical reinforcement, hydration, cytokine-mediated initiation of inflammation, and protection from ultraviolet damage are all provided by the corneocytes. The corneocyte has a highly structured cell surface and extracellular lipid coat forming the barrier against water loss, which prevents a large number of small and medium-sized molecules from passively passing through the epidermis.

MOLECULAR

IMMUNOCYTES IN THE EPIDERMIS (LANGERHANS CELLS AND γ-δ-T CELLS)

The stratum corneum barrier is formed by a two-compartment system of lipid-depleted, protein-enriched corneocytes surrounded by a continuous extracellular lipid matrix. These two compartments provide somewhat segregated but complementary functions that together account for the ‘barrier activity’ of the epidermis. Disulfide bonded keratins make up 80% of the mass of stratum corneum cells. The hydrophobic nature of the extracellular lipid chains, glycolipids, free sterol and phospholipids explains why lipophilic molecules pass through the epidermis more easily than hydrophilic molecules. Ceramides are the most abundant lipid in the extracellular space.

EPIDERMAL MELANOCYTES CELLS Melanocytes are neural crest-derived, pigment-synthesizing dendritic cells that reside primarily in the basal layer, although they are located in the spinous layer during fetal life. Through dendrites melanocytes have a close relationship with approximately 36 basal and spinous cells (‘epidermal melanin unit’).126 There are 1220 melanocytes/mm2 by age 16, but the highest melanocyte density is actually at birth. Melanocyte density is highest on the face and genital region, and lowest on the abdomen. Melanocytes are also present in the nail matrix and hair cortex. By light microscopy, these cells are recognized by their pale-staining cytoplasm, ovoid nucleus, and color of the pigment-containing melanosomes, the distinctive organelle of the melanocyte. Melanocytes synthesize melanin, which absorbs and scatters ultraviolet light, visible light, and near infrared radiation. Keratinocytes have a role in regulating whether melanosomes are distributed individually or clustered. Dark-skinned African-Americans have 450–600 melanosomes per melanocyte and light-skinned Europeans and Americans have 2–12 melanosomes per melanocyte. The function of melanocytes has been highlighted by disorders in melanocyte number or function. The classic dermatologic disease, vitiligo, is caused by the autoimmune depletion of melanocytes.127 Other disorders of pigmentation find their causes due to various defects in melanogenesis, including melanin synthesis, melanosome production, and melanosome transport and transfer to keratinocytes (see Ch. 10).

126. Nordlund JJ. The melanocyte and the epidermal melanin unit: an expanded concept. Dermatol Clin. 2007;25(3):271–281, vii. 127. Grimes PE. New insights and new therapies in vitiligo. JAMA. 2005;293(6):730–735.

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MOLECULAR Melanocytes contain prominent intermediate filaments composed of vimentin, which forms homopolymers and not the heteropolymers of keratin. Melanocytes also have integrin receptors (α6β4), receptors for fibronectin and laminin that may attach melanocytes to the dermal–epidermal junction, and Eand P-cadherins that may attach melanocytes to keratinocytes. Melanosomes are complex organelles and the site of melanin production. Melanosomes contain lysosomal enzymes, such as acid phosphatase, and β glucuronidase, and lysosomal markers such as Lamp-1, CD63, and specific enzymes and structural proteins related to the synthesis of melanin. Keratinocyte–melanocyte interactions are critical for melanocyte homeostasis and differentiation, influencing proliferation, dendricity, and melanization. Melanocytes produce growth factors and are greatly influenced by melanocortin and its derived factors. These peptides interact with a family of cell surface MSH receptors that functions with G-proteins, the cAMP pathway and protein kinase A. Frequent polymorphisms in the MSH receptor include mutations associated with red hair. Endothelin is a 21-amino acid peptide, which is increased after ultraviolet exposure, and functions via the protein kinase C pathway and tyrosine phosphorylation. Regulation of melanocyte proliferation and homeostasis is under intensive study as well as a means of understanding melanoma.69

IMMUNOCYTES IN THE EPIDERMIS (LANGERHANS CELLS AND γ-δ-T CELLS) CELLS Langerhans cells are part of the afferent limb of the immune system and, through their class II HLA receptors, process predominantly exogenous antigens. The γ-δ-T cells are a resident population of T cells that function predominantly in immunoregulation. Langerhans cells are dendritic antigen-processing and -presenting cells in the epidermis.128,129 Although they are not unique to the epidermis, they form 2–8% of the total epidermal cell population. They are mostly found in a suprabasal position, but are distributed throughout the basal, spinous, and granular layers. In histologic preparations, Langerhans cells are pale-staining and have convoluted nuclei. The cytoplasm of the Langerhans cells contains characteristic small rod- or racketshaped structures called Langerhans cell granules or Birbeck granules (Fig. 1.16). Langerhans cells principally function to sample and present antigens to T cells of the epidermis. Because of these functions, they are implicated in the pathologic mechanisms underlying allergic contact dermatitis, cutaneous leishmaniasis, and human immunodeficiency virus infection. Langerhans cells are reduced

128. Valladeau J, Saeland S. Cutaneous dendritic cells. Semin Immunol. 2005;17(4):273–283. 129. Merad M, Ginhoux F, Collin M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol. 2008;8(12):935–947.

Structure and function of the skin

1

located between basal keratinocytes; their functional presence in normal human epidermis is still under investigation.

MOLECULAR

MERKEL CELLS

A

Langerhans cells have several surface markers that relate to its function as an antigen-presenting cell. These include class I and II HLA-antigens, S-100 protein, receptors for the Fc region of IgG, a high affinity receptor for IgE (FcεR1), and a receptor to complement (C3bi/CR-III). The CD1a receptor distinguishes LCs from other antigen-processing dendritic cells. Langerhans cells secrete interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1. Langerhans cell–T cell interactions are facilitated by such adhesion molecules as integrins and intracellular adhesion molecule (ICAM-1) family members.

MERKEL CELLS

B

Figure 1.16  (A,B) Light and electron micrographs of Langerhans cells in the epidermis. Note the pale staining cytoplasm, the convoluted nucleus, and the dendritic nature of the cell (dendritic process indicated with arrows in (B). Several Langerhans cell granules (Birbeck granules) are enlarged in C. (A) ×400; (B) ×6000; (C) ×50 000 (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

The Merkel cell is a population of individual and grouped mechanical receptors, which respond to changes in movement and also may respond to changes in osmotic pressure.130,131 Merkel cells are slow-adapting type I mechanoreceptors located in sites of high tactile sensitivity.132,133 They are present among basal keratinocytes in particular regions of the body, including hairy skin and in the glabrous skin of the digits, lips, regions of the oral cavity, and the outer root sheath of the hair follicle. Like other non-keratinocytes, Merkel cells have a pale-staining cytoplasm, although they do have desmosomal connections. They contain Golgi-derived membrane dense core granules that are bound 80–100 nm in diameter. The contacting membrane between a neurite and a Merkel cell resembles a synapse (Fig. 1.17). Although increasingly more is being learned about the normal function of Merkel cells, they are of particular clinical note because Merkel cell-derived neoplasms are notoriously aggressive and difficult to treat.134,135

MOLECULAR

in the epidermis of patients with certain conditions, such as psoriasis, sarcoidosis, and contact dermatitis; they are functionally impaired by ultraviolet radiation, especially UVB. Cutaneous nerves that secrete calcitonin gene-related peptide (CGRP) join Langerhans cells and are a potential structural link between the nervous system and the immune system. Thy-1+ dendritic cells (γ-δ cells) are well described in mice and are

Immunohistochemical markers of the Merkel cell include K8, K18, K19, and K20 keratin peptides. K20 is restricted to Merkel cells in the skin and thus may be the most reliable marker. Ultrastructurally, Merkel cells are easily identified by the membrane-bounded, dense-core granules that collect opposite the Golgi and proximal to an unmyelinated neurite (Fig. 1.17). These granules are similar to neurosecretory granules in neurons and contain neurotransmitter-like substances and markers of neuroendocrine cells, including metenkephalin, vasoactive intestinal peptide, neuron-specific enolase, and synaptophysin. High levels of bcl-2 are present in Merkel cells, and may interfere with apoptosis induced by traditional chemotherapeutic regimens.

130. Passeron T, Mantoux F, Ortonne JP. Genetic disorders of pigmentation. Clin Dermatol. 2005;23(1):56–67. 131. Boulais N, Misery L. Merkel cells. J Am Acad Dermatol. 2007;57(1):147–165. 132. Halata Z, Grim M, Bauman KI. Friedrich Sigmund Merkel and his ‘Merkel cell’, morphology, development, and physiology: review and new results. Anat Rec A Discov Mol Cell Evol Biol. 2003;271(1):225–239.

133. Lumpkin EA, Caterina MJ. Mechanisms of sensory transduction in the skin. Nature. 2007;445(7130):858–865. 134. Henness S, Vereecken P. Management of Merkel tumours: an evidencebased review. Curr Opin Oncol. 2008;20(3):280–286. 135. Garneski KM, Nghiem P. Merkel cell carcinoma adjuvant therapy: current data support radiation but not chemotherapy. J Am Acad Dermatol. 2007;57(1):166–169.

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A

THE DERMIS A

Figure 1.17  (A) Transmission electron micrographs of a Merkel cell and (B) the dense-core granules from the skin of a premature infant. Small arrows point to a few granules in the cell and the larger arrows indicate the neurite. (A) ×9000; (B) ×51 000. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

B

THE DERMIS TISSUES The dermis is an integrated system of fibrous, filamentous, diffuse, and cellular connective tissue elements that accommodates nerve and vascular networks, epidermally derived appendages, and contains many resident cell types, including fibroblasts, macrophages, mast cells, and transient circulating cells of the immune system. The dermis is arranged into two major regions the upper papillary dermis and the deeper reticular dermis. (Fig. 1.18). These two regions are readily identifiable on histologic section, and they differ in their connective tissue organization, cell density, and nerve and vascular patterns. The papillary dermis abuts the epidermis, molds to its contours, and is usually no more than twice its thickness. The reticular dermis forms the bulk of the dermal tissue. It is composed primarily of largediameter collagen fibrils, organized into large, interwoven fiber bundles, with branching elastic fibers surrounding the bundles. In normal individuals, the elastic fibers and collagen bundles increase in size progressively toward the hypodermis. Based on fiber diameter, the reticular dermis may be divided into an upper ‘intermediate zone’ and a ‘deeper zone’. The subpapillary plexus, a horizontal plane of vessels, marks the boundary between the 22

B

Figure 1.18  Scanning electron micrographs of (A) papillary and (A,B) reticular dermis. In (A) note the small size of the collagen bundles in the papillary dermis in contrast to the larger bundles at the upper limit of the reticular dermis, called the intermediate dermis. The ‘cleft’ corresponds to a horizontal vessel of the subpapillary plexus. (B) shows the large collagen fiber bundles of the reticular dermis. (A) ×550; (B) ×550. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

papillary and reticular dermis. The lowest boundary of the reticular dermis is defined by the relatively abrupt transition of fibrous connective tissue to adipose connective tissue of the hypodermis. The hypodermis contains anagen follicles, and in its deeper portions apocrine and eccrine glands. It contains types I, III and V collagen. The dermis makes up the majority of the skin and provides its pliability, elasticity, and tensile strength. It protects the body from mechanical injury, binds water, aids in thermal regulation, and includes receptors of sensory stimuli. The dermis interacts with the epidermis in maintaining the properties of both tissues,

Structure and function of the skin

CELLS Fibroblasts, macrophages, and mast cells are the regular residents of the dermis, mostly found around the papillary region and surrounding vessels of the subpapillary plexus. They also occur in the reticular dermis in the interstices between collagen fiber bundles.

Fibroblasts The fibroblast is a mesenchymally derived cell that migrates through the tissue and is responsible for the synthesis and degradation of fibrous and non-fibrous connective tissue matrix proteins and a number of soluble factors. Fibroblasts provide a structural extracellular matrix framework as well as promote interaction between epidermis and dermis by synthesis of soluble mediators. Studies of human fibroblasts indicate that, even within a single tissue, phenotypically distinct populations exist, some of which relate to regional anatomical differences.136,137 They are also instrumental in wound healing and scarring, increasing their proliferative and synthetic activity during these processes.

hyperplastic in mastocytosis. Mast cells are secretory cells that are responsible for immediate-type hypersensitivity reaction in the skin and are involved in the production of subacute and chronic inflammatory disease. They synthesize secretory granules composed of histamine, heparin, tryptase, chymase, carboxypeptidase, neutrophil chemotactic factor, and eosinophilic chemotactic factor of anaphylaxis, which are mediators in these processes.

Dermal dendrocytes The dermal dendrocyte is a stellate, dendritic, or sometimes spindle-shaped, highly phagocytic fixed connective tissue cell in the dermis of normal skin. They are a subset of antigen-presenting macrophages or a distinct lineage that originates in the bone marrow. Similar to many other bone marrow-derived cells, dermal dendrocytes express factor XIIIa and CD45, and they lack typical markers of fibroblasts (e.g., Te-7). These cells are particularly abundant in the papillary dermis and upper reticular dermis, frequently in the proximity of vessels of the subpapillary plexus. Dermal dendrocytes function in the afferent limb of an immune response. They are also likely the cell of origin of a number of benign fibrotic proliferative conditions in the skin, such as dermatofibromas and fibroxanthomas.

MOLECULAR

Mast cells are specialized secretory cells, which in skin are present in greatest density in the papillary dermis, near the DEJ, in sheaths of epidermal appendages, and around blood vessels and nerves of the subpapillary plexus. They are also common in the subcutaneous fat. Mast cells are identified histologically by a round or oval nucleus and abundant, darkly staining cytoplasmic granules. The surface of dermal mast cells is coated with fibronectin, which probably assists in securing cells within the connective tissue matrix. Mast cells can become

The connective tissue matrix of the dermis is comprised primarily of collagenous and elastic fibrous tissue.138,139 These are combined with other, non-fibrous connective tissue molecules, including finely filamentous glycoproteins, proteoglycans, and glycosaminoglycans of the ‘ground substance’.140 In terms of acellular components, collagen forms the bulk of the dermis, accounting for approximately 75% of the dry weight of skin, and providing both tensile strength and elasticity. Briefly, collagen has many of its prolines hydroxylated and this allows the formation of the collagen triple helix; some of the lysines are hydroxylated, allowing for the formation of new cross-links intermolecularly between collagen molecules (Fig. 1.19). These hydroxylations require ascorbic acid and separate and specific hydroxylating enzymes for proline and lysine. Collagen is glycosylated with galactosyl or glucosyl-galactosyl residues covalently bound to hydroxylysine. The periodically banded, interstitial collagens account for the greatest proportion of collagen in adult dermis (type I 80–90%, III 8–12%, and V feet At tip of digits

Function

Slow-acting mechanoreceptor

Sensation

Touch

Precise touch, temperature, itching, pain

In subcutis and near arteriovenous anastomoses Palms and soles; some in nipple and genitals Vibration, pressure

Figure 1.37  Schematic representation of the location, overall morphology and function of the cutaneous receptors.

CUTANEOUS NERVES TISSUES The nerve networks of the skin contain somatic sensory and sympathetic autonomic fibers.133,173 The sensory fibers alone (free nerve endings) or in conjunction with specialized structures (corpuscular receptors) function as receptors of touch, pain, temperature, itch, and mechanical stimuli. The density and types of receptors are regionally variable, accounting for the variation in acuity at different sites of the body. Receptors are particularly dense in hairless areas such as the areola, labia, and glans penis. Sympathetic motor fibers are codistributed with the sensory nerves in the dermis until they branch to innervate the sweat glands, vascular smooth muscle, the arrector pili muscle of hair follicles, and sebaceous glands (Figs 1.37–1.40). Bare nerve cell endings are ensheathed by a basal lamina and Schwann cell processes. They are common in the papillary dermis close to the lamina densa and intraepidermally. They have large numbers of vesicles and mitochondria at their termi-

173. Johansson O. The innervation of the human epidermis. J Neurol Sci. 1995; 130(2):228.

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nals. Penicillate fibers are free nerve endings in hairy skin, which respond to touch, pain, temperature and itch. Arrector pili smooth muscles have adrenergic and cholinergic innervation with motor fibers that course along with the sensory fibers to the follicle. Meissner’s corpuscles and the Pacinian corpuscle are corpuscular receptors with a capsule and inner core and have both neuronal and non-neuronal components. Meissner’s corpuscles are individually situated within a dermal papilla with the endings of myelinated axons ensheathed with Schwann cells. The endbulbs of Krause on the lip, eyelid, perianal canal, clitoris and glans penis have a similar structure. The Pacinian corpuscle is a rapidly adapting pressure receptor in subcutis and at arteriovenous anastomoses. It has 30 or more layers (onion skin pattern) of perineurium and connective tissue surrounding the single axon of a digital nerve. Hair follicles have free nerve endings (papillary nerve endings) just below the entrance of the sebaceous gland and are slowly adapting mechanoreceptors. Nerves of hair follicles have a basket-like arrangement around the hairs; in addition, there are specific mechanoreceptors (Merkel cells) in the hair bulb.

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Structure and function of the skin

A B

C

Figure 1.38  Light and transmission electron micrographs of the bare nerve terminals that innervate the follicle (arrows). Note the position and structure of the terminals (T) and Schwann cells (S) just outside the basement membrane of the outer root sheath. A nerve fiber (F) surrounded by Schwann cells is also shown. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

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Figure 1.39  Light micrograph of a Meissner corpuscle in the palm. ×350. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

B

C

Figure 1.40  Light and transmission electron micrographs of Pacinian corpuscles in the palm. Note the A

position of the corpuscles (arrows) at the border of the deep dermis and the hypodermis adjacent to eccrine sweat gland and ducts. (From Holbrook KA, Sybert VP. Basic science. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995, with permission.)

Structure and function of the skin

Lowell Goldsmith and Karen Holbrook are acknowledged as previous authors of this section.

BASIC IMMUNOLOGY Thomas Schwarz

INTRODUCTION The skin represents a major barrier against the outside environment and is permanently confronted with microbial, chemical and physical insults. Thus it is a matter of course that it has to function as a kind of defense organ. Along this line, the skin does not only serve as a mechanical barrier to the outside, but also makes use of the immune system for protection. Hence, the skin is endowed with the capacity to generate an immune response, yielding the term skin-associated lymphoid tissues (SALT).174 The immune system in children is much like the immune system in adults, although there are some differences. The mechanisms of immunity are the same and the immune systems of children are usually effective and work better than the immune systems of adults, especially older adults. Children have not been exposed to as many antigens as adults and therefore normally have increased susceptibility to common infectious organisms. An increased incidence of infections also occurs in children with primary deficiencies of the immune system which in addition often cause non-infectious health problems. Two major types of immune responses have to be differentiated, the innate and the adaptive one. The major characteristics of the adaptive immune response, mostly referred as the classical immune response, are specificity and memory. Innate immunity represents a more primitive defense system which acts rapidly but is non-specific. Both innate and adaptive immune responses can be generated in the skin. There is also solid evidence for a cross talk between the innate and the adaptive immune systems which therefore should not be regarded in an isolated fashion with regard to their function and efficacy.

INNATE IMMUNE RESPONSE Innate immune responses developed earlier in evolution and are less complicated than adaptive responses since they lack immunologic memory.175 However, these primitive immune responses are essential, since failures can result in severe, even fatal health problems. Crucial members of the innate response are complement, cytokines, antimicrobial peptides, neutrophils, eosinophils, natural killer cells, and mast cells.

TOLL-LIKE RECEPTORS The major task of innate immunity is the recognition of invading microorganisms and the induction of a host defense response.

174. Streilein JW. Skin-associated lymphoid tissues (SALT): origins and functions. J Invest Dermatol. 1983;80(suppl):12s–16s. 175. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med. 2000; 343:338–344. 176. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2:675–680.

A family of pattern recognition receptors mediates responses to pathogen-associated molecular patterns which are conserved among microorganisms. Human toll-like receptors (TLR), the mammalian homologues of the toll receptors identified in Drosophila, represent one such family of pattern recognition receptors.176 Currently, 10 TLRs have been recognized. TLR2 recognizes lipoproteins and peptidoglycans, TLR4 lipopolysaccharide, TLR5 flagellin, TLR9 bacterial CpG DNA sequences. TLR6 participates in the discrimination of lipoproteins. TLRs may also be involved in the recognition of viral components. Dendritic cells were found to express several TLRs. Upon activation of these receptors by microbial components, dendritic cells mature and present pathogen-derived antigens to naïve T cells, thereby inducing an adaptive immune response. Thus, TLRs can be regarded as molecules bridging the gap between innate and adaptive immunity.

INNATE IMMUNE RESPONSE

Acknowledgment

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ANTIMICROBIAL PEPTIDES Plants and invertebrates cope with the ubiquitous micro­ organisms by producing antimicrobial proteins (AMPs). Human epithelia, including the epidermis, also secrete AMPs, thereby mounting an innate chemical defense.177 AMPs produced in the skin include defensins (hBD-2, hBD-3), RNAses, psoriasin, cathelicidin and dermicidin. Some of these peptides are constitutively expressed, others need to be induced, e.g., by bacterial products or by proinflammatory cytokines. There is strong evidence that AMPs are the much more relevant component of a powerful antimicrobial response than T cell-mediated immunity. The high expression of AMP in psoriasis may explain the lack of bacterial superinfections in psoriatic plaques despite the barrier disruption. In contrast, the frequent superinfection of atopic patients, in particular with Staphylococcus aureus may be supported by a lower expression of AMPs in atopic skin. β-defensins can also attract immature dendritic cells and memory T cells via the chemokine receptor CCR-6, indicating again a link between innate epithelial defense and adaptive immunity.

CYTOKINES The term cytokines comprises a large family of heterogeneous low-molecular weight mediators which are crucially involved in intercellular communication. Cytokines are secreted by almost any cell, thus they can act in an autocrine, paracrine or endocrine manner. Cytokines bind to specific cell surface receptors.178 The vast majority of cytokines occurs in a soluble form, but some can be membrane-bound, making the differentiation between cytokines and receptors difficult. This is further complicated by the fact that some receptors can occur in a soluble form as well. Cytokine exhibits multiple and overlapping activities, thus strict categorization is not possible. The term interleukins (IL) refers to cytokines which are produced by leukocytes and affect preferentially other white blood cells. The term colony-stimulating factors (CSF) designates those

177. Harder J, Schröder JM. Psoriatic scales: a promising source for the isolation of human skin-derived antimicrobial proteins. J Leukoc Biol. 2005;77: 476–486. 178. Thomson A, Lotze M. The cytokine handbook. 4th ed. London: Academic Press; 2003.

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mediators which induce differentiation and proliferation of hematopoietic progenitor cells. Interferons (IFN) comprise mediators which interfere with viral replication. Cytokines with chemoattractant activity are designated chemokines. Two main subgroups are differentiated according to the position of two cysteine (C) residues compared with the other amino acid residues (X), CXC- or α-chemokines and CC- or β-chemokines. Chemokines which attract leukocytes are called inflammatory chemokines, while those acting mostly in lymphoid tissues are termed lymphoid chemokines. Cytokines with inflammatory (e.g., IL-1, IL-6, TNFα, inflammatory chemokines) and antiviral (e.g., IFNα, IFNβ) activities are preferentially involved in innate immune responses, whereas adaptive immune responses are mostly driven by cytokines with immunomodulatory capacities (e.g., IL-2, IL-4, IL-10, IL-12, IL-13, IL-18, IL-23, IFNγ). However, strict separation into inflammatory and immunologic cytokines is not possible as most of these mediators exhibit multiple and sometimes overlapping activities. In addition, the list of newly discovered cytokines is still expanding per year.

tors for antibodies and complement.180 Hence, microorganisms coated with antibodies and/or complement are effectively phagocytosed by macrophages. Macrophages can also present processed antigens to T and B cells, though in a much less efficient fashion than dendritic cells. Activated macrophages release granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) which induce the division of myeloid precursors in the bone marrow and the release of neutrophils into the circulation. Usually, neutrophils circulate in the blood stream or roll along the vascular endothelium. Entry into the site of an infection is a complex process which involves proinflammatory cytokines, adhesion molecules, chemoattractants, and chemo­ kines. Neutrophils phagocytose the organisms by forming phagolysosomes. There the organisms are killed by an oxygendependent mechanism (respiratory burst) which involves the production of hydrogen peroxide, hydroxyl radicals, and singlet oxygen. An oxygen-independent response utilizes highly toxic cationic proteins and enzymes, such as myeloperoxidase and lysozyme.

COMPLEMENT

EOSINOPHILS

The complement system consists of at least 20 serum glycoproteins which are triggered by an enzymatic amplifying cascade.179 The classic pathway is activated by antigen–antibody reactions, the alternative pathway by bacterial polysaccharides. The more recently identified lectin pathway involves the interaction of microbial carbohydrates with mannose-binding proteins. At the very end of all three pathways C3 becomes activated, finally resulting in the release of a variety of immunologically active substances. The C3 cleavage product C3b binds to microbes, enhancing the phagocytosis of cells expressing receptors for C3b. In addition, complement components bind to antigen–antibody immune complexes, which help complement receptor-bearing antigen-presenting cells to target these immune complexes. C5b, C6, C7, C8 and C9 form the membrane-attack complex, which causes cell death by forming pores in the cell membrane. C5a attracts neutrophils and in concert with C3a and C4a, the so-called anaphylatoxins, induces the release of inflammatory mediators from mast cells. The complement system, however, is not only activated in a complex fashion but also tightly regulated. In contrast to microbes, human cells express the complement receptor type 1 (CR1, CD35), decay-accelerating factor (DAF, CD55) and membrane co-factor protein (MCP, CD46) which stop progression of the complement cascade. CD59 is a protein that binds to C8 and inhibits the insertion of C9 into the cell membrane.

Protection of the host from infections by parasites is the major function of eosinophils.181 Infections by parasites induce the production of antigen-specific IgE antibodies which bind to the parasite. Eosinophils bind to the IgE antibody via their lowaffinity receptors (FcεRII, CD23) and thus become activated. They release toxic products including major basic protein, eosinophilic cationic protein, eosinophil peroxidase and eosinophilderived neurotoxin which ultimately kill the parasites. In addition, eosinophils can be the source of prostaglandins, leukotrienes and various cytokines. Eosinophils play an important role in allergic reactions, the value of which in the defense scenario is still unclear.

Macrophages are phagocytic cells derived from blood-borne monocytes. Macrophages can discriminate between foreign and self molecules by expressing receptors for carbohydrates usually not expressed on vertebrate cells. Macrophages carry also recep-

Basophils and mast cells are closely related and share functional and morphologic characteristics. Basophils occur in the blood, while mast cells are found in the tissue. Connective tissue mast cells contain both trypsin and chymotrypsin, whereas mucosal mast cells contain only trypsin. Cutaneous mast cells express the receptor for the anaphylatoxin C5a (CD88) which results in cutaneous, but not systemic, reactions.182 In addition, both basophils and mast cells express the high-affinity receptors for IgE (FcεRI). Basophils and mast cells play an important role in immediate allergic reactions such as anaphylaxis and angioedema. Binding of a specific antigen to mast cell-bound IgE activates the FcεRI, which finally results in degranulation and release of preformed mediators, including primarily histamine and serotonin, but also prostaglandins, leukotrienes B4, C4, D4 and E4 and plateletactivating factor. This enhances vascular permeability, broncho­ constriction and induction of an inflammatory response.

179. Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344: 1058–1066. 180. Kantari C, Pederzoli-Ribeil M, Witko-Sarsat V. The role of neutrophils and monocytes in innate immunity. Contrib Microbiol. 2008;15: 118–146.

181. Hogan SP, Rosenberg HF, Moqbel R, et al. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy. 2008;38: 709–750. 182. Metz M, Siebenhaar F, Maurer M. Mast cell functions in the innate skin immune system. Immunobiology. 2008;213:251–260.

MACROPHAGES AND NEUTROPHILS

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NATURAL KILLER CELLS

ADAPTIVE IMMUNE RESPONSE The hallmark features of an adaptive immune response are specificity and memory which results in improvement of the response with each successive encounter with the same antigen. The initial critical process during the generation of an adaptive immune response is antigen presentation.

ANTIGEN-PRESENTING CELLS A variety of cells can present antigens. This depends on where and how the antigen first encounters cells of the immune system. The most effective antigen-presenting cells (APCs) are interdigitating dendritic cells (DCs) located in the T cell areas of the spleen and lymph nodes. Epidermal Langerhans cells (LCs) were the first APCs found in the skin.184 Later it turned out that the dermis also harbors DCs.

Langerhans cells

ADAPTIVE IMMUNE RESPONSE

The major targets of natural killer (NK) cells are either infected or malignant cells. NK cells express Fc receptors which bind IgG (FcγRIII, CD16) and thus can adhere to and kill cells coated with IgG (antibody-dependent cellular cytotoxicity, ADCC). NK cells can also recognize targets via killer-activating and killerinhibitory receptors. Killer-activating receptors recognize a number of molecules present on the surface of normal nucleated cells, giving the signal to kill the target cell by secretion of perforins, injection of granzymes which finally results in apoptosis. NK cells also recognize major histocompatibility complex (MHC) class I molecules which shuts off the killer signal.183 Thus, only foreign cells are attacked. Figure 1.41  In situ staining of Langerhans cells. Sheets of murine skin were stained with an antibody directed against MHC class II (green fluorescence) and an antibody directed against langerin/CD207 (red fluorescence). Dendritic cells staining positive with both antibodies represent Langerhans cells.

hematopoietic marker CD45, MHC class II antigens (HLA-DR), CD1a, S-100 protein, vimentin and Langerin. CD1a is the most useful marker for detecting human LCs, since within the epidermis it is exclusively expressed on LCs both in normal and inflamed tissue. But it is not expressed on murine LCs. In addition, LCs express the high-affinity IgE receptor (FcεRI), which was initially thought to be exclusively expressed on mast cells and basophils. It remains to be determined at which maturational stage LCs enter the epidermis. Furthermore, the mechanisms which regulate homing of LCs into the epidermis are quite unclear. In contrast to the previous hypothesis of a constant repopulation of LCs from the bone marrow, there is recent evidence that under steady-state conditions, LCs are maintained locally. But cutaneous inflammatory processes may cause their replacement by blood-borne LC progenitors. This recruitment appears to depend on the CCR2 chemokine receptor and on the secretion of CCR2binding chemokines.

In 1886, Paul Langerhans first described the LCs as DCs within the epidermis. Because of their dendritic shape (Fig. 1.41), Langerhans postulated the cells to be of neural origin. It took more than 100 years to show that they are derived from bone marrow. However, 15 years later it was discovered that LCs are intimately associated with nerve fibers which through the release of neuropeptides such as calcitonin gene-related peptide can influence the function of LC. LCs can only be identified by electron microscopy or histochemical analysis. Ultrastructurally, LCs harbor characteristic rod-shaped organelles, the Birbeck granules. Langerin, a Ca2+-dependent lectin with mannose-binding specificity, associates with Birbeck granules and even induces their formation. Generation of Birbeck granules may be a consequence of the antigen-capture function of Langerin, which allows routing of antigen into these organelles and provides access to a non-classical antigen-processing pathway. Histochemically, human LCs can be visualized by staining for adenosine triphosphatase. Antigenic moieties constantly present on human LCs and thus suitable for staining include the pan­

In extracutaneous sites and organs, other DCs are responsible for antigen presentation. DCs are defined as professional APCs, which exert an extraordinary capacity to stimulate naïve T cells and to initiate a primary immune response.185 This unique ability was initially described for the interdigitating DCs in the spleen. Meanwhile, it has become clear that the DC system is much more complex. This complexity is based on the phenomenon that DCs can arise from different types of progenitor cells and that in turn, different functional phenotypes of DCs can be generated from the same precursor cell.186 In addition, differences between the human and murine system exist.

183. Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med. 2000;343:37–49. 184. Schwarz T. Immunology. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. London: Mosby, Elsevier; 2008:63–79.

185. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–252. 186. Ardavin C. Martinez del Hoyo G, Martin P, et al. Origin and differentiation of dendritic cells. Trends Immunol. 2001;22:691–700.

Other dendritic cells

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There is evidence that at least in the murine system, spleenderived CD8α+ DCs induce Th1 responses, while CD8α− DCs favor Th2 responses. In contrast, in the human system, lymphoid/plasmacytoid DCs were found to induce Th2 responses, and myeloid DCs generated immune reactions of the Th1 type. Consequently, myeloid DCs were referred to as DC1 and lymphoid/plasmacytoid DCs as DC2. On the other hand, the outcome of an immune response appears also to depend on the state of maturation of the stimulating DC and the cytokine environment. The induction of a Th1 response is critically dependent on the presence of IL-12. DCs seem to produce IL-12 immediately after activation, driving T cells into a Th1 phenotype if T cells meet the DCs at this stage. At later time points, the production of IL-12 decreases, thereby favoring the development of a Th2 response. This concept suggests that the maturational state of the DC at which antigen presentation takes place determines the final type of immune response. According to this line, immature DCs induce tolerance due to an incomplete T cell activation and the final result is T cells of the regulatory type which suppress the immune response.

Antigen presentation For sensitization, antigens must be presented to the lymphocytes by APCs. Initially, LCs were thought to play the crucial role in the presentation of antigens which enter the skin. This assumption was supported by the observation that contact sensitization could not be induced in skin areas which were devoid of LCs or in which LCs had been depleted, e.g., by ultraviolet radiation. However, transgenic mouse models in which LCs can be depleted in a very specific fashion provided clear evidence that sensitization through the skin is possible even in the absence of LCs.187 Thus, other APCs, most likely dermal DCs, have to replace LCs. It was even proposed that the major function of LCs is the downregulation of immune responses, whereas sensitization within the skin is mostly driven by dermal dendrocytes. LCs may act in both ways, maybe tolerogenic when they present antigens under steady-state non-inflammatory conditions, but sensitizing upon stimulation by inflammatory mediators. The regional lymph nodes are the places where antigen presentation to lymphocytes takes place. Cutaneous DCs actively take up antigens, leave the skin triggered by inflammatory cytokines and migrate to the draining lymph nodes. During emigration, APCs change their phenotypic and functional behavior to become mature DCs.

Antigen presentation to T cells In contrast to B cells, T lymphocytes are unable to recognize soluble protein antigens per se since the T cell receptor (TCR) can only recognize antigen-derived peptides which are bound to MHC locus-encoded molecules expressed on APCs. CD4+ T cells recognize antigens in association with MHC class II molecules, while CD8+ T cells recognize antigens in association with MHC class I molecules.183

187. Bennett CL, Clausen BE. Dendritic cell ablation in mice: promises, pitfalls, and challenges. Trends Immunol. 2007;28:525–531.

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Antigens can be loaded on to MHC molecules in two ways. Antigens having been produced endogenously within the cell (e.g., viral or tumor proteins) are complexed with MHC class I molecules through intracellular processing pathways.188 The proteasome degrades these antigens to peptides with a predominant length of 8–12 amino acid residues. These peptides are imported into the endoplasmic reticulum in a TAP (transporter associated with antigen processing)-dependent manner and loaded on to MHC class I molecules. Finally, peptides bound to a MHC class I-β2 microglobulin complex are transported to the cell surface via the Golgi apparatus. As the vast majority of nucleated cells express MHC class I molecules, many cell types can serve as APCs for MHC class I-restricted antigen presentation in a secondary immune response. In contrast, MHC class II-dependent antigen presentation targets exogenous antigens and is critically dependent on DCs. Exogenous antigens are taken up via macro- or micropinocytosis or via receptor-mediated endocytosis, e.g., via DEC-205 receptor (CD205). Proteins are degraded in the endo-/lysosomes to peptides consisting of 15–22 amino acid residues. The peptide fragments enter specialized endosomal compartments containing MHC class II molecules which are generated in the endoplasmic reticulum. Newly synthesized MHC class II molecules are associated with an invariant chain which inhibits dissociation of empty MHC class II molecules and transports the MHC class II complex from the endoplasmic reticulum to the specialized endosomal compartments. Here the molecules can interact with the antigen peptide fragments. The invariant chain is cleaved by proteases into a small fragment called CLIP (class II-associated invariant peptide) which binds to the class II molecule. Upon interaction with the antigenic peptides, the CLIP fragment is released from the complex. Finally, the MHC class II molecule with the bound antigen peptide is expressed on the cell surface allowing antigen recognition by T cells which carry the appropriate TCR. In general, MHC class I molecules present self- or pathogenderived antigens that are synthesized within the cell to CD8+ T cells, whereas exogenous antigens derived via endocytic uptake are loaded on to MHC class II molecules for presentation to CD4+ T cells. However, some DCs may be also able to process exogenous antigens into the MHC class I pathway for presentation to CD8+ T cells. Through this mechanism, called crosspresentation, DCs can induce either tolerance (to self-antigens) or immunity (to exogenous pathogens).

T CELLS Stem cells from the bone marrow constantly migrate into the thymus where T cells develop.189 In contrast to antibodies which function as the antigen receptors on B cells and which recognize antigens in their naïve form, the α/β TCR recognizes only short peptide fragments which are generated during antigen processing in the APCs (see above). The processed antigens are presented to the TCR by MHC molecules on the cell surface. Hence, the amino acid sequences recognized by the TCR derive from the

188. Parkin J, Cohen B. An overview of the immune system. Lancet. 2001; 357:1777–1789. 189. Kruisbeek AM. Regulation of T cell development by the thymic microenvironment. Semin Immunol. 1999;11:1–2.

Structure and function of the skin

antigenic peptide as well as the MHC molecule. Thus, the TCR recognizes its own MHC molecules together with peptides derived from foreign antigens. Since the MHC molecules are highly polymorphic, only T cells which recognize their own MHC molecules (but are not autoreactive) can become activated during antigen presentation. To fulfill this requirement, T cells bearing the α/β TCR are subjected to a complex selection process within the thymus which involves both positive and negative selection.

an appropriate TCR, these immature T cells exhibit the capacity to recognize antigenic peptides associated with either MHC class I or MHC class II molecules because of their double-positive stage. During maturation, either CD4 or CD8 is lost, resulting in single-positive CD4 or CD8 T cells which can then recognize a peptide presented only by MHC class II or MHC class I molecules.

T cell development

The hallmark feature of an adaptive immune response is the recognition of specific antigens. This can be achieved either by antibodies during a B cell response or by the TCR during a T cell-mediated response. T cell receptors are transmembrane molecules consisting of α/β or γ/δ heterodimers. The vast majority of T cells belong to the α/β type, while γ/δ T cells represent not more than 10% of the total population.







T cell receptor

Diversity of T cell receptors An amazing feature of the immune system is its ability to offer specific receptors for any possible antigen. Calculations predict that B cells should be capable of producing approximately 1015 different antibody variable regions and T cells a comparable number of TCR variable regions. Surprisingly, this enormous amount of proteins is encoded by fewer than 400 genes. A unique recombination process which cuts, splices, and modifies variable-region genes makes this tremendous diversity possible.183 Four segments of genes called the variable (V), diversity (D), joining (J), and constant (C) regions are involved in receptor formation. In contrast to the TCRβ and the TCRδ loci, the TCRα and the TCRγ loci do not contain D segments (Fig. 1.42). The segments are cut out by nucleases and spliced together by ligases,



Recombination





C J

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Recombination CD8+ T cell

CD4+ T cell

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ADAPTIVE IMMUNE RESPONSE

Within the cortex of the thymus developing T cells engage MHC complexes on thymic DCs. Only when recognizing the MHC molecules via their TCR, they survive (positive selection). If not, the cells die by apoptosis. It is more than 95% of the developing T cells which die at this stage in the thymus since they are useless because of their inability to recognize their own MHC molecules. Those T cells which express a TCR with a high affinity for the complex of a self-peptide plus a self-MHC molecule are also eliminated by apoptotic cell death since they later would react with self antigens and thus are potentially harmful (negative selection). Hence, positive and negative selection allow the survival only of those T cells which will recognize foreign but not self peptides but only in the context of self-MHC molecules. This prevents auto-attack. A variety of surface molecules are switched on and off during thymic education. CD4 and CD8 molecules together with the components of CD3 form an essential backbone of the TCR complex. Usually CD4+ T cells act as helper T cells recognizing antigens presented by MHC class II molecules, whereas CD8+ T cells are in general cytotoxic and recognize antigens in association with MHC class I molecules. In their early stage of development, T cells express both CD4 and CD8. Upon expression of

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Figure 1.42  Types of antigen presentation. Antigens are presented by antigen-presenting cells to the T cell receptor of CD4+ or CD8+ T cells in association with either MHC class II or MHC class I molecules. The diversity of the T cell receptors is generated by gene rearrangement. For reasons of clarity, the simplified gene rearrangement of the α chain is shown only in the CD4+ T cell, that of the β chain in the CD8+ T cell. aa, amino acids; β2m, β2-microglobulin; V, variable; D, diversity; J, joining; C, constant. (Adapted from Modlin RL. Lymphocytes. In: Freedberg IM, Eisen AZ, Wolf K, et al. (eds). Fitzpatrick’s dermatology in general medicine. Vol. 1. New York: McGraw-Hill; 1999.)

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which determines the final gene sequence which encodes the receptor molecule. The tremendous diversity is explained by the multiplicity of all these regions within the genome (V ≈ 70–80 genes, D ≈ 25 genes, J ≈ 60 genes), but only one of each is needed for a particular TCR. Any one of the genes can join with any other one to form the final VDJ region, thereby ensuring the tremendous diversity. Among these numerous T cells, only a tiny minority will become functional over a lifetime, whereas the vast majority will die without ever having met their antigens. Defects in the recombination-activating genes RAG-1 and RAG-2 which encode two of the enzymes mediating the recombination of variable-region genes in both B cells and T cells cause a severe combined immunodeficiency, since the affected patients are unable to produce lymphocytes expressing functional antigen receptors.

Antigen-presenting cell

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ADAPTIVE IMMUNE RESPONSE

T cell receptors are associated with the CD3 complex. This complex consisting of CD3γ, CD3δ, two molecules of CD3ε and a disulfide-linked ζ chain homodimer is crucial for the transmission of the signals when antigens bind to the specific TCR.190 Upon binding to the peptide-MHC complexes, the TCRs become cross-linked. The aggregation of the TCRs causes phosphorylation of tyrosines in the cytoplasmic tails of the CD3 complex (Fig. 1.43). Phosphorylation involves kinases such as p56ick, p59fyn, and ZAP-70. Activation also involves binding of p56ick to the cytoplasmic tails of CD4 and CD8. These events finally induce the transcription of certain genes which encode cytokines and which induce cellular proliferation and differentiation.

Costimulatory signals Signaling by the TCR alone, however, does not suffice to activate T cells. Involvement of costimulatory signals is essentially required.191 Only upon these costimulatory signals T cells expand in an antigen-specific and clonal fashion (Fig. 1.44). Hence, two signals are required. The first is the interaction of the TCR with peptide–MHC complexes presented by the APC. This determines the specificity of the immune response. The second signal is provided by surface molecules and cytokines which promote the clonal expansion of specific T cells and their differentiation into effector and memory cells. Without this second event, signaling by the antigen receptors alone will either cause anergy (nonreactivity) or apoptotic cell death. The best characterized costimulators for T cells are B7–1 (CD80) and B7–2 (CD86). Both molecules are induced on immature, resting APCs by cytokines including TNFα, IL-1 or by lipopolysaccharide. The CD28 receptor on T cells recognizes the B7 molecules and delivers activating signals, including the expression of anti-apoptotic genes and the production of cytokines like IL-2. CTLA-4 (CD152) also binds to the B7 molecules but, unlike CD28, downregulates IL-2 production and cell cycle progression. In turn blockade of CTLA-4 signaling prolongs T cell activation, indicating CTLA-4 as a negative regulatory T cell-associated molecule.

190. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med. 2000;343:108–117.

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CD4+ T lymphocyte Nucleus

Figure 1.43  T cell receptor-mediated signal transduction. Activation of the T cell receptor by presentation of the appropriate antigen by antigen-presenting cells in association with MHC molecules induces a complex signal transduction cascade. The T cell receptor-associated signal transduction is primarily mediated by the CD3 complex and the ξ chain. Upon activation, the cytoplasmic tails of these molecules become phosphorylated by protein kinases (p56lck, p59fyn, ZAP70). This causes downstream signaling which ultimately leads to transcriptional activation of particular genes. Additional stimuli are provided by the signaling of costimulatory molecules (CD2, ICAM-1, CD28). DAG, diacylglycerol; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C. (Modified from Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd edn. London: Mosby, Elsevier; 2008, with permission.)

Cytokines, in particular inflammatory mediators like IL-1, IL-6, and TNFα, also provide costimulatory signals by themselves but also upregulate costimulatory molecules. Hence, a T cell is much more likely to be activated if it encounters its specific antigen presented by an APC which has been exposed to an inflammatory environment.

Clonal expansion If a T cell recognizes its specific peptide in association with the appropriate MHC molecules and, in addition, becomes activated by costimulatory signals, it divides and expands clonally. Some of the activated T cells remain in the lymph nodes and function there as central memory cells. Memory T cells have a much longer life span than effector cells and express the surface molecule CD45RO, while naïve T cells express CD45RA. Human memory T cells can be divided into two further subsets, CCR7+ and CCR7- memory T cells. CCR7+ memory cells stay in the lymph nodes due to the expression of lymph node homing receptors and thus are called central memory T cells (TCM). They

191. Tamada K, Chen L. T lymphocyte costimulatory molecules in host defense and immunologic diseases. Ann Allergy Asthma Immunol. 2000;85:164–175.

Structure and function of the skin

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Figure 1.44  Role of costimulatory molecules during T cell activation. Presentation of the antigen by antigen-presenting cells to the T cell receptor in association with MHC molecules delivers the first signal necessary for T cell activation. The second signal is provided by the interaction of costimulatory molecules present on APC and T cells. An antigen-specific response is only induced when signal 1 and signal 2 are provided. Presentation of the antigen in the absence of signal 2 does not lead to an antigen-specific response but induces anergy and tolerance, respectively. APC, antigen-presenting cell; CSM, costimulatory molecule; MHC, major histocompatibility complex; TCR, T-cell receptor. (Modified from Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd edn. London: Mosby, Elsevier; 2008, with permission.)

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do not display effector function, but efficiently stimulate DCs for IL-12 production and can differentiate into CCR7- effector cells upon secondary stimulation. CCR7- memory cells express receptors for migration into inflamed tissues, exert immediate effector function and thus are called effector memory cells (TEM). Memory T cells react rapidly when they reencounter their specific antigen. The vast majority of these cells up-regulate receptors enabling them to leave the lymphoid tissue. Organ-specific adhesion molecules guide these cells to various locations, including the skin. The majority of human T cells in the skin express the α/β TCR, are either CD8 or CD4 positive, express CD2 and CD5 and have the memory phenotype CD45RO+/CD45RA−.192

Effector function of T Cells Effector T cells comprise to major subtypes, CD4+ T helper (Th) cells and CD8+ cytotoxic T (Tc). CD8+ Tc cells are mostly responsible for antiviral and antitumor responses.190 CD4+ Th cells play a major role in recognizing foreign antigens and activate other components of the cell-mediated immune response to eliminate these pathogens. They are also crucially involved in activating B cells.

Mph

PC

Cell-mediated immunity

Humoral immunity

Figure 1.45  Development of the Th1 and Th2 responses. Th1 and Th2 cells can differentiate under the influence of cytokines which are secreted by various ) bystander cells. Cytokines can act in a stimulatory (→) and inhibitory ( fashion. Th1 cells are crucial for T cell-mediated immunity, while Th2 cells support the development of humoral immunity. DC, dendritic cell; Eo, eosinophil; MC, mast cell; Mph, macrophage; NK, natural killer cell; PC, plasma cell; IL, interleukin; IFN-γ, interferon-γ. (Adapted from Modlin RL. Lymphocytes. In: Freedberg IM, Eisen AZ, Wolf K, et al., eds. Fitzpatrick’s dermatology in general medicine. Vol. 1. New York: McGraw-Hill; 1999; 32.)

T helper cells express CD4+ and recognize the specific antigenic peptides in association with MHC class II molecules. Several subtypes of Th cells have been described primarily based on differences in the secretion of cytokines.193 The precursor cell Th0 releases a multitude of different cytokines (IL-2, IFNγ, TNFβ, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, GM-CSF, TNFα).

During development into either a Th1 or Th2 cell, the cytokine secretion pattern changes and becomes more restricted and specific (Fig. 1.45). Th1 cells: Typical Th1 cytokines are IFNγ, TNFβ and IL-2, whereas Th2 cells are typified by the secretion of IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13. Since there are no specific surface markers for either Th1 or Th2 cells, the cytokine secretion pattern is still the best parameter for differentiating Th1 from Th2 cells. Th1 cells produce IL-2, which in turn induces proliferation of CD4+ cells but also stimulates CD8+ T cell division and cytotoxicity, thereby providing help for CD8 cells.

192. Robert C, Kupper TS. Inflammatory skin diseases, T cells, and immune surveillance. N Engl J Med. 1999;341:1817–1828.

193. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138–146.

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The other major cytokine released by Th1 cells is IFNγ which induces NK cells and activates macrophages to kill intracellular pathogens. Thus, Th1 cytokines preferentially induce a cell-mediated inflammatory response, e.g., the granulomatous lesions of tuberculosis or leprosy. IFNγ stimulates macrophages to release huge amounts of IL-12 that triggers Th0 cells to develop into Th1 and inhibits Th2 differentiation, providing a kind of positive feedback loop. A Th1 response, however, has not necessarily to be beneficial since Th1 cells can also contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Th2 cells: Th2 cells produce primarily IL-4, IL-5, IL-6 and IL-10. These cytokines favor antibody production. IL-4 switches B cells to produce IgE and IL-5 promotes the growth of eosinophils. Thus, a Th2 response is often associated with allergic reactions. Comparable to the role of IL-12 in the Th1 response, IL-4 provides positive feedback for further Th2 responses and suppresses Th1 differentiation. IL-10, another Th2-derived cytokine, inhibits the development of a Th1 response. Whether an immune response tends to drift into either a Th1 or Th2 type is tightly regulated. The cytokine profile and balance induced by the antigen is critical. Other factors that influence the Th1/Th2 decision include the dose of the antigen, the APCs involved and the cytokines secreted from these cells, the genetic background of the host and the presence of costimulatory molecules. On the other hand, immune responses are not always strongly polarized. Th3 cells: Th3 cells are another type of CD4+ Th cell which were detected in the model of oral tolerance. They primarily secrete TGFβ, provide help for IgA production and exert suppressive properties against both Th1 and Th2 cells. Since Th3 cells are triggered in an antigen-specific fashion but suppress in an antigen-non-specific manner, they share some features of regulatory T cells. Th17 cells: Recently a further subset of T helper cells has been described which has been designated as Th17 cells since they release IL-17.194 In the murine system Th17 cells develop from Th0 cells in the presence of TGFß and IL-6. In the human system IL-23, a cytokine closely related to IL-12, sharing the same p40 subunit, is crucial for the induction of Th17 cells. There is good evidence for an important role of the IL-23/IL-17 axis in the development of autoimmune diseases which were initially thought to be driven by Th1 cells. Among many other activities, Th17 cells appear to be involved in mediating allergic contact dermatitis.

Cytotoxic T cells Cytotoxic T (Tc) cells express CD8+, recognize the specific antigenic peptides in association with MHC class I molecules and are directly cytotoxic to cells which bear the antigen, e.g., virally infected cells or tumor cells. Tc cells bind to the peptide–MHC complex and subsequently kill the cell via at least two different mechanisms.195 First, Tc cells via perforins induce pores in the membrane through which granzymes are released finally result-

194. Romagnani S. Human Th17 cells. Arthritis Res Ther. 2008;10:206. 195. Shresta S, Pham CT, Thomas DA, et al. How do cytotoxic lymphocytes kill their targets? Curr Opin Immunol. 1998;10:581–587. 196. Beissert S, Schwarz A, Schwarz T. Regulatory T cells. J Invest Dermatol. 2006;126:15–24.

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ing in induction of apoptosis. Second, Tc cells can activate the death receptor Fas (CD95) on the target cell by expressing the cognate death ligand FasL (CD95L). Similar to Th0 cells, Tc0 cells can develop into Tc1 and Tc2 cells. Tc1 and Tc2 cells can be differentiated by their different cytokine secretion patterns. However, these subtypes have a limited cytokine repertoire and their functional roles still remain to be determined.

Regulatory T cells More than three decades ago, a subpopulation of T cells was proposed, which suppress an immune response. Most convincing evidence for the existence of these cells which were called T suppressor cells was provided by adoptive transfer experiments in which suppression could be transferred in an antigen-specific manner. However, the phenotype of these cells and the molecular mechanisms underlying the suppression were only poorly characterized. Consequently, the term T suppressor cells was almost banned and the entire concept of suppression drawn into question.196 Immunologic unresponsiveness and peripheral tolerance were explained mostly by passive phenomena, such as clonal deletion, clonal anergy and immunologic ignorance. The entire subject was resuscitated by the observation that chronic activation of both human and murine CD4+ T cells in the presence of IL-10 induced CD4+ T cell clones which produced high levels of IL-10, low levels of IL-2 and no IL-4. These antigen-specific T cell clones suppressed the proliferation of CD4+ T cells in response to antigen, and prevented T cell-mediated colitis in SCID mice. This CD4+ T-cell subset was designated T regulatory cells 1 (Tr1). Another subset of CD4+ regulatory T (Treg) cells is characterized by the constitutive expression of the α chain of the IL-2 receptor (CD25). CD4+CD25+ Treg cells are generated in the thymus and are supposed to mature upon re-encountering their antigen in the periphery. CD4+CD25+ cells may play a crucial role in preventing autoimmunity since thymectomized mice which do not generate CD4+CD25+ T cells develop autoimmune diseases.197 In turn, the development of the autoimmune phenomena can be prevented by reinjection of these cells. The transcription factor Foxp3 appears to be a key regulatory gene for the development of Treg. There is also evidence for the existence of Treg cells within the CD8+ subpopulation of T cells. Recently, it was proposed that immature DCs may be involved in inducing human Treg cells. Upon repetitive stimulation with immature DCs, allogeneic CD4+ T cells differentiated into nonproliferating, IL-10-producing T cells expressing the negative regulatory molecule CTLA-4. In coculture experiments, these T cells inhibited the antigen-driven proliferation of Th1 cells in a cell contact-dependent manner. The same may apply for damaged APC since it was shown that LCs damaged by UV radiation support the generation of UV-induced Treg. Thus, immature and mature DCs induce different types of T cell responses: mature DCs induce inflammatory Th1 cells, immature or damaged DCs IL-10-producing Treg cells. These

197. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–562.

Structure and function of the skin

Natural killer T cells Natural killer (NK) T cells share the characteristics of T cells as well as NK cells. They express the NK marker NK1.1 and an invariant TCR restricted to class I MHC molecules (CD1d). Since they are present at the early stages of ontogeny in the thymus, they are supposed to be involved in the differentiation of various T cell subsets including Th2 and Tr1 cells. NK T cells are numerically and functionally deficient in mice with autoimmune diseases, implying a role of NK T cells in controlling autoimmunity. NK T cells also seem to play a role in UVinduced immunosuppression in that they down-regulate tumor immune responses.

γ/δ T cells A much smaller proportion of T cells carry a TCR composed of γ and δ protein chains. However, in certain infectious diseases such as leprosy and leishmaniasis, γ/δ T cells can account for almost one-third of the T cells infiltrating the skin. Their detailed functional role still remains to be determined but they may be involved in the recognition of non-peptide moieties expressed on microbial pathogens and thereby be involved in the defense against these microorganisms. Antigen recognition by γ/δ T cells appears to be independent of classical MHC molecules, although MHC-like (non-classical MHC) molecules such as CD1 may present certain antigens, preferentially lipids and glycolipids.

Lymphocyte recruitment The challenge for lymphocytes is to be at the right place at the right time to encounter the antigen. Naïve lymphocytes meet their antigens for the first time in the lymphoid organs, while memory cells have their encounters in the periphery. Naïve T cells continuously recirculate between the blood and lymphoid organs.192 Via the expression of the surface molecule L-selectin (CD62L) naïve T cells can attach to and roll on the inner surface of the high endothelial venules, specialized postcapillary venules within the lymph nodes. The venules express secondary lymphoid-tissue chemokine (SLC/CCL21) which activates T cells via

interaction with the chemokine receptor CCR7. T cells further adhere in a more tightly fashion to the venules via interaction of intercellular adhesion molecule 1 (ICAM-1, CD54) with lymphocyte functional antigen 1 (LFA-1, CD11a). Finally, T cells extravasate through the high endothelial venules into the lymph node and accumulate in the T cell-rich areas.198 They can return into the blood stream by leaving the lymph node via the efferent lymphatics. However, they are entrapped in the lymph nodes and cannot enter extranodal tissues since they lack the necessary expression of a specific combination of adhesion molecules and chemokine receptors. Upon activation by APCs presenting specific antigenic peptides, the respective T cells start to proliferate and begin to express activation molecules, thereby developing into memory T cells. They now start to express new surface molecules which allow them to exit the blood vessels and enter extranodal tissues. A characteristic feature of memory T cells is their ability to remember the anatomical site which the lymph node was draining. Due to the expression of tissue-specific adhesion molecules, they exhibit the capacity to migrate primarily into those sites where the antigen was first met. Hence, lymph nodes draining different organs generate distinct, ‘tissue-specific’ memory T cells. Some 10–20% of all memory T cells home to the skin due to the expression of a glycoprotein called cutaneous lymphocyte antigen (CLA).192 CLA is generated by modification of the pre-existing protein P-selectin glycoprotein ligand 1 (PSGL-1, CD162) by glycosylation enzymes. Memory T cells entering the skin express CLA, while memory T cells found in other tissues are primarily CLAnegative. CLA allows the early tethering of T cells to the endothelium of cutaneous postcapillary venules. This finally results in slowing, arrest, and extravasation of the T cells. The ligand for CLA is E-selectin (CD62E) which is constitutively expressed at low levels on cutaneous microvessels. Its expression is strongly upregulated by inflammatory stimuli. Although interaction between CLA and E-selectin is the initial step, the interaction of LFA-1 (CD11a) and the β-integrin very late antigen 4 (VLA-4) with ICAM-1 (CD54) and VCAM-1 (CD106), respectively, is required for extravasation of T cells from the blood into the skin.

ADAPTIVE IMMUNE RESPONSE

observations support the concept of a constant control of peripheral tolerance to self-antigens. In this scenario, immature DCs permanently take up proteins from normal cells undergoing regular cell turnover. Since no inflammatory signals are present, DCs do not mature and therefore enter the regional lymph nodes in an immature stage. Treg cells recognize the self-antigen expressed on the immature DCs and become primed Treg cells which then migrate to the respective organ where they exhibit suppressive effects. During an infection, immature DCs continue to take up the self-antigens but mature in the presence of inflammatory signals. In the regional lymph nodes, the mature DCs prime naïve CD4+ or CD8+ T cells which become effector T cells. These cells re-migrate to the initial site of inflammation. However, there they are inhibited by those Treg cells already present on site. This would inhibit development of autoimmunity under both normal and inflammatory conditions.

1

B CELLS The major task of B cells is the production of immunoglobulins which bind antigens, thereby acting as antibodies. Antibodies also interact with components of the innate immune system by activating complement and by opsonizing bacteria for phagocytosis. Immunoglobulins are secreted products of mature B cells, but during early B cell development they function as the antigenspecific B cell receptors expressed on the cell membrane, equivalent to the TCR on T cells. CD19, CD20 and CD22 are the main markers currently used to detect B cells. Activation of B cells results in cell division and maturation into plasma cells which secrete the specific antibodies.

Immunoglobulins There are five major types of immunoglobulin, namely IgG, IgM, IgA, IgD, and IgE. All immunoglobulin molecules have a similar

198. von Andrian UH, Mackay CR. T-cell function and migration. Two sides of the same coin. N Engl J Med. 2000;343:1020–1034.

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putative antigen. A typical immunoglobulin molecule is composed of two heavy chains of identical amino acid composition and two light chains of identical amino acid composition. One light chain is associated with one heavy chain by disulfide bonds, which hold them together.

Immunoglobulin M The basic structure of IgM is composed of two heavy and two light chains, but usually IgM exists in serum as a pentamer of 10 heavy chains and 10 light chains containing one J chain. Its molecular weight is about 900 000 Da, about five times heavier than IgG. IgM is the first antibody detected after antigenic stimulation, and therefore IgM constitutes the first line of antibody defense against infectious organisms. Upon binding to its antigen, IgM effectively induces agglutination and activates the classic complement pathway. Unlike IgG, IgM cannot cross the placental barrier. Its half-life in plasma is about 5 days, which is about one-tenth that of IgG and thus IgM plays little role in long-lasting immunity.

Immunoglobulin G C-terminus

Figure 1.46  Structure of a prototype immunoglobulin. The basic immunoglobulin structure consists of two identical light polypeptide chains and two identical heavy polypeptide chains, which are linked together by disulfide bonds. The antigen-binding site is at the N-terminal end. (From Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd edn. London: Mosby, Elsevier; 2008, with permission.)

structure consisting of large and small polypeptide chains.198 The large polypeptide chain is called heavy or H chain, the smaller light or L chain (Fig. 1.46). The sequence of amino acids within about three-quarters of the heavy chain determines its immuno­ globulin class (e.g., IgG). Although there are five major types of heavy chains (designated γ, µ, α, δ, and ε), there are only two major types of light chains, namely κ and λ. The light chains and the heavy chains each have long sequences of amino acids that are relatively constant for each immunoglobulin class, regardless of the antigen specificity. This portion of the immunoglobulin molecule is called the constant region and its end is called the Fc end. Phagocytes and some other cells express on their surface Fc receptors that can bind this ‘back end’ of the immunoglobulin molecule, for example, as an initial step toward phagocytosing an immune complex. The formation of antibody, the titer and immunoglobulin subclasses are highly influenced by the physical and chemical properties of the antigen, the route of application, duration, repetition and amount of the antigenic stimulus, and the individual susceptibility to recognize the antigen as foreign. The sequence of amino acids at the other end (the Fab end) of the immunoglobulin molecule is highly variable and called the variable region. Through the variable regions, antibodies recognize the conformational structure of the respective epitopes. Thus, no antigen processing is required. As is the case for the TCR, extensive gene rearrangement involving V, D and J regions allows for the generation of infinite immunoglobulins specific for any 48

Immunoglobulin G is responsible for long-lasting immunity. Of all the immunoglobulins, it is the one present in the highest concentration in plasma. There are four subclasses of IgG defined by the amino acid residue sequences of their constant region of the heavy chain. These subclasses are designated IgG1, IgG2, IgG3, and IgG4. IgG (except IgG4) can activate complement by the classical pathway. In addition, IgG1 and IgG3 bind more avidly to mononuclear cells and thus are more cytophilic. IgG can enter the fetal circulation by passing across the placental barrier in utero.

Immunoglobulin A Two subclasses of IgA exist, IgA1 and IgA2. IgA molecules can be joined by a J chain to a dimer which is mostly found in secretions, while in the serum IgA circulates primarily as a monomer. Although some IgA is present in plasma, much IgA is secreted into the respiratory tract or the gastrointestinal tract where it functions to neutralize infectious agents and toxins before they can be absorbed into the body. Therefore IgA serves as a sort of protective coating to limit attachment of these molecules to the mucosal cells of the respiratory or gastrointestinal tract. IgA cannot pass across the placental membrane and its half-life in plasma is about 6 days. Aggregated IgA activates complement by means of the alternative pathway.

Immunoglobulin E IgE consists of two heavy chains and two light chains. It is the classic anaphylactic antibody which mediates most immediate allergic and anaphylactic reactions. Very little IgE can be found circulating in plasma. The half-life is about 2 days, and the concentration of IgE in plasma is about 0.0001 that of IgG. Instead of circulating, most IgE is bound to mast cells and basophils in tissue where its half-life is much longer. Mast cells and basophils bind IgE via high-affinity receptors for the Fc portion of IgE (FcεRI). When an antigen bridges across two IgE molecules with specificity for that antigen, the entire mast cell is triggered to degranulate and release histamine, serotonin, leukotrienes and

Structure and function of the skin

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the surface of the B cell, the respective antigen gets internalized, processed, and re-expressed within the MHC class II molecule on the surface of the B cell. The B cell can then present the antigen to a primed specific Th cell. The T cell, in turn, releases cytokines (IL-2, IL-4, IL-5, IL-6) which function as B cell growth factors inducing B cell division and maturation to plasma cells which secrete the specific antibodies. Activation of CD40 expressed on B cells by CD40 ligand (CD154) expressed on T cells induces isotype switching from IgM to IgG. After this switch, some of the activated cells become long-lived memory cells which react rapidly upon reexposure to the same antigen. Defects in the expression of CD40 ligand are associated with an immunodeficiency state (X-linked hyper-IgM syndrome) characterized by elevated IgM levels but low or undetectable levels of IgG, IgA and IgE. ADAPTIVE IMMUNE RESPONSE

IgG

KERATINOCYTES AND SKIN IMMUNE RESPONSES Figure 1.47  T cell-dependent B cell activation. B cells present the antigen

in association with MHC II molecules to CD4+ T cells. This results in the upregulation of CD154/CD40 ligand which interacts with CD40 expressed on B cells. CD40–CD40L interaction causes isotype switching of immunoglobulins and upregulation of CD80/86 which interacts with CD28 expressed on T cells. This results in further activation of T cells. Ag, antigen; CD40L, CD40 ligand; Ig, immunoglobulin; MHC II, major histocompatibility complex II. (Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd edn. London: Mosby, Elsevier; 2008, with permission.)

prostaglandins. The second IgE receptor FcεRII (CD23) exhibits weaker binding affinity and is expressed on macrophages, eosinophils, platelets and particular subtypes of T and B cells. More recently, it became clear that LCs,199 dermal DCs and peripheral blood DCs as well as monocytes from atopic individuals can also express the high-affinity FcεRI and thereby bind monomeric IgE.

Immunoglobulin D IgD is present in plasma in minute quantities. IgD is found on lymphocytes especially at times early in lymphocytic development, where it functions as a cell-membrane receptor. A lymphocyte is triggered to mature and divide after the IgD molecule combines with antigen. The function of IgD in plasma, if any, is entirely unknown.

B cell activation B cells can respond to particular antigens in a T cell independent manner. Such antigens, mainly polysaccharides, exhibit numerous repeating epitopes which bind and cross-link multiple B cell receptors and activate the B cells directly to secrete IgM. However, this response is limited to IgM and is of short duration and poor specificity due to the lack of germinal center formation, immunoglobulin class switching and a generation of memory. Thus, most B cells are activated in a T cell-dependent manner (Fig. 1.47). Upon recognition by the specific IgM expressed on

Although LCs and dermal DCs are the major immunologic cells within the skin, keratinocytes also contribute to the induction of a cutaneous immune responses.184 Keratinocytes can affect LCs by the expression of specific surface molecules due to their close physical proximity. In addition, keratinocytes are able to provide immunologic and inflammatory signals by releasing soluble mediators. The first cytokine identified as being released from keratinocytes was IL-1. Subsequently, keratinocytes were shown to exert the capacity to secrete a multitude of soluble mediators. These included pro- and anti-inflammatory, immunomodulatory and immunosuppressive cytokines. Any perturbation of the skin may induce the release of these mediators by the keratinocytes. Chemicals provoking irritant or allergic reactions as well as UV radiation are such stimuli for keratinocytes to the release cytokines.

CONTACT HYPERSENSITIVITY: THE PROTOTYPE OF A CUTANEOUS IMMUNE REACTION Allergic contact hypersensitivity (CHS) is the pathogenic basis for allergic contact dermatitis, one of the most frequent inflammatory dermatoses. In addition, CHS represents a valuable immune model in which major discoveries relevant for immunology in general have been made.

Induction phase of CHS The vast majority of contact allergens are low-molecular-weight chemicals. They are also called haptens since after penetration into the skin they have to bind to host-derived proteins to become full antigens. Upon epicutaneous application to a naïve host, APCs have to take up the hapten, process it and migrate towards the regional lymph nodes, where the antigen is presented to naïve T cells (Fig. 1.48). For a long time it was thought that epidermal LCs are the most relevant and even only cells in this process. However, transgenic mouse models in which LCs can be depleted in a very specific fashion provided clear evidence that sensitization through the skin is possible even in the absence

199. Grabbe S, Schwarz T. Immunoregulatory mechanisms involved in elicitation of allergic contact hypersensitivity. Immunol Today. 1998;19:37–44.

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Figure 1.48  Induction of contact hypersensitivity. Application of contact allergens (Ag) induces the release of cytokines by keratinocytes, Langerhans cells (LCs) and other cells within the skin. These cytokines in turn activate LCs, which uptake the antigen and emigrate into the regional lymph nodes. During this process, the LCs mature into dendritic cells. In addition, the antigen is processed, re-expressed on the surface, and, finally, presented to naive T cells in the regional lymph node. Upon appropriate antigen presentation, T cells bearing the appropriate T cell receptor clonally expand and become effector T cells. These alter their migratory behavior due to the expression of specific surface molecules like CLA. Effector T cells recirculate into the periphery, where they may later meet the antigen again. Ag, antigen; CLA, cutaneous lymphocyte antigen; KC, keratinocyte; LC, Langerhans cell. (From Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd edn. London: Mosby, Elsevier; 2008, with permission.)

Neutrophils Inflammationinduced recruitment CLA+ T effector cell

Upregulation of E-selectin

Mast cells

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Figure 1.49  Elicitation of contact hypersensitivity. Application of contact allergens (Ag) into a sensitized individual causes the release of cytokines by keratinocytes and Langerhans cells (LCs). These cytokines induce the expression of adhesion molecules and activation of endothelial cells, which ultimately attracts leukocytes to the site of antigen application. Among these cells, T effector cells are present, which are now activated upon antigen presentation either by resident cells or by infiltrating LCs. Antigen-specific T cell activation again induces the release of cytokines by T cells. This causes the attraction of other inflammatory cells, including granulocytes and macrophages, which ultimately cause the clinical manifestation of contact dermatitis. Ag, antigen; CLA, cutaneous lymphocyte antigen; dDC, dermal dendritic cell; KC, keratinocyte; LC, Langerhans cell. (From Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd edn. London: Mosby, Elsevier; 2008, with permission.)

Effector phase of CHS of LCs.187 Thus, other APCs, most likely dermal DCs, can replace LCs. During the emigration, APCs convert from a resting into an activated functional state. This process is initiated by keratino­ cytes which secrete inflammatory cytokines as a result of hapten application. Activation of APCs requires induction of cytokine secretion (IL-1β, IL-6, IL-12, chemokines), enhanced cell surface molecule expression (MHC class I and II molecules, adhesion molecules, costimulatory molecules), and results in antigen uptake, processing and presentation.199 IL-1β appears to play a crucial role, the secretion of which is a direct and immediate effect of epicutaneous hapten application. This appears to be specific for haptens, since it is not observed with irritants or tolerogens. Presentation of the hapten in the regional lymph nodes causes activation of naïve T cells which carry the appropriate TCR. This finally results in the generation of effector cells. In contrast to other types of delayed type hypersensitivity responses, which are mediated by CD4+ T cells, most haptens induce a T cell response in which mainly CD8+ effector T cells are involved.199 In addition, T cell populations are induced which down-modulate the CHS response. These inhibitory T cells appear to belong to the group of regulatory T cells.

200. Grabbe S, Steinert M, Mahnke K, et al. Dissection of antigenic and irritative effects of epicutaneously applied haptens in mice. Evidence that not the antigenic component but non-specific proinflammatory effects of

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T cells which have been primed in the draining cutaneous lymph nodes start to express the skin homing marker CLA and thereby exhibit the capacity to enter the skin.192 These T cells become activated when they encounter their relevant hapten presented by APCs within the skin (Fig. 1.49). However, in contrast to the sensitization phase, antigen presentation can now be taken over by cells other than classical APCs including keratinocytes, dermal mast cells and macrophages, all of which are readily capable of presenting antigen at least in an MHC class I-restricted fashion.199 Alternatively, inflammatory cells that infiltrate the site of hapten application very early during the response may function as APCs. Although activation of antigen-specific T cells is the initial event in the elicitation of CHS, the pathophysiologic events that result in allergic contact dermatitis are caused by other cells including neutrophils, macrophages and mast cells which enter the site of elicitation. However, low doses of hapten which are sufficient to stimulate hapten-specific T cells do not suffice to elicit a CHS response. This indicates that the elicitation of a CHS response requires, in addition to hapten-specific recognition, some type of proinflammatory stimulus that appears to be provided by the hapten itself and to be quite dose-dependent.200

haptens determine the concentration-dependent elicitation of allergic contact dermatitis. J Clin Invest. 1996;98:1158–1164.

Christine E. Wittmann, Paula K. Rauch and Michael S. Jellinek

INTRODUCTION Children with dermatologic complaints are seen by pediatricians and dermatologists in settings characterized by large numbers of patients, short individual visits, and many weeks elapsing between appointments. An estimated 60% of patients in a pediatric dermatology clinic are seen only once.1 Clinicians are under pressure to keep the flow of patients moving. They must contend with restless patients and families in the waiting room, unexpectedly lengthy office procedures, and unscheduled visits. Insurance reimbursements reward short, frequent visits over lengthier encounters. All of these factors may encourage the pediatric dermatologist to focus attention more on the parade of dermatologic lesions, with little attention to psychosocial considerations. In this chapter, we discuss how an understanding of psychosocial issues can potentially increase efficiency, enrich practice, and improve the quality of care. We will present clinical vignettes that illustrate how a developmental understanding can aid effective diagnosis and treatment, leading to better clinical outcomes, and a more satisfying clinical encounter, for doctor, patient, and parent alike. Larry is a cherubic, 4 1 2-year-old boy, who presents in the clinic with two warts on his hand and one on his foot. Quick cryosurgical treatment with liquid nitrogen is planned. As Larry enters the examining room, the dermatologist notices he is looking increasingly frightened. The doctor smiles. He makes an effort to cheer Larry up by splashing liquid nitrogen over the office floor. As the smoke rises off the carpet, Larry begins to wail. He desperately tries to squirm off his mother’s lap. The doctor and Larry’s mother try unsuccessfully to hold Larry still. They struggle to pry open his fist in order to apply the liquid nitrogen. Neither the doctor’s reassurances nor Larry’s mother’s promises of candy seem to help. The procedure takes three times as long as anticipated and fewer than the optimum number of applications are administered to the warts. On a chance meeting with the primary pediatrician, the dermatologist learned Larry had had several nightmares following the wart removal. To understand why this treatment resulted in a losing battle, it is helpful to view the same appointment through Larry’s

1. Schachner L, Ling NS, Press S. A statistical analysis of a pediatric dermatology clinic. Pediatr Dermatol. 1983;1(2):157–164.

2



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Psychosocial development in children with cutaneous disease

4 1 2-year-old eyes. To him, adults, like the dermatologist, have superhuman powers far exceeding his cognitive understanding. Although the powers are reassuring when an adult is protecting him, the same imagined powers become frightening when Larry feels threatened by a stranger in a new setting. From his young vantage point, any injury to his body must be an angry attack directed against him. The seemingly magical smoke of liquid nitrogen reinforces Larry’s propensity to imagine scary fantasies. He imagines his hand going up in smoke, or worse his arm, or perhaps something unimaginably horrible. An adult might view this simply as Larry misbehaving, but to the 4 1 2-year-old, the possibility is real, impending, and terrifying. From his perspective, he is struggling against being badly hurt, so a fierce battle seems the appropriate response. Similarly frustrating clinical vignettes could describe a schoolage child or a teenager. Ten-year-old Doug adamantly refused to expose his psoriatic skin to the healing summer sun. The dermatologist did not know that Doug worried about being teased by his peers. In another case, Ann presented as an intelligent 14-year-old, who seemed, during her appointments, to understand her acne medication plan, yet returned every 6 weeks without having carried out the treatment at home. The physician was surprised to learn that Ann feared becoming ‘addicted’ to her antibiotics. No physician wishes to scare a young child, and noncompliant patients are time-consuming and do not benefit from their medical treatment. The compliance and satisfaction of the three patients described above could be improved by addressing the developmental concerns of the children and adolescents involved.

THE PERSONAL AND CULTURAL SIGNIFICANCE OF THE SKIN The meaning attached to the state of a person’s skin is multifaceted, ranging from a broad cultural perspective to the individual’s very personal experience. The dermatologist’s challenge is to consider the complexity of meanings and offer treatment that tries to integrate medical and psychological perspectives.2

2. Czyzewski DI, Lopez M. Clinical psychology in the management of pediatric skin disease. Dermatol Clin. 1998;6:619–629.

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The cultural significance of skin goes beyond style or beauty. Clean clear skin has long been used to symbolize purity. Skin color has been used to determine social hierarchies and justify discrimination. In the Bible, of the 10 plagues God used to punish the ancient Egyptians, only one organ system, the skin, was directly assaulted through the affliction of boils. The mass media reflect the current societal emphasis on appearance. Consumers are exposed to a barrage of advertisements for a vast array of skin care products. There are countless cleansers, moisturizers, toners, soaps, creams, powders, and pastes. They feature a multitude of ingredients: honey, oatmeal, aloe, estrogen, protein, and vitamins, to name only a few. Advertisements touting the appeal of these products used to be directed exclusively at women, but today men as consumers represent a growing proportion of the billion-dollar beauty aid industry. Adolescents, too, are spending millions on over-the-counter products to fight acne and clean, moisturize or decorate skin and hair. First impressions and attraction are often based on superficial appearance. In a study of adult psoriasis sufferers, 88% reported that the worst feature of their disease was the embarrassment caused by their appearance.3 Among patients’ most common concerns were that they would be viewed as infectious and be stared at or ostracized in social situations. Not surprisingly, the level of shame and embarrassment experienced by adolescents is even more acute. Unless physicians question patients directly about their inner experience, significant psychological morbidity is likely to go undetected. This is well demonstrated in a study of port-wine stain (facial nevus flammeus) patients who only revealed their feelings of stigmatization when asked probing questions.4 Although adolescents are particularly sensitive about how they appear to others, even younger children associate popularity with an attractive appearance.5,6 Data on children disfigured by burns7 suggest that the change in appearance seriously affects their subsequent peer relationships. Observable skin disorders cause stress for the sufferer, especially during initial meetings with others. In a large-scale, multicenter study of psychosocial adjustment in school-age children (6–12 years old) seen in pediatric dermatology clinics, children judged to have substantial alteration of their appearance by their skin condition were also more likely to show significant psychosocial distress when compared with those whose impact on appearance was rated as minimal. Furthermore, the parental ratings of impact on appearance were surprising. Nearly one-quarter of all parents indicated that their child’s appearance was affected ‘a lot’ (the highest rating) by the presenting skin condition.8 In addition to the role of appearance, or perceived appearance, subjective life experience and family environment play roles in the expression of skin conditions. In a study of children with

atopic dermatitis, increased individual stress and family discord correlated with increased symptom severity.9 Literature review suggests that psychological morbidity is a complex function of diagnosis, impact on appearance, family context, and subjective experience.10 Atopic dermatitis in childhood highlights the interplay of family or caretaker stress and psychological symptomatology in a child.11,12 When this condition interferes with an infant’s sleep, the parent’s sleep is also compromised and the result is often an irritable infant and an exhausted parent.13 More basic than the cultural or interpersonal associations, skin has primary psychological significance as the sensory organ through which the developing infant first experiences the world. It defines newborns’ boundaries as they discover their separateness from the mother and the pleasures of her touch. It signals danger in the form of pain to the inquisitive toddler exploring the environment. It is the human armor of 4 and 5 year olds who admire superheroes and fear their own vulnerability. It is the outer layer that the adolescent recognizes as ‘me’ in the mirror. It is suntanned, tattooed, scarred, and decorated. It is imbued with sexuality and intimacy. It heralds the onset of old age with telltale signs of wrinkling and discoloration, and finally loses its color in death. The skin is an integral part of every step of development. Acting in the cultural, interpersonal, and personal arenas, it is crucial to self-esteem and identity formation that individuals be comfortable in their skin. A single disorder takes on many different meanings throughout the phases of its development. Progressive phases in the development of the condition are characterized by new capacities to understand different interpersonal situations. The experience of having eczema, for example, is different at age 2, age 10, and age 17.

3. Stankler L. The effect of psoriasis on the sufferer. Clin Exp Dermatol. 1981; 6(3):303–306. 4. Lanigan SW, Cotterill JA. Psychological disabilities amongst patients with port wine stains. Br J Dermatol. 1989;121(2):209–215. 5. Porter J, Beuf AH, Nordlund JJ. Psychological reactions to chronic skin disorders: a study of patients with vitiligo. Gen Hosp Psychiatry. 1979; 1(1):73–77. 6. Dion KK, Berscheid E, Walster E. What is beautiful is good. J Pers Soc Psychol. 1972;24:285–290. 7. Molinaro JR. The social fate of children disfigured by burns. Am J Psychiatry. 1978;135(8):979–980. 8. Rauch PK, Jellinek MS, Murphy JM, et al. Screening for psychosocial dysfunction in pediatric dermatology practice. Clin Pediatr. 1991; 30(8):493–497.

9. Gil KM, Keefe FJ, Sampson HA, et al. The relation of stress and family environment to atopic dermatitis symptoms in children. J Psychosom Res. 1987;31(6):673–684. 10. Howlett S. Emotional dysfunction, child–family relationships and childhood atopic dermatitis. Br J Dermatol. 1999;140:381–384. 11. Lawson V, Lewis-Jones MS, Finlay AY, et al. The family impact of childhood atopic dermatitis: the Dermatitis Family Impact Questionnaire. Br J Dermatol. 1998;138:107–113. 12. Absolon CM, Cottrell D, Eldridge SM, et al. Psychological disturbance in atopic eczema: the extent of the problem in school-aged children. Br J Dermatol. 1997;137:241–245. 13. Pauli-Pott U, Darui A, Beckmann D. Infants with atopic dermatitis: maternal hopelessness, child-rearing attitudes and perceived infant temperament. Psychother Psychosom. 1999;68:39–45.

PSYCHOLOGICAL RESPONSES TO DERMATOLOGIC DISEASE A mild, a moderate, and a severe dermatologic condition (a small facial port-wine stain, atopic dermatitis, and epidermolysis bullosa, respectively) have been chosen to illustrate dominant developmental issues in an effort to emphasize how the age of the child alters the way an illness is experienced. Although it is now possible to treat a facial port-wine stain with laser, for many children, the resolution is not complete. Therefore, we have elected to use it as an example through childhood development, as a developmental understanding of a cosmetic problem, with or without solution, remains clinically germane. We are not suggesting that dermatologic conditions cause psychopathology, but rather that there is a wide range of responses to an

Psychosocial development in children with cutaneous disease

THE RELATIONSHIP OF INFANT AND PARENT Parental expectations of their child begin before conception. In concert with intrauterine growth, parental hopes and dreams for the unborn child are an expression of the parents’ own wishes and aspirations. They are often humorously expressed during pregnancy in discussions about the football players and doctors still in utero. The best and worst combinations of maternal and paternal family traits are considered, along with wishes for a preferred eye color, complexion, or profile. At the core of these rising hopes is the process of attachment, a biologically determined mechanism to ensure the survival of the vulnerable, dependent infant. This is symbolic of the increasing emotional attachment and the preparation for the demanding caretaking work to come. Creation of a strong and stable attachment between parent and child is critical to the wellbeing of the developing child. Children whose attachment is impaired are at higher risk for various forms of psychological disturbance and psychiatric illness, including mood and anxiety disorders.

Port-wine stain When an infant is born with any defect, regardless of how minor, it is a disappointment to the parents. Their disappointment in the child’s appearance is often transformed into blaming themselves for the child’s defect. The actual infant in front of them differs from the expectation of a perfect, imagined one. Parents’ capacity to adjust to the reality of their infant’s appearance and the extent of their disappointment is based on multiple factors related to the seriousness of the defect and to the parents’ capacities to tolerate stress and loss. An infant with a port-wine stain is likely to evoke a combination of parental feelings, including shock, embarrassment, fear, and guilt. The parents’ awareness that their child is in some way defective is exacerbated by the constant reminder of the portwine stain on the child’s face. As the parents find their attention focused on the birthmark, feelings of embarrassment are aroused. Their own disappointment about the port-wine stain raises concerns about whether other people will find their infant attractive. All physicians need to be aware of the anxiety generated by confusing medical terminology. Medical jargon should be avoided whenever possible. What is unfamiliar is likely to be frightening, so that even a ‘benign’ port-wine stain arouses potential fear. The word ‘benign,’ although intended to reassure, may be associated in a parent’s mind with a dreaded cancer. Common parental worries include potential danger to the infant’s health, the possibility of the lesion enlarging, and the concern that the nevus overlies a more serious illness. The port-wine stain on the cheek is ‘benign’ but the parental fear that it is cancer or another life-threatening condition can seriously interfere with the development of the critical process of attachment. Birth defects commonly arouse parental guilt. Regardless of the medical etiology, one or both parents may feel responsible for causing the infant’s problem. A mother may worry particu-

larly that during pregnancy her child was exposed to potentially harmful agents such as cigarettes, medication, or alcohol, and therefore feels guilty about the infant’s defect. Even a mother who tried to maintain exemplary behavior during pregnancy may have deeply held notions of how she caused her infant’s defect. The experience of disappointment and mixed feelings about the infant are often in themselves very upsetting. The parents have imagined feeling unequivocal delight at seeing their infant and instead may feel more distant than expected. The capacity to negotiate through a disappointment about the infant and the ease with which it is put into perspective will depend on the relationship between the parents, their individual maturity, and the severity of past losses or experiences. It is easier if the decision to have a child was shared equally by the parents and the anticipation during pregnancy was enjoyed together. Mutually supportive parents can more easily focus on the attributes of their joint product. Conversely, in the setting of marital discord, an imperfection in the infant’s appearance may become more ammunition for fighting. A typical scenario would be one parent blaming the other for the existence of the patch, or the more distressed parent being belittled by the other for experiencing such distress because of the defect. Parents with greater individual maturity, particularly in terms of their sense of self-worth, adapt more easily to an infant that differs from their original expectation. Parents who rely heavily on the attributes of the infant to enhance their own sense of self-worth will experience the infant’s defect in a more stresscausing manner. A parent’s own past experiences with attractiveness will affect how the infant’s facial imperfection is viewed. A parent whose childhood appearance has little memorable impact will ascribe less significance to the lesion than the parent who remembers being teased or feeling socially handicapped by, e.g., a misshaped nose or a strabismus. Lastly, the parent’s feeling about the imperfection will create the level of expectations for the dermatological treatment. Assessing the expectations of each parent and how well they accept the realities of what is possible is desirable early in the course rather than facing parental anger when expectations are not met. At the end of this section, we will discuss specific interventions that dermatologists can make to improve parental adjustment to their child’s illness.

PSYCHOLOGICAL RESPONSES TO DERMATOLOGIC DISEASE

illness that can be better understood from a developmental perspective.

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Atopic dermatitis The attachment between mother and child depends on many factors, including the five senses. The importance of the experience of touching in the development of mother–infant attachment was first highlighted in Harlow’s research with rhesus monkeys. He offered isolated newborn monkeys the choice of two types of surrogate mothers. One surrogate was made out of wire-mesh with a bottle; the other surrogate was wire-mesh covered in a soft material but without a bottle. The infants spent most of their time clinging to the soft mother and ignoring the uncovered wire-mesh mother, except at feeding times.14 This behavior challenged the earlier hypothesis that the bond of attachment occurred on the basis of satisfying hunger, and highlighted the role touch plays in attachment. Recent studies have

14. Harlow HF. Love in infant monkeys. Sci Am. 1959;200(6):68–74.

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demonstrated that rat pups who receive greater amounts of maternal touch show a more moderate response to stress in adulthood.15 Varying levels of maternal touch behaviors lead to differences in the expression of the pup’s DNA, mediated through changes in methylation patterns. As adults, rats who received more touch are less fearful and have a less pronounced hypothalamic-pituitary axis response to stress. It is easy to imagine that a red, scaly, weepy dermatitis alters the relationship between mother and infant by affecting the mother’s spontaneous touching of her infant. More spontaneous and soothing touching may be replaced by hesitancy and regimented medication applications, especially if the mother attempts to restrict scratching. Affected infants often are irritable and appear uncomfortable. This behavior challenges the mother’s confidence in her caretaking skills and can lead to feelings of inadequacy and self-doubt. Attachment is in part biologically determined, but the individual infant–mother relationship is shaped by the intensity or temperament of the infant, and the mother’s comfort with the infant’s style. In pioneering research, Chess and Thomas16 suggested that infants demonstrate variability in temperament from birth. They differ in their intensity of responses and thresholds of irritability. This variability in temperament influences the broad range of infant reactions seen with equally severe cases of atopic dermatitis. A mother’s relative comfort and ease in adaptation to her infant’s temperament allows greater leeway to accommodate stress caused by the condition. Fortunately, most mothers and infants attach well in spite of the challenges imposed by skin sensitivity. However, a combination of an infant with a difficult temperament, an irritating skin condition, and a less well-attuned mother may lead to attachment problems. A mother’s frustration, guilt, and sense of inadequacy in her mothering skills adversely affect her relationship with her infant. A stressed mother is more vulnerable to withdrawal or overinvolvement. For example, a mother may withdraw when she feels her best efforts at soothing her infant seem to result only in continued crying, believing the less she handles her infant, the happier the infant will be. At the opposite end of the spectrum, it is the over-involved mother who responds to her infant’s irritability with constant anxious attentiveness, repeatedly offering the infant food and diaper changes without waiting for or discerning the cues from the infant. The father’s role is also important during the attachment phase. Depending on how the couple divide the parenting duties, the father may be called on to negotiate the same issues previously ascribed to the mother. However, the father who assumes less of the primary caretaking role with his infant may be vulnerable to feeling excluded by the intense relationship between the mother and the infant. He may feel less important to his wife because she is focusing most of her attention on the infant. Even a mild case of atopic dermatitis may be problematic for such a father because of his increasing awkwardness in handling his infant. A willing father can be included in the caretaking process of treating the skin condition, thus offering him more involvement with both the wife and the child.

Atopic dermatitis may also exert some impact in the patient’s siblings. As atopic children need special support and dedication, their parents may spend more time and effort with sick children than with their siblings. On the other hand, atopic dermatitis is a genetic disease and healthy siblings may experience fear from the possibility of suffering the disorder in the near future. Finally, irritability affecting atopic patients may distort relations between siblings, as healthy children may be less capable to deal and sympathize with a ‘sick and nasty’ brother or sister.

15. Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7(8):847–854.

16. Chess S, Thomas A. Temperament and development. New York: Brunner/ Mazel; 1977.

Epidermolysis bullosa The birth of an infant with a potentially severely disfiguring or life-threatening disorder intensifies previously outlined parental stresses. The maternal response to an infant that may be dying can be one of distance and premature mourning, a reaction that inevitably causes severe guilt. Attachment is further inhibited when touching the infant is prevented by the risk of infection, while recurrent medical crises add the additional emotional burden of uncertainty. The postpartum period in general is a vulnerable time for maternal depression. When the infant is critically ill, the physician needs to be alert to changes that suggest the parent’s grief is evolving into a clinically significant depression. It is common for a grief-stricken individual to have some symptoms associated with depression, such as appetite loss, insomnia, and less interest in previously pleasurable activities. The parent who demonstrates persistent feelings of worthlessness, severe guilt, or difficulty functioning at home and work may be experiencing more than uncomplicated grief, and should be referred for psychiatric evaluation. The stress of a prolonged acute illness or chronic disease may become manifest in the relationship between the parents. Ideally, each parent will be emotionally available and supportive of the other in their sadness. However, rate and style of grieving is an individualized process. It is likely that the parents will use different coping styles and proceed at somewhat different rates. For example, one parent (commonly the mother) may feel the need to review repeatedly the circumstances of the infant’s illness and treatment, while the other parent may find such discussions painful and frustrating, perhaps preferring to return to work with an extra determination that comes from the grief. The risk is that one parent will feel that the other does not appreciate his or her sense of loss. Struggles can arise over whose sadness is greater or whose response is more reasonable. In some inherited forms of epidermolysis bullosa, an additional conflict can arise between the parents. The genetic responsibility can be used as a weapon by one parent against the other in marital fights. A terminally ill infant may have a profound effect on the other children in the family. Children of all ages are vulnerable to the withdrawal of grief-stricken parents. In their sadness, the parents may find it difficult to react in the usual ways to their other children’s relatively less serious daily concerns. The more support the parents have, including that from each other and from available relatives and friends, the greater the likelihood that they will have more of a reservoir to draw upon to nurture the other children in the family.

Psychosocial development in children with cutaneous disease

The role of the dermatologist The dermatologist can play an important role in facilitating parents’ adjustment to dermatologic conditions, and therefore support the crucial developmental task of attachment in infancy. By inviting the parents to ask questions, even ones viewed by the parents as silly, the dermatologist gives them permission to verbalize their mixed feelings. Explaining that it is common for loving parents also to feel disappointment, embarrassment, or distance from their infant may help the parents to recognize that such feelings are not unusual and do not make them bad parents. The physician may want to inquire specifically about whether each parent feels responsible for causing the problem; alternatively, parental guilt can be addressed indirectly by describing the etiology of the condition. Dermatologists cannot avert marital discord, but by taking a stance that is considerate of each parent’s experience of the skin disorder, they can model an attitude that will perhaps leave the infant’s condition out of the center of the marital fighting. In the event that either parent presents with clinically significant depression or there is intense marital discord, dermatologists are in a position to make a psychiatric referral because of their role as trusted caretaker of the infant. The dermatologist may also discuss a potential psychiatric referral with the infant’s pediatrician or family practitioner.

DERMATOLOGIC CONDITIONS IN PRESCHOOLERS The preschool child, 3–5 years of age, has developed a new awareness of his body and its parts. This emerging sense of self includes a pride in physical capability and fear about bodily injury. Preschoolers express many of their feelings through their imaginative play (fantasy), becoming such characters as superheroes, tea party hostesses, and wild animals. They charm adults with their uniquely unscientific explanations for why things happen and how they work. Children at this age have an extreme sense of self-importance; they believe they are responsible for all the things that happen around them.

Port-wine stain Preschoolers have developed the cognitive capacity to examine their physical appearance and thus to become aware of their port-wine stain. Children at this age are curious about their bodies and will commonly raise questions about their port-wine stains. The lesion now gains a personal meaning for the child. The preschooler usually spends a significant part of the day out of the home for the first time in a nursery school or preschool

setting. The reactions of non-parental adults, especially teachers and peers, are added to the children’s own view of themselves. There is now research to suggest that laser treatment of port-wine stain prior to or during these early years may benefit the child’s later adjustment. Preschoolers’ interest in the different parts of their body carries with it a heightened concern about bodily injury. By adult standards, children often overreact to minor cuts and bruises. Preschoolers commonly present small ‘boo boos’ with tearful requests for Band-Aids, while hardly seeming to react to more painful injuries, such as hitting their heads, if there is no visible wound. The combination of fantasy and age-appropriate concern about bodily injury makes surgery particularly frightening to preschoolers (see below). When a 4-year-old makes a new discovery, such as the portwine stain on his cheek, he arrives at an intermingling of realitybased and fantasy-based conclusions. For example, having been told he was born with the nevus flammeus, he might explain, ‘There was a fire when I was born and it got on my face,’ or, ‘I was sleeping when I was born and my brother hit me.’ Preschoolers do not understand the concept of chance occurrences. Without the mediating influence of adult explanations, they invent their own etiologies, some of which are frightening. In the second explanation above, e.g., the child may be frightened of what might happen to him while he sleeps or if his brother hits him. The pediatrician or dermatologist is helping the child by eliciting the fantasy ‘how do you think you got that spot?’, reassuring the child if the fantasy is anxiety provoking, and offering a simply worded statement that people are born different (freckles, eye color, etc.).

PSYCHOLOGICAL RESPONSES TO DERMATOLOGIC DISEASE

Preschoolers and early school-age children are particularly vulnerable to feeling responsible for the death of a sibling. Children at this age cannot distinguish between ‘wishing’ and ‘causing.’ The preschooler is likely to have felt jealous of the sickly infant, wished the infant would disappear or die, thereby not taking so much of the parents’ attention. The child then worries that the wish actually caused the infant to die. Young children can be reassured by verbalizing their fear and by the parents explaining the reality of the situation by explaining, e.g., ‘It’s not your fault that the baby died. You are a good boy. The baby died because he was born sick.’

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Atopic dermatitis Every preschooler is moving along a continuum towards increasing independence, while maintaining the wish to remain close to and be cared for by the parental figure. An expected balance between independence (leaving the parent) and dependence (checking back for security) is commonly seen. The relative balance varies with different children and varies over time with respect to the same child. It is expected, e.g., that 5-year-olds may want to shampoo their hair without their mother’s help one day and request her assistance from start to finish of the bath on another day of the same week. An acute illness results in a predictable, temporary return to a more dependent state (regression). A chronic illness, such as atopic dermatitis, by virtue of its persistent presence, becomes a part of the hour-to-hour parent–child interaction. Most children and parents adapt relatively easily to the chronic dermatitis, especially when mild. Treatments are applied as needed and the usual state of the dermatitis is accepted as normal for the child. The child is able to continue the expected course toward independence with little tension between parent and child in regard to the dermatitis. However, some children may respond to the condition with increasing dependence, e.g., claiming they are unable to dress themselves because it itches too much, or needing a parent to stay at the bedside with them every night until they fall asleep to help keep them from scratching. Other children may adopt an overly independent stance, such as resisting prescribed treatments applied by parents or refusing to permit parents to view elbows, knees, and other affected areas. The temperament of the child and the caretaking style of the parent 55

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may contribute to the development of equally problematic patterns of overdependence or a false independence. A developmentally appropriate task for the preschooler is to begin to express feelings with words. Young children may use words on one occasion and body actions on another. For example, a 4-year-old who is prevented from getting a cookie may angrily say, ‘I want that cookie and I hate you,’ or may walk around the kitchen stomping his feet and kicking the cabinets. Children with an itchy dermatitis may find an outlet for a range of feelings by scratching instead of using words to express themselves. The scratching may initially elicit a pleasurable sensation that only becomes painful with continued scratching. Aggravating the relentless itching by continued scratching may become an expression of frustration and irritability. Scratching may also be a weapon to remind parents of their relative powerlessness against the child’s discomfort. The preschooler’s understanding of events is a mixture of reality and fantasy. Hence, uncomfortable or painful experiences, like itching, burning skin, are often construed to be punishment for bad thoughts or behaviors, and raise concerns about the body’s vulnerability. Itching is affected by fantasy, mood, temperament, and anxiety. Intensity and tolerance of itching vary between children and with regard to different contexts for the same child. Like an adult who reaches for a cigarette in certain situations, the preschooler may begin scratching at the dermatitis when stressed. For example, a shy 5-year-old girl scratches her arm furiously as her mother drives her to a classmate’s birthday party in an unfamiliar house. When she sees her best friend from school at the party, she takes the friend’s hand and stops scratching. In anticipating the party, her anxiety heightened her sensation of itchiness, which declined when she was more relaxed. Similarly, a child happily involved in play may be oblivious to the itchiness and later be acutely aware of it when trying to fall asleep. The impact of scratching on the interaction between parent and child is influenced by how the scratching is viewed. Most parents encourage their children to try not to scratch, but recognize that some scratching is inevitable. Children at this age have little self-control. They are more likely to stop scratching when distracted by other interests rather than by parental rules, particularly at the times when the parent is not present. Problems commonly occur when parents expect complete control (i.e., no scratching). The behavior may be seen as either the child’s being bad or the parent’s own failure to exert control. Some children respond to unreasonable expectations with a sense of shame at their own lack of control, while others respond by open defiance, expressing their anger at their parents by increased scratching. The latter response is problematic for treatment, but both extremes cause injury to the child. The dermatologist can help this difficult interaction between parent and child by sharing reasonable expectations for the child with the parent. This helps both the parent and child to feel less burdened by an expected response to an itchy dermatitis.

Epidermolysis bullosa Independence is particularly problematic for a child with epidermolysis bullosa because minor injuries may result in dramatic 17. Rey HA, Rey M. Curious George goes to the hospital. Boston: Houghton Mifflin; 1966.

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blistering. This adds a painful reality to the age-appropriate fears about bodily integrity and physical vulnerability. Parents are likely to have more difficulty allowing a child with epidermolysis bullosa to determine a balance between dependence and independence as suited to the child’s particular temperament. Motivated by the wish to protect their daughter, e.g., the parents may find it difficult to foster her emerging independence. By creatively seeking safe ways for the child to express her independence, such as picking her own clothes each day, choosing her dessert, or painting her room the color of her choice, parents can facilitate the developmental task of increased independence. A tendency to be overprotective would be further complicated by parental guilt. Such feelings are often especially intense in a genetically transmitted illness because the parent feels so responsible for the child’s suffering. If the parent has the disorder, his or her attitude will be influenced by personal experiences with the illness during childhood. The personal memories may be so powerful that the parent has difficulty seeing the ways the child’s experience differs from his or her own. Alternatively, for some parents, personal knowledge of the disorder can be positive by enhancing their sensitivity to the child’s needs. Most preschoolers spend time with a number of different adults, primarily at preschool. These new adults are likely to be unfamiliar with the illness and may be overly cautious and restricting. It is important to foster a relatively safe environment, but also one that interferes as little as possible with the child’s relationship with peers in order that the developmentally important process of playing can occur.

Surgery for dermatologic problems Children aged 3–5 years do not understand the concept of chance, nor do they understand the difference between wishing something would happen and making it happen. They are pre­ occupied with concerns about body injury and are likely to view an accidental injury or surgical procedure as punishment for bad thoughts or behavior. Because of this, surgery for a preschooler is a particularly frightening prospect. When surgery is indicated for the preschooler, preparation of the child and taking additional history from the parents are essential.

Preoperative preparation In preparation for surgery, it is important for the physician to discuss the following with the patient and the parents: 1. Describe the procedure, including both painful and pain-free steps. 2. Visit the office or hospital where the procedure is to take place. 3. Supply the names of age-appropriate books and videos.17 4. Ensure the presence of parents throughout the awake portions of the procedure. Preschoolers can benefit from simple education as preparation for the surgery. The dermatologist should describe each step of the procedure. A tour of the hospital or outpatient setting, with an explanation of what will happen where, will also decrease the anxiety associated with the uncertainties. Parents should be

Psychosocial development in children with cutaneous disease

Preoperative history There are five major stressful events for the young child that can be expected to increase preoperative anxiety: 1. 2. 3. 4. 5.

Previous injuries or surgeries Previous hospitalizations or other separation from the family Illnesses of family members Deaths in the family Family discord.

Preschoolers are likely to generalize from previous experience and therefore assume their upcoming surgery and/or hospitalization will be like their past experiences. This can be especially frightening if the earlier experiences are remembered as unpleasant or there is a physical reminder from a previous injury. If children have experienced a family illness or death, they are likely to assume their fate will be like that of their relative. In cases of family discord or divorce, preschoolers are vulnerable to seeing the surgery as punishment for the trouble they believe they have caused in the family, and they may be very frightened about their safety.

Postoperative considerations Postoperative symptoms may include recurrent nightmares and prolonged regression with such symptoms as enuresis, baby talk, and needing more help with activities such as dressing. It is normal for these symptoms to occur transiently after the stress of surgery, but if they persist for more than a few weeks, psychiatric referral is indicated.

Behavioral interventions For children who may require a course of multiple interventions that may be painful or anxiety producing, a referral to a behavioral specialist may be indicated. Children and their parents can learn various techniques that can ease anxiety, decrease pain, and strengthen children’s sense of control by allowing them to play an active, rather than passive role, in participating in treatment.18 These interventions include distraction techniques, breathing and muscle relaxation skills, and guided imagery.

The role of the dermatologist The dermatologist can ease the preschooler’s anxiety about treatments and procedures by collaborating with parents to provide simple explanations for what to expect prior to treatment. Chil-

dren with reasons to feel more insecure, such as previous experiences with painful procedures, frightening accidents, or stressful family situations will need more preparation and support. Common symptoms of stress, as mentioned above, should be noted. If symptomatology persists more than a few weeks after surgery, psychiatric attention is warranted.

SCHOOL-AGE CHILDREN The school-age child is developing new skills in all areas such as sports, academics, and the arts. The peer group takes on new significance as children compare their own performance with that of their friends. Status within the group becomes important with fighting, teasing, and scapegoating as ways of establishing the social hierarchy. PSYCHOLOGICAL RESPONSES TO DERMATOLOGIC DISEASE

encouraged by the dermatologist to give their children ample opportunity to explain their understanding of the procedure as a way of uncovering their misconceptions and offer them the opportunity to ask questions. Children will want to know where their parents will be before, during, and after the procedure. Following the procedure, the child should be encouraged to continue to ask questions both in the hospital and at home. Questions can be followed up and facilitated at home with hospital play. Many children will enjoy being the doctor to their dolls or stuffed animals, especially if Band-Aids, gauze, or other medical supplies are offered.

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Port-wine stain School-age children look for acceptance from their peer group and for a sense that their various skills compare favorably with those of their peers. A port-wine stain has the potential to be used as an instrument for teasing. Some children, however, are more vulnerable than others. The child who has an area of competence that is valued by the peer group is likely to withstand teasing and aggression better than a less capable child who is more apt to become the scapegoat. For example, the 10-year-old star pitcher of his minor league baseball team is less likely to be teased about a port-wine stain than his unathletic teammate in the outfield who strikes out whenever he is up at bat. Parents play a key role in supporting the child’s appreciation of emerging skills. But some children expect themselves to be the best in all arenas, and thus it is the responsibility of the parents to help them set more reasonable expectations. The distressed parent and child may present to the dermato­ logist’s office requesting treatment of the port-wine stain because the child is being teased. The parent and child may view the lesion as an isolated problem, without recognizing that some teasing is a part of life for the school-age child. For less fortunate children who become the frequent scapegoat because of lesser skills in particular areas such as athletics, it is helpful to find another peer setting in which their competencies are supported. Organized groups such as photography or computer clubs can serve this function.

Atopic dermatitis Most children adapt well and are more interested in mastering new activities within the peer group than they are preoccupied with or limited by their skin disorder. School-age children are most likely to be concerned with how the atopic dermatitis affects their image among their peers. It is common for children to attempt to conceal the affected skin under long sleeves, long pants, and high collars. Some children will restrict their activities, e.g., not swimming because of embarrassment about the dermatitis. Children who limit their activities in order to hide the dermatitis miss developmentally important experiences with other children.

18. Uman LS, Chambers CT, McGrath PJ, et al. Psychological interventions for needle-related procedural pain and distress in children and adolescents. Cochrane Database of Systematic Reviews 2006; (4):CD005179.

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The increased cognitive capacity of children at this age enables them to conceptualize the dermatitis as an isolated entity that affects their skin. This contrasts with the earlier experience, where affected younger children viewed themselves as broadly damaged. School-age children are less worried about their physical vulnerability and more confident about their ability to take charge of their environment. The dermatitis may perpetuate existing parent–child struggles, but new struggles are less likely if children are involved as collaborators in their own treatment. With encouragement, they can communicate their concerns, such as if the dermatitis or the treatment is interfering in their important peer activities. The demonstration of motivation and capability for assuming more responsibility for self-care suggests better adjustment. PSYCHOLOGICAL RESPONSES TO DERMATOLOGIC DISEASE

Epidermolysis bullosa Epidermolysis bullosa presents many challenges to the developing school-age child. The self-image at this age is based on the mastery of new skills, many of which depend on physical capacities such as speed, strength, and coordination. To the extent that the epidermolysis bullosa limits the child’s liberty to join in age-appropriate activities and to play one’s hardest, it may challenge the child to find other arenas of accomplishment in order to build a positive self-image. Many children with epidermolysis bullosa will find safe activities that permit the development of a sense of competency and peer group connectedness. Appropriate choices include such activities as swimming, bowling, nature study, action movies, and video games. Some children are not able to take advantage of the safe activities available to them, and feel isolated from their peer group and personally inadequate. Of equal concern are the children who engage in reckless contact sports or other self-injurious activities in defiance of their illness. They are eager to prove themselves to the peer group in ways that are self-destructive. The extremes of inactivity and recklessness are maladaptive and warrant psychiatric consultation.

The role of the dermatologist The dermatologist can help parents to support the child’s emerging competencies and, if necessary, direct the child toward particular activities that foster a positive self-image and do not aggravate the skin disorder. The pride in mastering a task provides a good context for encouraging children to take increasing responsibility for their own treatment.

ADOLESCENCE Adolescents are establishing a sense of autonomy by scrutinizing, modifying, or rejecting their parents’ values and identifying with the standards of their peer group. An example of this is seen in adolescent fashion trends that appear extreme in comparison to adult clothing fashions. However, within the adolescent peer group, every member dresses almost alike. The adolescent has

19. Mallon E, Newton JN, Klassen A, et al. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol. 1999;140:672–676.

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an internal struggle between the wish to be both independent and dependent at the same time. For some teenagers, this internal struggle, which they are not consciously aware of, gets acted out in control struggles with parents. The emphasis on autonomy and sexuality makes these years exciting and anxiety provoking. Adolescents can be challenging patients to treat. They often question rules in the developmental context of resenting authority figures (including physicians). Non-compliance with medical regimes poses a significant problem for this age group.

Acne In large part, adolescents’ self-esteem depends on their own sense of attractiveness. Teenagers are both vain and selfconscious. Most are dissatisfied with their appearance, and acne increases this dissatisfaction more than one might predict. From the adolescents’ perspective, acne is as stressful as asthma, epilepsy or diabetes.19 Some of this impact may be lessened by education directed at misconceptions about the causes of acne, but the cosmetic impact remains significant.20 Some adolescents look into the mirror and actually see only their pimples, not their faces. Adolescents are particularly sensitive to peer rejection, especially when it involves the opposite sex. The considerable variability in physical maturity among teenagers of the same age results in many feeling inadequate in comparison with their friends. The self-consciousness associated with appearance makes the adolescent with acne more vulnerable to interpreting behavior, such as a classmate’s unenthusiastic greeting, as further evidence of being unattractive. In some teenagers, these feelings lead to social withdrawal and isolation. For example, it is common for adolescents to worry before a party that no one will want to dance with them. Usually, however, they are able to bear this concern and go to the party. Some adolescents with acne use their skin condition as an excuse to avoid such social situations, feeling that the acne makes them too unattractive to make it worthwhile to go to a party. It is easy to identify the acne as the source of social frustration. The short-term satisfaction of attacking the frustrating pimples results in continued aggravation and worsening of the acne. It is difficult for adolescents to be patient and passively wait for the dermatologist’s treatment to work. Acne, like atopic dermatitis, is a chronic dermatologic condition that the adolescent must learn to live with, at least for some time. As one pimple clears up, another one appears. Passivity is a particularly difficult stance for adolescents who want to be actively in control in all aspects of their lives. The impulsive and at times short-sighted perspective of the adolescent is reflected in the high incidence of accidents in this age group. Similarly, allowing pimples to heal untouched requires a future-oriented perspective more characteristic of an adult, not an adolescent. Addressing the frustration and temptation to attack the pimples may help the adolescent to choose to ‘tough it out’ and wait for a medication to take action. The dermatologist can

20. Pearl A, Arroll B, Lello L, et al. The impact of acne: A study of adolescents’ attitudes, perception and knowledge. NZ Med J. 1998;111:269–270.

Psychosocial development in children with cutaneous disease

Port-wine stain Issues of sexual attractiveness may arouse insecurities that make a life-long lesion take on new significance at this age. The teenager’s style of coping depends largely on earlier emotional development. Some social withdrawal is commonly seen as a technique for coping with adolescent social awkwardness, but when the birthmark becomes an excuse for exaggerated withdrawal and isolation, psychiatric consultation is indicated.

Epidermolysis bullosa Adolescents live in the present and tend not to worry about their future. They tend not to fear death and enjoy showing off with daredevil antics. They engage in a range of reckless activities from cigarette smoking to diving off bridges. It is difficult for the adolescent with epidermolysis bullosa to confront the physical limitations and consider the long-term effects of current behavior. Overreaction to physical restrictions imposed by the epidermolysis bullosa may be maladaptively expressed as rigid limitation of all activities at one extreme and careless disregard for potential risk at the other. Overreaction in either direction is reason for psychiatric consultation.

Sexually transmitted diseases

The discovery of skin lesions on the genitals is likely to frighten adolescents regardless of the etiology. They may not know who to turn to in order to get answers to questions about a condition. Peers may be the easiest to approach but are unlikely to have accurate information. Fear of parental discovery and punishment or parental rejection may inhibit seeking medical advice, as well as treatment. Fear of HIV may not lead adolescents to practice ‘safe sex,’ and may accentuate the fear of seeking medical help once they are aware of a problem. Acknowledging a sexually transmitted disease to peers may arouse concerns about peer rejection from angry previous contacts and about future sexual isolation. Some adolescent fears and misconceptions may respond to simple education. Patients may be too shy to express their actual fears. The dermatologist’s careful explanation of how diseases are transmitted, the symptoms, the treatment, and the prevention of transmittal may answer many important, yet unexpressed questions, and may make it easier for some teenagers to ask their remaining questions. The physician can invite adolescents to share their own understanding of the disease as a way of ascertaining any additional confusion. The opportunity for such dialogue is particularly important in our age of ready access to the internet. Adolescents frequently turn to the Web to try to answer questions about their health.22 Although the internet can be a tremendous resource for adolescents, misinformation is rampant, and it is extremely valuable for the dermatologist to have a chance to correct it. It is important that the dermatologist knows the statutes concerning confidentiality, the reporting of sexually transmitted illnesses, and the notification of sexual partners.

PSYCHOLOGICAL RESPONSES TO DERMATOLOGIC DISEASE

present potential benefits of the treatment along with presenting the risks of self-inflicted scarring, but the ultimate decision to implement treatment is up to the adolescent. Often, parents seek treatment for their adolescent child’s acne. In this situation, it is easy to fall into the trap of negotiating a treatment plan with the parent instead of with the teenager. It is key that the dermatologist establishes an alliance with the teenager around the wish to improve the acne. Without establishing a relationship with the patient around a shared treatment goal, dermatologists are likely to find themselves in the middle of a parent–adolescent struggle. In other words, adolescents may assert their independence from their parents by defying the treatment plan endorsed by them. The struggle is manifest by non-compliance. Pigmentation disorders, such as vitiligo, may cause even more distress in other teenagers, particularly those with darker skin in whom the lesions are more pronounced.

2

The role of the dermatologist The adolescent patient is most likely to follow through if the dermatologist presents the pros and cons of the treatment and explicitly leaves the choice and responsibility of implementation up to the adolescent. Parents who confidently offer to make sure the adolescent follows through on the treatment may only increase non-compliance by placing the treatment in the middle of existing parent–child struggles. Adolescents may be hesitant to ask the dermatologist questions unless they are actively invited to do so and have a sense of confidentiality, which gives the dermatologist a chance to correct misinformation from peers or from the internet.

Over 12 million adolescents in the USA are sexually active by the age of 18;21 however, the meaning of the sexual contact varies. Common motivations include curiosity, peer pressure, a wish for intimacy or companionship, and rebellion against parental or religious rules. Usually, the choice to engage in sexual activity is determined by a number of factors. The experience arouses many feelings that may interfere with seeking appropriate treatment for sexually transmitted diseases. Sexual activity is often so important to the adolescent’s self-image that appropriate precautions against transmitting these illnesses to others and protecting against human immunodeficiency virus (HIV) are not exercised.

CONCLUSION

21. Teenage pregnancy. The problem that hasn’t gone away. New York: Alan Guttmacher Institute; 1981.

22. Borzekowski DLG, Rickert VI. Adolescent cyber surfing for health information: a new resource that crosses barriers. Arch Pediatr Adolesc Med. 2001;155(7):813–817.

The psychological meaning of a dermatologic condition changes according to the development stage of the affected child. In infancy, a skin disorder is viewed in terms of how it affects survival of the newborn and the mother–infant attachment. In the preschool years, attention is focused on the fears about body injury and consideration is given to the important role of fantasy. During the school-age period, a dermatologic condition will be most significant in terms of its effect on the child’s status in the peer group and any limitations it puts on new skills. In adolescence, skin disorders increase the normal self-consciousness

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about appearance. Successful treatment requires establishing a doctor–patient alliance sensitive to developmental and family issues.

THE PSYCHOSOCIAL INTERVIEW

THE PSYCHOSOCIAL INTERVIEW

The focus of this chapter thus far has been on the potential impact at different developmental points of dermatologic disorders. In cases where psychosocial concerns become evident, either in the distress of the patient or family, or as an interference with optimal therapy, the dermatologist needs a strategy for evaluating the underlying problem.23 The fundamental skills necessary for this process are expressed in the evaluation interview. The goal of the interview is to elucidate the problem and assess the need for further treatment by the dermatologist or by a consultant. After identifying a psychosocial concern, dermatologists must consciously change their mindset temporarily from the usual rapid pace and style of routine office practice to one that is slower and more reflective. Obviously, there are time constraints for the dermatologist based on the economics of practice and the pressure of knowing other patients are waiting. A psychosocial evaluation does take more time, for which hopefully the physician can be at least partially compensated. At the minimum, the dermatologist must allot 10 min for this purpose. Once the initial decision is made, it should be communicated to the patient and family, e.g., ‘I am concerned about Billy giving you a hard time about the medicine. I would like to take the next 10 minutes to talk with you about this. If we need more time, I will set up a follow-up appointment sooner than usual.’ Communicating the time constraints serves multiple purposes. The physician has set clear limits as to the amount of time available; this protects against feeling pressured by thoughts about the interview going on indefinitely, and making the remainder of the day impossibly rushed. It lets the patient and family know that the time is limited, so an effort will be made to focus and prioritize concerns. When the time ends, they are prepared and are less likely to feel hurt that the physician has interrupted them in the middle of the discussion or is rushing them out. In addition, the potential for further discussion at another appointment has been offered at the outset. The next step in the interview process is to communicate interest by relaxing and assuming a listening posture. Communicating this change in mindset can be accomplished by sitting down in a relaxed posture at eye level with the child or lower, and putting down pens and other equipment. This conveys an intent to engage the child in a true dialogue. Asking, if possible, not to be interrupted by phone calls or by staff walking into the room indicates that this communication is important. Thinking about the likely area of concern given the disorder, age of the child, and family situation, the dermatologist must decide which of two types of interviews will be conducted. One type gives information and the other tries to gain an understanding of psychosocial concerns. The major goal of an interview that attempts to communicate information is to be sure that both the parent and the patient have a reasonably accurate understanding of the issues being

23. Hack S, Jellinek M. Early identification and behavioral problems in a primary care setting. In: S Friedman, D DeMaso, eds. Adolescent

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presented. For example, do they understand the seriousness of the illness? Underestimating the seriousness will possibly result in non-compliance or later anger and disappointment. Overestimating will likely result in unnecessary anguish and possible withdrawal of the parent from the child or physician. It is common for parents to distort or ‘not hear’ bad news. Some studies of parents remembering medical information suggest that well over half of the factual information is rapidly forgotten. The dermatologist giving worrisome or complex information should present the material in clear, easily understood terms, and then ask the patient or parent to give a brief summary of what is understood to be the nature, treatment, and prognosis of the disorder. It is often useful to make quite clear the etiology of the illness in a manner that relieves that parent, as much as possible, of guilt feelings for having caused the child’s problem. If the child is very ill, it is especially important for physicians to be certain that the parents understand the critical nature of the situation with as little distortion as possible. The physician could ask, e.g., ‘Now that you have heard my summary of the current problem, could you tell me on a scale of 1 to 10, with 1 being complete recovery and 10 being a child near death, what number you feel is appropriate given what I have said?’ Parents will usually be able to give a numerical assessment, which physicians can then compare with their own in a way that results in congruence with the parents in understanding the situation. The second type of interview is designed to elicit information in order to gain an understanding of a psychosocial problem or non-compliance with treatment recommendations. The opening question is especially important. When physicians are in a hurry, there is a tendency to ask questions that both in number and grammatical structure must be answered ‘yes’ or ‘no.’ The purpose of a psychosocial evaluation interview is to help the patient paint as detailed a picture as possible of the current problem. Questions in this type of interview are most effective if they cannot be answered with a yes or no response. Some examples of such questions include: ‘How do you feel it is reasonable to deal with your child’s constant desire to scratch his eczema?,’ ‘Do you and your spouse agree on how to handle this problem?,’ ‘What seems to be most difficult about taking (or giving) the medicine?’ These types of questions encourage the patient or parent to describe specific problems in their own words. Interviews that give information or attempt an understanding of the problem serve a therapeutic function. An interview that accurately gives information to parent and patient will help forge the doctor–patient and doctor–parent relationships, increase compliance with medical regimens, and in serious disorders support the parents’ intellectual attempts to cope with the illness. Interviews that give information to children, such as preprocedure or pre-surgical preparation, will build an alliance with the child, reduce anxiety before the procedure, increase cooperation, and possibly reduce post-procedure stress. Preparing or giving information to adolescents is especially important in order to build a relationship with the patient somewhat independent of the parents, and thus increase compliance. The interview that elicits a deeper understanding of a problem is intrinsically therapeutic. The dermatologist’s questions should

medicine, state of the art reviews. Philadelphia: Hanley and Belfus; 1998:335–350.

Psychosocial development in children with cutaneous disease

SCREENING FOR PEDIATRIC PSYCHOSOCIAL DYSFUNCTION IN THE DERMATOLOGIST’S OFFICE Given the barriers of time and complexity, a number of questionnaires are available to assess psychosocial functioning. The best validated and most convenient to use focus on children of 4–16 years of age. At the ages of ≤4, the questionnaires are not as effective because of the child’s limited school experiences. Above the age of 14, these parent-completed questionnaires cannot identify adolescent depression successfully. With these caveats in mind, the two best questionnaires are the Child Behavior Checklist (CBCL), which is comprehensive and takes 20–30 min to complete and score, and the Pediatric Symptom Checklist (PSC),24–26 which is shorter and takes 3–5 min. The PSC is a 35-item single-page questionnaire (Table 2.1) that parents typically complete in the waiting area prior to their child’s appointment. Office staff scores the PSC by assigning one point for any questions answered ‘sometimes’ and two points for ‘often’ (zero points for ‘never’). If the total number of points is ≥24 for 4–5 year olds, or ≥28 for children 6–16, there is a high probability that the child has substantial psychosocial dysfunction. The PSC can be used as a screening tool for all patients, or selectively if the physician suspects psychosocial difficulties, especially those that might interfere with treatment or overall psychosocial development. A positive score could then lead the dermatologist to pursue a more in-depth interview, or refer the child for mental health consultation. In a multicenter pediatric dermatology study, 377 patients aged 6–12 years were screened using the PSC. The results parallel those found in primary care settings in that 13% of all children screened positive. Social class, as in other epidemiologic samples, had a major impact, with poor children having approximately twice the positive rate (19% versus 9%), compared with those from the middle class. Of note is that children whose

24. Jellinek MS, Murphy JM. The recognition of psychosocial disorders in pediatric office practice: the current status of the pediatric symptom checklist. J Dev Behav Pediatr. 1990;11(5):273–278. 25. Jellinek MS, Murphy JM, Robinson J, et al. The pediatric symptom checklist: screening school age children for psychosocial dysfunction. J Pediatr. 1988;112(2):201–209.

dermatologic disorder was perceived to have a greater impact on their appearance were at higher risk for psychosocial dysfunction. This study highlighted the convenience of using the PSC in a dermatology office setting, parental acceptance, and the sensitivity parents feel concerning their child’s appearance. Thus, the PSC may be appropriate for general screening, but particularly so if the dermatologist suspects parental or patient concerns about appearance, if there is poor compliance with treatment, or if there is a clinical sense that psychosocial issues are impairing the child’s functioning and development. The PSC, in a number of languages, is available on the internet at no cost (go to: http://psc.partners.org or www.massgeneral.org/allpsych/ psc/psc_home.htm).

PSYCHOSOCIAL CONCERNS AND PSYCHIATRIC ILLNESS

PSYCHOSOCIAL CONCERNS AND PSYCHIATRIC ILLNESS

convey many implicit messages, such as: that the patient’s experience of the disorder is important; the parents are not to blame; they are not alone or unique in blaming themselves; treatment complications are not their fault; and chronic diseases are stressful for all families. By making the effort to ask about these problems, some tension is relieved and a process of attempting solutions can begin. Beyond the immediate benefit of relieving guilt and isolation, the interview will likely result in the physician giving additional reassurance, correcting misperceptions about etiology or prognosis, and possibly adapting medical regimens to the family’s pattern. If the issues presented are complex and cannot be understood in the 10 min of available time, then the physician can consider an additional appointment. If the family’s or child’s health or age-appropriate functioning is adversely affected, then a child psychiatric referral is indicated.

2

Dermatologists and pediatricians are in a particularly challenging setting for identifying children at risk for psychiatric illness. The high volume of patients, short visit lengths, and extended periods between appointments necessitate setting priorities about what can realistically be accomplished in a brief visit. In this section, we highlight, for the dermatologist and pediatrician, psychiatric symptomatology that can be appreciated within these office constraints and address when psychiatric consultation can be most useful. A common inhibition to requesting psychiatric consultation is concern about the patient’s or family’s reaction to the referral. Often, a physician fears that asking for a psychiatric consultation will be viewed as tantamount to calling the patient crazy, and therefore will result in the patient angrily leaving treatment. The patient and family are likely to respond to a psychiatric referral in concordance with the attitude of the dermatologist and the explanation for why a consultation is being requested. It is best first to identify the symptoms of concern, such as, ‘I noticed Jane is losing weight, and I am concerned about the sleep difficulties and school problems you have described.’ It can then be helpful to let the patient and family know that it is common practice to make psychiatric referrals, saying, e.g., ‘When I see patients with symptoms like Jane’s, I like to consult Dr A, a child psychiatrist, to see if he has some ideas about what might make her feel better.’ In this context, the parents and the patient can be asked permission for the requested consultation: ‘Mr and Mrs Smith, would that be all right with you?’ and, ‘Jane, I think you will like Dr A, he is a doctor who talks to children about their worries. Would you be willing to talk with him?’ This is an appropriate way of asking permission from a younger child. A teenager’s permission should be asked first, and then the permission of the parent asked thereafter. An alternative approach, if child psychiatric consultation is available, is to develop protocols with specific criteria for referrals, such as having all patients with potentially disfiguring disorders be evaluated by a psychiatrist as part of the initial workup,

26. Jellinek MS, Murphy JM, Pagano ME, et al. Use of the pediatric symptom checklist (PSC) to screen for psychosocial problems in pediatric primary care: A national feasibility study. Arch Pediatr Adolesc Med. 1999;153:254–260.

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Table 2.1  Pediatric symptom checklist

Please mark under the heading that best fits your child: NEVER

SOMETIMES

OFTEN

1. Complains of aches or pains 2. Spends more time alone 3. Tires easily, little energy 4. Fidgety, unable to sit still 5. Has trouble with a teacher 6. Less interested in school 7. Acts as if driven by a motor 8. Daydreams too much PSYCHOSOCIAL CONCERNS AND PSYCHIATRIC ILLNESS

9. Distracted easily 10. Is afraid of new situations 11. Feels sad, unhappy 12. Is irritable, angry 13. Feels hopeless 14. Has trouble concentrating 15. Less interest in friends 16. Fights with other children 17. Absent from school 18. School grades dropping 19. Is down on him or herself 20. Visits doctor with doctor finding nothing wrong 21. Has trouble with sleeping 22. Worries a lot 23. Wants to be with you more than before 24. Feels he or she is bad 25. Takes unnecessary risks 26. Gets hurt frequently 27. Seems to be having less fun 28. Acts younger than children his or her age 29. Does not listen to rules 30. Does not show feelings 31. Does not understand other people’s feelings 32. Teases others 33. Blames others for his or her troubles 34. Takes things that do not belong to him or her 35. Refuses to share

or referring any patient who is non-compliant after three visits. Such an approach is used at the Massachusetts General Hospital, with all pediatric oncology patients and cystic fibrosis patients referred for child psychiatric evaluation at the time of initial diagnosis. The majority of patients and families appreciate the referral and many request, or need, follow-up services. Psychiatric consultation is most useful when the dermatologist develops a working relationship with one or two child psychiatrists who can become familiar with the particular needs of the dermatologist. This allows the dermatologist and psychiatrist to determine what information or interventions prove most useful. 62

The most common psychosocial issues in dermatologic practice are non-compliance, parent–child interaction, and the psychiatric diagnoses of depression and anxiety. We will also briefly discuss developmental disorders, such as autism and related spectrum disorders, as they may be unfamiliar to the dermatologist, and can have a significant impact on how the child understands instructions and relates to the physician. Although there is a broad range of other issues, many of these will be discovered by pediatricians and schools. The two relatively uncommon entities of trichotillomania and factitial skin ulcers are also presented in this section, because although somewhat rare, they often

Psychosocial development in children with cutaneous disease

NON-COMPLIANCE Non-compliance is discussed at the outset, because it interferes dramatically with providing quality care. Also, it often does not occur to the dermatologist to refer these patients for a psychiatric evaluation. Several common etiologies leading to non-compliance are described here. Sometimes non-compliance is due to treatment regimens that are too complicated for the child and family to manage, are poorly communicated, or are not understood. Reviewing the essential features of the treatment and/or modifying the times or frequency of applications to accommodate the child’s and family’s schedule will often improve compliance in these cases. Some patients or parents equate treatment with illness, as if ignoring the treatment would negate the existence of the illness. These patients benefit from exploring in a psychiatric interview their denial of the illness, which often comes from unexpressed fears and past experiences. At times, non-compliance is a symptom of a larger problem with the parent–child relationship. In these cases, the treatment may become one more opportunity for a struggle. Unfortunately, these occur at the expense of the child’s skin condition and the dermatologist’s valuable time. The psychiatric consultant may be able to determine what role the non-compliance serves in the ongoing struggle between parent and child, and work toward separating the treatment goal from the ongoing struggle. Adolescent rebellion is a developmentally based etiology for non-compliance and is described more fully in the section on adolescence. Some adolescents may require more time to develop a reasonable treatment alliance with the dermatologist, who is viewed as suspect, either as an authority figure or because treatment has not been quickly successful. A psychiatric consultant may be helpful if the dermatologist is having difficulty establishing a treatment alliance. Another etiology for non-compliance is as a symptom of family problems such as marital discord, alcoholism, or parental depression. The child’s non-compliance or worsening of the skin condition may serve any one of a number of functions, such as temporarily uniting the parents or focusing the parents’ attention on the child instead of on the more threatening family issues. When parents share custody, there may be inconsistencies in the way treatments are provided in one home versus the other, or the parent who did not accompany the child to the office may not fully understand what is required. The dermatologist can make a referral to the child psychiatrist to have the role of the family stress evaluated as it affects the treatment non-compliance. Finally, it is important for the dermatologist to take into account cultural and socioeconomic factors that may have an impact on compliance. As an example, recent immigrants may have belief systems about illness that differ significantly from that of the dermatologist. When these differences are not voiced and discussed, the risk that patients and families will not be compliant with the treatment regimen recommended by the dermatologist is increased. Impoverished children of any culture may not have access to the medications that a dermatologist considers first-line. Their parents may have difficulty arranging transportation to the office when the course of treatment requires

multiple visits. For homeless children, access to refrigeration for medications or to hot baths may be lacking; however, this may be something that parents are reluctant to point out to the dermatologist, given issues of shame and embarrassment.

Case study Carrie is a 12-year-old with atopic dermatitis. She has been seen on a twice-yearly basis for a mild to moderate condition up until the previous 6 months, during which time her dermatitis took a turn for the worse. For this period, she was being seen on a monthly basis, and despite topical steroids, her skin was more red and raw at each visit. Carrie’s mother was becoming more irritable with the dermatologist, asserting that an improvement should have occurred by this time. She complained of the daily struggles with Carrie surrounding the application of the medicine, as well as the scratching. In the office, Carrie always agreed with the medication regimen eagerly, but at home she was increasingly non-compliant. Carrie and her mother were referred for psychiatric consultation. What the psychiatrist learned was that Carrie’s parents, who had been separated for several years, were now getting divorced. Because her mother could not drive, Carrie’s father always drove them to all of her doctor’s appointments. He would wait in the car reading, and his presence was unknown to the dermatologist. Carrie’s secret hope was that all these car rides would result in reuniting her parents. The psychiatrist recommended to the parents that someone other than the father drive Carrie to her appointments. He also scheduled a session with Carrie, where she could talk about how sad she was feeling about her parents’ divorce. At the 6-month follow-up visit, Carrie’s dermatitis was markedly improved, as was her compliance.

PSYCHOSOCIAL CONCERNS AND PSYCHIATRIC ILLNESS

present to the dermatologist first, and pose particular challenges to treatment.

2

PARENT–CHILD RELATIONSHIP DIFFICULTIES Some pediatric dermatology patients present in the dermatologist’s office demonstrating a disquieting relationship between the mother and child. The dermatologist may recognize that the parent’s expectation of the child is not in keeping with the child’s age. At one extreme, the parent may describe her implementation of a treatment plan as a battle in which compliance is demanded of the child, without allowing for age-appropriate initiative or flexibility in the regimen. Often the child is described as becoming either increasingly obstinate or increasingly passive and dependent. It is common for a child to adopt either stance in response to the parent’s over-control. At the other extreme are under-involved parents, who expect their children to be responsible for their own treatment beyond what is developmentally appropriate. A mother may report, e.g., that her son is not disciplined. Therefore, she reports her 6-year-old’s steroid cream is left with his toothbrush and toothpaste each night, and she does not remind him or help him with its application. In some cases, the child is in control and resistant. The mother is afraid or unable to enforce the dermatologist’s recommendation except on the days when the child accepts the treatment. Often these patients, even young children, are more in control of their treatment regimen than are their parents. This control is of concern in view of the child’s inability to appreciate the usefulness of the treatment, and because it signals a broader parent– child problem. 63

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Case study

PSYCHOSOCIAL CONCERNS AND PSYCHIATRIC ILLNESS

Willie is an 11-year-old fifth grader with severe atopic dermatitis. He is seen routinely in the clinic, and the receptionist has learned to tell his mother to bring him at least an hour earlier than needed, so that he may arrive on time. His mother always complains to her about how hard it is to get Willie to come to the clinic. In the dermatologist’s office, Willie’s mother described her daily struggles over getting Willie to take his baths and apply his topical medication. She highlights struggles such as the time Willie threatened to break her most expensive bottle of perfume if she added his medication to the bath water, to let the doctor know how impossible Willie has become. Willie smiles mischievously through the diatribes and then flatly denies that they occurred. Willie sat next to his mother during his appointment, episodically scratching furiously. When he would scratch, his mother would grab his hand and force it down to his side. After a few seconds he would begin scratching with his heel in exaggerated motions. His mother would glare at Willie, repeat his name in a threatening voice, and slap his knee. Willie would appear worried for an instant, then smile and wait 2 minutes to begin the scratching cycle again. Willie’s mother reported to the dermatologist, ‘I don’t think it even itches. He only scratches to aggravate me.’ Willie responded with, ‘How would you know?’ His mother then shook her head and said, ‘He’s like this about everything. I keep trying to help him, but he doesn’t appreciate it. He is impossible.’ Willie is a frustrating patient for dermatologists to attempt to treat. He would benefit from the usual treatment for atopic dermatitis, especially if he was not scratching himself so aggressively, but he and his mother are locked in a struggle over who is in control. Their adversarial relationship prevents successful treatment. A psychiatric consultant would take a detailed developmental history on Willie, looking for indications of how the relationship between mother and son developed. He would inquire about the child’s behavior in other settings, such as at school, with friends, at home with his siblings, and with other adults. Depending on the scope of the problem, a short-term therapy primarily addressing the skin condition and its treatment, or more comprehensive long-term treatment could be initiated. The psychiatrist, through an understanding of the mother–son relationship, will be able to make some suggestions about how the destructive pattern of their interaction can be altered to allow good dermatologic treatment.

DEPRESSION Adults view childhood as such a happy time that the depressed child is frequently overlooked. Young children in particular do not have the capacity to express their feelings of sadness in

27. Snyder J, Jellinek MS. Depression and suicide in children and adolescents. Pediatr Rev. 1998;19:255–264. 28. Bachmann C, Grabarkiewicz J, Theisen FM, et al. Isotretinoin, depression and suicide ideation in an adolescent boy. Pharmacopsychiatry. 2007;40(3):128. 29. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol. 2000;136(10):1231–1236.

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words. A depressed child is likely to present in the dermatologist’s office as glum, irritable, or apathetic. It is often difficult to engage these children in conversation or to arouse their curiosity about the office and its contents, or even about an upcoming procedure. The key symptoms for dermatologists to consider in the diagnosis of depression come from questioning the patient and the parent.27 They should inquire about appetite disturbance (either extreme increases or decreases), sleep disturbance (insomnia or hypersomnia), psychomotor alteration as either retardation or agitation, and loss of pleasure in previously enjoyable pastimes. It is also important to ascertain whether the child is having difficulty in social or academic functioning. It is particularly important to consider the possibility of depression in children who are being treated with isotretinoin. Case reports have documented the development of depression and suicidal ideation in both adults and adolescents28 treated with isotretinoin, but larger follow-up studies have failed to document this association.29–31 Although the issue of whether isotretinoin truly increases the risk of depression and suicidal ideation remains questionable, it is important to be aware of this risk, and to screen patients appropriately. Children with symptoms of depression (see below) should be asked whether they have had thoughts that life is not worth living, or thoughts about ending their life. Any child who is experiencing suicidal ideation should be evaluated immediately by a psychiatrist. Other classes of medications commonly used in dermatology that can have psychiatric side-effects are listed in Table 2.2.

Case study Louis is a 10-year-old fourth grader who attends a Catholic school. He was seen in the clinic on two previous occasions about a year earlier for treatment of his atopic dermatitis. He and his mother arrived late for this appointment and the doctor noticed he was scheduled for two previous appointments that were cancelled. Louis looks thinner and is unusually silent. His

Table 2.2  Medications used to treat dermatologic illnesses that may have psychiatric side-effects MEDICATION

PSYCHIATRIC SIDE-EFFECT

Oral corticosteroids

Depression, mania, anxiety, sleep disturbance

Interferon

Depression

Oral contraceptives

Depression, mood lability

Isotretinoin and other retinoids

Depression, questionably suicidal ideation

30. Chia CY, Lane W, Chibnall J, et al. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study. Arch Dermatol. 2005;141(5):557–560. 31. Ng CH, Tam MM, Celi E, et al. Prospective study of depressive symptoms and quality of life in acne vulgaris patients treated with isotretinoin compared to antibiotic and topical therapy. Australas J Dermatol. 2002;43(4):262–268.

Psychosocial development in children with cutaneous disease

ANXIETY DISORDERS The anxious child is likely to present in the dermatologist’s office as agitated, often crying and clinging to the parent, overactive, or fretful. The dermatologist is usually aware that a level of anxiety exists exceeding what might be expected, or that social reticence is present. During the exam, anxious school-aged children may refuse to sit on the examining table without a parent holding them. The children may verbalize extreme fears that neither respond to the dermatologist’s reassurances nor are appropriate to the treatment at hand such as, ‘I know he is going to hurt me,’ or, ‘Don’t let him touch me!’ while the dermatologist is not even near the child.

It is important to get a history from the parent about how the child’s behavior in the office compares with behavior at home and at school. The dermatologist can inquire whether the child has excessive worries about his parents dying or about his own behavior being acceptable. Anxious children often fear being away from their parents. Key times to ask about include going to school in the morning, going to sleep at night, and being left at home with a babysitter when the parents go out. The child’s anxiety is considered significant if it interferes with peer relationships, school functioning, or comfort at home.

Case study In the dermatologist’s office, it was difficult to coax 9-year-old Max into allowing his foot to be examined. The doctor remembered him from his previous appointment. Max had hopped out without his shoe on when his mother stepped outside the office to talk with the nurse. On this visit, Max sat tearfully in his mother’s lap worrying aloud about the dermatologist hurting him. His nervousness was striking, since only a painless examination of a nevus was being done on this appointment and the previous ones. Perplexed by Max’s fearfulness and his clinging to his mother, the dermatologist asked Max what he was scared about. Max was silent, but his mother, Mrs Roth, responded for him. Max had told her he thought the dermatologist did not like him and he worried before every visit that he would get yelled at. The doctor knew he had never spoken harshly to Max. Mrs Roth said Max was always worrying. He hated his parents going out at night because he worried they would get into an accident and die. He routinely thought his teacher and his friend’s mother were angry at him, despite his exemplary behavior. Max presents with an anxiety disorder that warrants a psychiatric evaluation. Anxious but well-behaved children are less likely to be noted and referred by their school. Their potential to benefit from treatment, however, is significant. When the child psychiatrist sees Max, he will explore the symptoms of distress. He will look for separations or losses, such as a death in the family, a move, or a relative leaving. He will take a detailed history of Max’s early development with special attention to difficulties starting preschool. It will be important to assess the family looking for possible sources of stress. Treatment approaches may include individual or family psychotherapy. Psychopharmacologic agents may offer some benefit for anxiety disorders in childhood, and are discussed below. Childhood depression may present with symptoms of anxiety and should be considered in the differential diagnosis.

PSYCHOSOCIAL CONCERNS AND PSYCHIATRIC ILLNESS

dermatitis appears mild. The doctor inquires about how he has been feeling lately, but Louis remains silent. His mother responds to the doctor’s questions by saying that Louis is not himself of late. He is scratching more than he used to and even crying. Over the past 6 weeks, Louis’s grades have gone down at school, he refuses to play with his friends, and it is a struggle to get him to go to soccer practice, which he used to love. He complains of headaches and stomach aches that keep him out of school and were the reason why they had to cancel their previous two appointments. When the dermatologist inquires about sleep and appetite, Louis tells him he lies in bed awake until after his parents are asleep each night and wakes up very early in the morning. He used to love hamburgers and french fries, but lately eating is a chore. Louis blames his dermatitis, saying he is in a bad mood because it itches and looks ugly. His mother wonders how the skin condition could be responsible for the change in her son’s behavior. Louis presents as a depressed child. He has had persistent mood change of more than 2 weeks’ duration, with sleep and appetite disturbance, as well as loss of interest in a favorite activity. It interferes with his schoolwork, his peer relationships, and, as is often seen in children, is associated with somatic complaints such as headaches or stomach aches. When Louis is seen by a child psychiatrist, he will take a detailed history including his current symptoms, and his functioning at home, at school, and with peers. A family history will be gathered to assess stressors that may be affecting Louis’s presentation, and to learn if there is a family history for affective illness. A medical history, recent physical exam and, if necessary, labwork will be reviewed to assess for any possible contribution of medical illness. He will subsequently be referred for psychotherapy and/or psychopharmacologic intervention. In the hands of an experienced psychiatrist, antidepressants can be safe and effective for use in children. Untreated depression leads to a child missing out on important age-appropriate experiences. In addition to making an appropriate referral to a psychiatrist, it may also be important for the dermatologist to consider the safety profile of whatever medications he or she may prescribe. Particularly for a depressed adolescent, it is best, when possible, to avoid medications that are especially toxic in overdose (e.g., quinines, colchicine).

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DEVELOPMENTAL DISORDERS Autism and related spectrum disorders, also known as ‘pervasive developmental disorders (PDD),’ are being diagnosed with increasing frequency.32 This has led some to question whether the prevalence itself is increasing, or whether a higher proportion of cases is being identified. The specific symptoms of this dis­ order can vary widely from case to case, but are characterized by difficulty in social interactions, rigidity, and difficulty with

32. Newschaffer CJ, Falb MD, Gurney JG. National autism prevalence trends from United States Special Education Data. Pediatrics. 2005;115:e277–e282.

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change in routines. Children with these disorders can also be intensely sensitive to textures and tastes, and may not tolerate tight clothing, dressings, or bandages.

Case study

PSYCHOSOCIAL CONCERNS AND PSYCHIATRIC ILLNESS

On meeting 12-year-old Joey for the first time, the dermatologist was struck by his poor eye contact and odd statements, e.g., when he told the dermatologist exactly how many minutes they had been waiting for her. Joey’s father stated that it had been a major struggle to get Joey to the appointment, as he had been insistent that he wanted to go straight home. The dermatologist diagnosed an excoriated bug bite that had become infected due to Joey’s inability to stop scratching it, and prescribed an oral antibiotic, as well as an ointment, to be applied twice daily. On follow-up, Joey’s father reported that Joey had been completely unwilling to apply the cream, complaining that he did not like the texture of the cream on his skin. He had also had a very hard time following parental instructions not to continue to scratch the lesion. Children, like Joey, who have a history of PDD, can be very rigid, and may have difficulty with the disruptions to their usual routine that are caused by the need for treatment. They may demonstrate exquisite sensitivity to textures. This is often noted at home in children who cannot wear shirts with tags, or cannot bear to tie their shoes tightly at the ankle. In the dermatology clinic, it may become an issue when the tactile sensation of the treatment recommended is noxious to the child. On occasion, these children tolerate topical treatments more readily if they can be covered, e.g., by wearing plain white cotton gloves over an ointment that must be applied to the hands. Taking these sensitivities into account early in the treatment planning will lead to improved compliance and, therefore, better clinical response.

TRICHOTILLOMANIA Case studies

Marcia is a 3-year-old girl, who was brought in by her mother to have a facial nevus evaluated for possible excision. In examining Marcia, the doctor found 10 partially healing or healed small circular burns extending over her back and buttocks. When the

Debbie is a 5-year-old brought to the dermatology clinic because she pulls out her hair during temper tantrums. She has an obvious bald patch on the right side of her head. Although previously Debbie had occasional temper tantrums without pulling out her hair, the trichotillomania began approximately 6 months ago while her mother was hospitalized for several weeks with hepatitis. Rosa is a 16-year-old who presents with no eyelashes and few eyebrow hairs. With obvious embarrassment she explains how she pulls out her eyelashes and eyebrow hairs, especially at bedtime. She has tried many times to make herself stop, but at the moments she pulls out the hairs the feeling of needing to do so is just too strong to stop. She finds her habit repugnant, and fears her friends will learn of it and view her as bizarre. On careful history, she has other compulsive behaviors. The other behaviors are of little concern to her; they include needing to touch certain objects in her room before going to school and needing to arrange her books in alphabetical order in her locker. Trichotillomania is a perplexing condition. It has been reported in association with a wide array of psychiatric disorders (autism, obsessive-compulsive disorder, depression, schizophrenia, borderline personality disorder), mental retardation, and as an isolated symptom with no clinical significance.33 Some patients will respond to a combined treatment of cognitive behavioral therapy and medication.34 Anecdotally, it has been associated with actual or feared loss of an important person in the patient’s life. Debbie’s experience of her mother’s absence during her prolonged illness seems consistent with this etiology, while Rosa’s trichotillomania is more suggestive of obsessive-compulsive disorder. Rosa finds her own behavior alien, yet is unable to stop it. She has other compulsive, ritualized behavior. Each child was referred to a child psychiatrist. Debbie benefitted from short-term play psychotherapy. Rosa had a psychopharmacologic trial of an antidepressant from the selective serotonin reuptake inhibitor class, which was effective in lessening her symptoms. (see Pediatric psychopharmacology, below).

33. Krishnan KR, Davidson JR, Guajardo C. Trichotillomania: a review. Compr Psychiatry. 1985;26(2):123–128.

34. Keuthen NJ, Stein DJ, Christenson GA. Help for hair pullers. Oakland: New Harbinger; 2001.

CHILD ABUSE Child abuse is not a childhood psychiatric illness, but psychiatrists are often asked to evaluate and treat children and families with this problem. Physical and sexual abuse of children is, unfortunately, a common problem. Abusing parents often bring the abused child to a physician with genuine concern for the wellbeing of the child. It is the moral and legal responsibility of health professionals to educate themselves about the symptoms of abuse and to notify the appropriate agency as determined by the site in which they practice when there is suspected abuse. It is also important to keep in mind that neglect must also be reported. The failure to obtain appropriate treatment for a child’s serious dermatologic condition may constitute reportable neglect.

Case study

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doctor asked Marcia’s mother about the burns, she hesitatingly reported that they were from a pot of boiling water, which splashed accidentally on Marcia. Noting the old burns, she reported that Marcia had been born with them. The scars seemed too round for scalding and the dermatologist suspected that they were cigarette burns. The process for reporting suspected child abuse cases varies among locations, but the key word is ‘suspected.’ If a physician believes there is a possibility of abuse, the appropriate agency must be notified. In nearly every state, physicians are mandated reporters who must report any suspicion of abuse or neglect. It is not the responsibility of the doctor to determine whether it is actual abuse that has occurred, but only to report the possibility.

Psychosocial development in children with cutaneous disease

Case study Tracy is a 15-year-old who was followed in the dermatology clinic for several months with progressively worsening circular lesions on her abdomen and thighs. Over the months of care in the clinic, the lesions increased in number and size until there was hardly any unaffected skin on her abdomen, but no lesions on her back. The etiology of the condition remained unclear despite careful history-taking and two skin biopsies. Tracy’s mother, a single parent and a registered nurse, was distraught over her only child’s escalating illness. At her request, Tracy was admitted to the hospital for closer observation. On the third hospital day, Tracy was inadvertently discovered applying cream depilatory to her abdomen to cause a chemical burn. Tracy initially denied the etiology of her lesions, but later admitted that after accidentally discovering her skin sensitivity to the depilatory, she began causing the skin lesions as a way to get her mother’s attention and the sympathy of her friends. Tracy was referred for a psychiatric evaluation, which she refused, but her mother prevailed upon her. After the evaluation, she began a course of psychotherapy. Factitious disorder is perplexing and often provokes anger from the physicians caring for the patient. Commonly, the factitious etiology is discovered after the physician has invested many hours and performed numerous unnecessary procedures. Discovery is the result of good detective work in addition to good medical care. Suspected cases often require an in-hospital evaluation during which the patient can be carefully observed. Many patients escape close scrutiny by switching from doctor to doctor. Although psychiatric intervention is the only treatment for this condition, it is difficult to get these patients to accept referral. There are differing views on whether it is preferable for the dermatologist (or primary physician) to confront the patient or to defer to the psychiatrist.35 This decision is best made in a consultation between the primary physician and the psychiatrist prior to recommending the psychiatric referral to the patient.

MÜNCHAUSEN BY PROXY SYNDROME Münchausen by proxy syndrome (MBPS) must be in the differential diagnosis of a suspicious illness in a younger child. This is a condition in which a parent either makes a child ill or makes a child appear to be ill. This uncommon entity carries a high risk of child mortality.36 Children should be carefully monitored medically as long as they are cared for by the parents, and the appropriate agencies, as in child abuse cases, should be alerted. The parents should be referred for psychiatric treatment, but they are likely to be resistant unless it is mandated by court action. As difficult as it is to feel empathy for the parent in such a 35. Fras I. Factitial disease: an update. Psychosomatics. 1978;19(2):119–122. 36. Waller DA. Obstacles to the treatment of Münchausen by proxy syndrome. J Am Acad Child Psychiatry. 1983;22(1):80–85. 37. Olfson M, Marcus SC, Weissman MM, et al. National trends in the use of psychotropic medications by children. J Am Acad Child Adolesc Psychiatry. 2002;41(5):514–521. 38. Patel NC, Crismon ML, et al. Trends in the use of typical and atypical antipsychotics in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2005;44(6):548–556.

situation, it is important to provide support to the parent when confronting him or her about the diagnosis. Without such support, parents may respond to an abrupt confrontation by taking their child and fleeing treatment, or in a psychiatric decompensation that can include suicidal ideation.

PEDIATRIC PSYCHOPHARMACOLOGY The intersection between pediatric dermatology and psycho­ pharmacology can be approached from two angles: psychological disturbances that may be associated with dermatologic illnesses, or psychiatric illnesses that may result in dermatologic disturbances. We have spent most of this chapter looking through the former lens, but will now shift to discuss the latter. The dermatologist is likely to see three categories of psychiatric conditions. There are primary psychiatric entities that may present with dermatologic findings, such as trichotillomania,36 neurotic excoriations, factitious disorder and body dysmorphic disorder. There are psychiatric illnesses, such as depression and anxiety, that may aggravate primary dermatologic disorders, such as eczema, psoriasis, alopecia areata, and acne. Finally, there are the disorders of conduct or attention not directly related to a skin disorder, but of importance because of the impact on compliance. Each diagnosis carries with it potentially appropriate pharmacotherapy. The decision to medicate children with psychoactive drugs demands a risk–benefit assessment, a thorough premedication workup, informed consent by parents, and careful monitoring of potential side-effects and sometimes of drug levels during use. Numerous studies have documented that, since the late 1980s, increasing numbers of children in the USA are being treated with psychotropic medications.37–41 Depending on the age group, demographics, and specific medication studied, recent estimates of prevalence of psychotropic use among children have found frequencies as high as 2–4%. This increase has occurred both in use of medications that have been used in children for decades, such as psychostimulants, as well as in medication classes that were formerly rarely seen in the pediatric population, such as mood stabilizers and antipsychotics.38 Given the likelihood that the pediatric dermatologist will come into contact with many children who are prescribed these medications, it will be useful to have a basic understanding of the indications for the most common psychiatric medications. It is important to note that we are providing a description of common psychopharmacologic practice, rather than endorsing it; many medications commonly prescribed to children do not have Food and Drug Administration indications for use in children, and additional study is greatly needed. Given the complexity of psychopharmacologic interventions in children, prescribing of these medications is best performed by a consulting psychiatrist. With the increase in psychotropic prescriptions for children, dermatologists will also see cases of children whose psychiatric

PSYCHOSOCIAL CONCERNS AND PSYCHIATRIC ILLNESS

FACTITIAL SKIN ULCERS (MÜNCHAUSEN SYNDROME)

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39. Cooper WO, Arbogast PG, Ding H, et al. Trends in prescribing of antipsychotic medications for US children. Ambul Pediatr. 2006;6(2):79–83. 40. Hunkeler EM, Fireman B, Lee J, et al. Trends in use of antidepressants, lithium, and anticonvulsants in Kaiser Permanente-insured youths, 1994–2003. J Child Adolesc Psychopharmacol. 2005;15(1):26–37. 41. Zito JM, Safer DJ, Valluri S, et al. Psychotherapeutic medication prevalence in Medicaid-insured preschoolers. J Child Adolesc Psychopharmacol. 2007;17(2):195–204.

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Table 2.3  Commonly used psychiatric medications CLASS

SUBCLASS

EXAMPLES

Antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

Fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine Venlafaxine, duloxetine

Serotonin and norepinephrine reuptake inhibitors (SNRIs) Tricyclic antidepressants (TCAs) Other agents CONCLUSION

Anti-anxiety medications

Benzodiazepines Other agents

Mood stabilizers

Anticonvulsants

Other agents Antipsychotics

Atypical

Typical

Amitriptyline, nortriptyline, clomipramine Bupropion, trazodone, mirtazapine Lorazepam, alprazolam, clonazepam Buspirone, gabapentin Valproic acid, carbamazepine, oxcarbazepine Lithium Risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone Haloperidol, chlorpromazine

medications have caused dermatological problems. Perhaps the most serious of these is the referral to assess for possible Stevens–Johnson syndrome for children taking lamotrigine. However, other psychiatric medications may also have dermatologic side-effects, such as lithium, which can worsen psoriasis and acne (Table 2.3)

Antidepressants Antidepressants are used to treat depression and other mood illnesses, as well as anxiety disorders. The antidepressants most commonly used today in pediatric populations are the selective serotonin reuptake inhibitors (SSRIs). Also commonly used are the serotonin-norepinephrine reuptake inhibitors (SNRIs), and less commonly, agents in older classes, such as tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs).

Mood stabilizers Increasing numbers of children and adolescents are being treated with mood stabilizers, a class of medications that includes

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lithium, valproic acid, carbamazepine, and oxcarbazepine. The primary indication for these medications is bipolar disorder.

Stimulants (psychostimulants) and anti-adrenergic medications Stimulant medications are the mainstay of treatment to address symptoms of attention-deficit hyperactivity disorder (ADHD). Medications such as clonidine and guanfacine are used to address ADHD symptoms, as well as to address sleep disturbances and aggression.

Anti-anxiety medications SSRIs, described above, are not only the first-line treatment for anxiety, but are also the mainstay of treatment of many forms of anxiety disorders. Other medications that can be used to address anxiety, particularly short-term anxiety, in the form of a PRN medication, include benzodiazepines. Diphenhydramine is also used, at times, to address anxiety or insomnia. Of note, some children will experience a paradoxical agitation in response to benzodiazepines or diphenhydramine.

Antipsychotics Antipsychotics are increasingly being prescribed to children, both for psychotic illnesses and for other indications. Atypical antipsychotics are used to address agitation in children with autism and related illnesses, and for mood stabilization in children with bipolar disorder. The use of antipsychotics carries with it significant risks, including risks of metabolic complications, such as weight gain, diabetes, or elevated cholesterol, and movement disorders.

CONCLUSION The high volume and fast pace of pediatric and dermatology practices can encourage a narrow perspective that focuses on the skin only as an organ, rather than reflective of a whole person and thus imbued with many personal, interpersonal, and cultural meanings. Especially for children, understanding these many meanings within a developmental context can be valuable, or even critical, for patients, families, and physicians. Surgery can be made less anxiety provoking, compliance with medical regimens improved, parents’ tendency toward guilt and/or marital discord at least moderated, and psychological damage to the child kept to a minimum. Lastly, a fuller appreciation of the developmental, psychological, and familial implications of dermatologic disorders will enrich the physician’s professional life as the repetitious nature of evaluating lesions is replaced by a sensitivity towards treating the child as a whole person.

Henning Hamm, Robert Johr, Sibel Ersoy-Evans and Angela Hernández-Martín

INTRODUCTION Diagnosis in dermatology is, just as in other clinical disciplines, based on three pillars: careful history, thorough examination, and various diagnostic methods. Among them, the observation of individual lesions is commonly of greatest significance. The morphology of skin lesions, their arrangement, and distribution will often lead to a suspected diagnosis or at least allow for a differential diagnosis to be generated. There is a wealth of diagnostic aids: non-invasive, little invasive and invasive, with the help of which a suspected diagnosis may be confirmed or a differential diagnosis may be excluded. In pediatric dermatology, particularly in young children, doctors will try to get as much information as possible from noninvasive diagnostic methods and to confine themselves to a minimum of invasive diagnostic procedures to arrive at the correct diagnosis. This chapter summarizes an approach to the clinical diagnosis of pediatric skin disease, including history-taking and refined dermatological examination, and gives an overview on the most important diagnostic aids available to the dermatologist and pediatrician.

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issues that could impede treatment adherence. For practitioners who have not received specific training in pediatrics, we present guidelines for evaluating and treating children and for educating their parents.

THE PARTICULARITIES OF PEDIATRIC DERMATOLOGY

Pediatricians are well aware that children are not merely ‘small adults’.1–3 Their presentation and spectrum of diseases as well as range of treatment options and responses to medical intervention are unique. The parents are usually very concerned about their children’s diseases, and physicians must respect the parental perception. Clinical interview should involve the child as much as possible, and physical examination and dermatological procedures should be carried out in the caretaker’s proximity when feasible, especially for painful or frightening procedures. When treating children, physicians should always consider the availability of less painful but effective methods, and address

Pediatric dermatology is not just dealing with skin diseases appearing in children. The pediatric patient has specific needs which must be met, as well as many obvious differential features that make it necessary to develop certain skills for physicians who devote their practice to the skin care of children. Pediatric dermatologists must be trained in creating a climate of confidence in the office and also must be patient and sympathetic with the attitudes of children and parents; these attitudes are obviously variable according to the psychosocial background of the families and also differ with age. However, there are many skin diseases which will exclusively appear during childhood, and there are also many others which begin in the first years of life; likewise, many disorders that may present at any age show differential features in children. Needless to say, the therapeutic approach to the child with skin disease will be different in terms of indications, side-effects, dosage, follow-up, and outcomes. Children with skin diseases are attended both by pediatricians and dermatologists worldwide, and it is our experience that because of different training, they have different approaches to the dermatologic patient. Pediatricians with no specific training in dermatology are many times able to make brilliant diagnoses and accurate treatments, but lack the dermatological background which permits wider differentials. On the other hand, dermatologists without any training in pediatrics can diagnose properly most skin-affected children, but will experience difficulties in specific disorders of childhood and in managing dosages, performing medical procedures, and setting indications for clinical and ancillary examinations. Physicians with training and experience both in dermatology and pediatrics are best indicated

1.

3.

APPROACH TO THE PEDIATRIC PATIENT

2.

Rauch P, Jellinek MS. Developmental and psychosocial considerations in pediatric dermatology practice. Pediatr Dermatol. 1986;3:380–383. To T, Cadarette SM, Liu Y. Biological, social, and environmental correlates of preschool development. Child Care Health Dev. 2001;27:187–200.

THE PARTICULARITIES OF PEDIATRIC DERMATOLOGY

Principles of diagnosis in pediatric dermatology

Mallin K, Lazarus MC. Treating children is different. Dermatol Clin. 2005;23:171–180.

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THE CLINICAL HISTORY AND EXAMINATIONS

for the proper and comprehensive approach and management of children with skin diseases, and that is why pediatric dermatology arose enthusiastically during the late twentieth century; it is acknowledged, however, that pediatric dermatology had been practiced for many years in some pediatric hospitals worldwide. Ideally, skin care for children should be carried out in pediatric clinics and hospitals. On the one hand, it is a universal requirement that sick children must be completely separated from sick adults. On the other hand, a pediatric setting with adequate size instrumentals and furniture is desirable to create a comfortable and highly hygienic setting, with temperature and air humidity conditions appropriate for children of different ages. During consultation, children must be accompanied by their parents or responsible adults, and young children should never be left alone on examination beds without close monitoring. Loud voices should be avoided and examining physicians must have proper hand cleansing, and both hands and instrumentation for the clinical examination must be kept at a warm temperature.

THE CLINICAL HISTORY AND EXAMINATIONS For a proper diagnosis and management, a complete clinical history is a tool of the utmost importance. We estimate that a skilled pediatric dermatologist can diagnose and manage correctly more than 80% of patients based only on medical history and clinical examination. Less than 20% will need further examinations including skin biopsy or imaging. There are different strategies of obtaining a clinical history. Some physicians prefer to perform a ‘blind’ interview with the parents and the child (when possible), and then proceed to clinical examination. Others, including ourselves, prefer to begin with clinical inspection of the child and then obtain a directed history and clinical examination. It is extremely important that not only dermatological examination is performed, but a general examination which is extremely useful. Besides dermatological examination, which will be discussed below, inspection of the general status of the child, temperature, skull and fontanelle palpation, complete lymph node and abdominal examination, as well as many other signs help diagnose dermatoses that are a sign of internal diseases. Especially in young children, attention to weight and height gain is crucial to evaluate general development. Poor breast-feeding and decreased spontaneous activity may be signs of serious infection even in the absence of fever, especially in infants. The central nervous system (CNS) and the eyes are embryologically connected with the skin, and subtle dermatological signs can be the ‘iceberg tip’ of a severe neuro­ cutaneous disorder. Careful attention must be paid to developmental neurological milestones in young children, and signs such as decreased reflexes, mild spasticity or hypotonia should alert the dermatologist about a serious illness. Pain is very hard to identify in infants, but achy toddlers manifest themselves irritable, sleepless and with permanent crying. Any mood change

4.

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Bauchner H, Waring C, Vinci R. Parental presence during procedures in an emergency room: results from 50 observations. Pediatrics. 1991;87: 544–548.

in young children as reported by their parents is a guiding light to a potentially serious disorder. To carry out a clinical examination in children can be sometimes a difficult task. Very young children may cry when they are laid on a bed without any contact from their mother. A stranger’s tough hand may also be scary. A gentle and soothing touch on the infant’s belly can be reassuring and may permit a quieter examination. Toys, simple tricks and candies may help calm preschool and school-age children for a correct examination. Older children seldom require such techniques, but dialoguing about ‘hot topics’ according for their ages is a simple way of gaining their confidence. It is important to be honest to children and not lie to them when talking about minimally painful procedures that should be performed, and also discuss with the parents the convenience that they are present or not during such procedures.4 A climate of friendliness is important, as is the need to create a ‘medical’ atmosphere. Sick children are usually worried about their disease; as children regard adults, especially their parents, as almighty individuals, the caring physician must play this role with honesty and reassure the sick child. Conversely, from a child’s point of view, the almighty adult also has the capability of inflicting a serious damage, and the physician must be very careful when dealing with these conflicting feelings of trust and fear in the child’s mind.

INDICATION OF MEDICAL TESTINGS AND PROCEDURES The best tool for any physician is organ visualization. Because the skin is virtually the only organ that can be readily accessed by the naked eye, no further testings are indicated in many cases. However, many children may need medical testing and procedures for a correct diagnosis of a skin eruption, to determine the internal involvement of a dermatosis or tumor, to confirm or rule out that a skin disorder is a sign of an internal disease, or to obtain a baseline for further follow-up. On the other hand, once a diagnosis is achieved, some medical or surgical pro­ cedures such as cryotherapy, curettage or skin surgery can be indicated. Before any procedures are done, one must take into account the potential benefits and risks for the child. For example, an MRI is a non-damaging procedure, but the need for long immobilization may create anxiety in a school-age child; in very young children, MRI should be carried out under anesthesia or sedation. To obtain a simple thorax X-ray, a degree of cooperation from the child is needed, and a fearful child may not cooperate. Obtaining blood samples can be very frightening for children, and, especially for the younger ones, a neck peripheral vein access may be the only way. However, if a certain medical testing is considered necessary, all these drawbacks must be overcome and it must be recommended to the parents. Sometimes parents may consider testing unacceptable for their child, but it is the physician’s role to explain the need for the examination and their benefits and risks. Written consents are warranted in many

Principles of diagnosis in pediatric dermatology

COLLABORATION WITH OTHER PEDIATRIC SPECIALTIES Especially for severely affected children, multidisciplinary teams are advisable. Children with toxic epidermal necrolysis or purpura fulminans can be managed in intensive care units. Pediatric surgeons, otolaryngologists, ophthalmologists, neurologists, and radiologists must collaborate with pediatric dermatologists in the best management of hemangiomas and vascular malformations. A strong connection with geneticists is highly desirable. Finally, the help of a pediatric dermatopathologist is absolutely necessary for a high standard of medical care. The pediatric dermatologist should ideally be well trained in dermatopathology.

OBTAINING CLINICAL PICTURES OF CHILDREN Clinical images belong to the patient himself, and are usually protected by regulations. However, since they are an important tool for the clinical history, it is widely recommended that photographic pictures are taken on as many patients as possible, under written consent of the parents and children. Pictures must be kept safe according to data protection laws and should be managed under highest standards of security. Many modern available digital cameras in the market permit high-quality imaging. Storing pictures in computers requires software to permit a ready managing of the images and its protection by usernames and passwords. Older pictures stored in photoprints and slides are still in the files of many hospitals, and they should be managed observing the same data protection regulations. Obtaining clinical pictures from children is sometimes difficult, and some degree of immobilization may be required. Selecting a green, blue, or black background is ideal. Parents must be informed of the importance of clinical pictures for healthcare purposes, and also for teaching.

THE AGES OF CHILDREN AND THEIR DERMATOSES Pediatric dermatology deals with the diseases and skin care requirements in individuals from birth to adolescence, a relatively short period in lifetime when significant physiological, psychosocial and maturity changes take place. The pediatric age spans from the first day of life to 18 years, and includes the neonatal period (from birth to 1 month), infancy (1 month to 2 years), childhood (2 to 12 years) and adolescence (12 to 18 years). Children have different problems and diseases in each period, and their ways of enduring them are also dissimilar depending on the type of illness, the social environment and family support. These factors greatly affect the child and the physician’s relationship, a complex bond in which the parents also play an important role. Viewing pediatric skin diseases in a developmental framework will improve both the physician– patient–parent relationship and the compliance rates.

NEONATAL PERIOD The neonatal skin shows distinctive characteristics that make it reflect physiological and pathological events in a very unique way. Right after birth, the newborns assume the challenge of independent life, where the external temperature is no longer stable, and they make contact with other individuals, the sunlight and environmental germs. At term, the cutaneous integument is well developed and offers an effective barrier function, but it shows important anatomic differences with adult skin. At birth, the most obvious difference with adult skin is the presence of a coating of vernix caseosa, lanugo and desquamation, which give the baby a peculiar appearance during the first days of life. In newborns, skin immaturity leads to predisposition to specific diseases that will not be observed in later life, such as dehydration, hypothermia, increased absorption of topically applied substances, injuries from sunlight and iatrogenic lacerations and burns. Neonatal nurseries must be well prepared to minimize the incidence of iatrogenic complications. The first month of life is a time for transient benign physiologically derived eruptions that will never be seen again in life, such as toxic erythema of the newborn, sebaceous hyperplasia, neonatal cephalic pustulosis, and others. Temporary embryonic rests may also be transiently seen, such as Bohn’s nodules or Epstein’s pearls, and physicians must know them to avoid aggressive diagnostic or therapeutic procedures and to reassure the parents. In other cases, the neonatal skin reveals significant pathological conditions, including maternal diseases transmitted in utero or during delivery, either autoimmune (neonatal lupus or neonatal pemphigus) or infectious (syphilis, varicella, toxoplasma, herpes, candidiasis, and others). Many skin dis­orders can be present at birth, including developmental abnormalities, epidermolysis bullosa, keratinization disorders, or vascular malformations, and the newborn skin may offer essential clues to the diagnosis of complex genetic syndromes such as incontinentia pigmenti, neurofibromatosis, piebaldism, or Leopard syndrome). Examining neonates is generally easy, because anxiety to strangers does not develop until the age of 8–10 months. The whole newborn skin must be carefully examined with the patient lying on a bed with clean sheets, and under appropriate temperature and humidity conditions. Non-dermatological exam­ ination includes fontanelle inspection, head and neck palpation, abdomen examination, cardiac and lung auscultation, peripheral pulses and neurological signs such as tone and basic reflexes (grasping and Moro reflex). Height, weight and head circumference are important signs of general development. Once the newborn has been examined, he must be dressed up and kept in a safe and warm place with his parents. The physician must keep in mind that the parents had a set of expectations for their unborn child, including a nice healthy skin. Imperfections in the children’s appearance cause anxiety and sometimes feelings of guilt in the parents, so it is essential that the dermatologist provides enough information about the actual cause of the condition and anticipates its course as much as possible.

THE AGES OF CHILDREN AND THEIR DERMATOSES

parts of the world before any medical procedure is performed. Older children who can be considered mature must also be informed about the nature of the procedure, and their signature is encouraged.

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INFANCY After the neonatal period, children experience a highly significant intellectual, physical, socio-emotional and motor development. During this period of life, important milestones are crucial 71

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to determine general development of the infant and are a useful aid to detect specific areas of delay. Social smile, following objects with the eyes, reactions to separation from his mother, sitting, standing, walking alone, audition, early language, and other developmental milestones should be documented specifically in this period of life. The infant’s skin becomes mature and architecturally organized into adult patterns with increasing postnatal age. For example, melanin synthesis and collagen I production increase gradually after the neonatal period and the hair follicles and nails progressively grow stronger. During infancy, eczema becomes the most significant skin problem, especially atopic dermatitis. Diaper dermatitis with or without associated candidiasis is particularly frequent between 6 and 9 months of age, as well as miliaria rubra after the first month of life. Some diseases are also seen in later life, but they have a peculiar appearance at this age, such as scabies, or even a totally different prognosis, such as mastocytosis. Tumors may become apparent in early infancy, congenital melanocytic nevi and hemangiomas being the most prevalent ones. A wide variety of genetic diseases, including hair shaft disorders, RothmundThomson’s syndrome, progeria and many others, appear during infancy. The infant is now exposed to infectious conditions, which were uncommon before the 6th month of life because of maternally transmitted immunity, and many of these infectious and exanthematous disorders will leave permanent immunity and will not ever appear later in life. Recurrent severe infections may herald the presence of a congenital immunodeficiency. Physical examination in toddlers may be difficult because they develop fear of the physician and stranger anxiety, which peaks at 18 months of age. Whenever possible, infants should be examined in parent proximity to facilitate their confidence and cooperation. Parents must be at ease to keep permanent eye contact with the child on the examination bed, or even be able to hold his or her hand. Infants may require medical procedures for diagnosis, such as skin biopsies, MRI or blood testing. It is impossible to explain to an infant the nature of the procedure, and he will react to pain with crying and motion. Most infants will be calmed and relaxed after local anesthesia is injected and working. Especially for skin biopsies a degree of immobilization is required. Parent cooperation and reassurance are very important in this setting.

CHILDHOOD Children undergo essential maturity changes, such as sphincter control, intellectual and language development, socialization, self-control, autonomy and complex motility functions. Atopic dermatitis is the most prevalent disorder at this age. Direct contact with other individuals and animals increases the incidence of superficial cutaneous infections such as warts, chickenpox, tinea, molluscum contagiosum, scabies, pediculosis, impetigo, and herpes simplex, whereas leisure activities in open spaces promote insect bites, photo-toxic dermatitis or contact eczema. It is also time for some diseases to appear for the first time, such as psoriasis, vitiligo or alopecia areata, and certain genetic disorders may flare up in early or late childhood, such as Gorlin’s syndrome or erythropoietic protoporphyria. At this age, children have their own individual temperament and behave differently at the physician’s office; some appear sociable, sound and cooperative, whereas others look reserved and uncooperative. This behavior depends on past experiences 72

and educational background, but also on individual personality. The physician may get better cooperation by engaging the child with direct questions to him or her about school, brothers and sisters, sports, or clothes. In extremely fearful children, the physical approach must be gradual, using a soft voice and slow movements; examining children at their own level, sitting on the next chair or along with them on the examination bed may help the physician to appear less powerful to their eyes. It is important to involve children in the medical history as much as possible, because they are already able to locate the skin problem, explain the symptoms and tell what make them better or worse. Painful diagnostic or therapeutic procedures such as skin biopsies, curettage, cryotherapy, or excisions can be discussed and explained to the child, but they may not be old enough to understand why the procedure is needed. Simple explanations given to children and their parents before the actual procedure make it a less difficult experience for all concerned. However, some children fail to relax even a little when exposed to a fearful situation. In such instances, sedation can be an alternative. The physician should encourage children and praise them for cooperating. Offering them any kind of material reward (stickers, cartoons, etc.) is also helpful. Overall, preschool and young school-age children are the most difficult patients to deal with in terms of performing medical procedures. Gaining the trust of the patient is crucial, and it is a complex process that should begin at the first moments of the consultation.

ADOLESCENCE During adolescence, teenagers experience changes in their physical development at a rate of speed unparalleled since infancy. They rapidly gain in height and weight, and changing hormonal levels activate the development of secondary sex characteristics, including growth of pubic hair, increased sweat gland activity and production of sebum. Anatomic and physiological changes result in the occurrence of new diseases such as acne or seborrheic dermatitis. Some infectious diseases, infrequent before puberty, are now common (tinea pedis, pityriasis versicolor, onychomycosis). Teenagers tend to exhibit a ‘this can’t happen to me’ attitude and take unnecessary risks such as unprotected sex, so the possibility of a sexually transmitted disease must be kept in mind. In spite of their genetic basis, certain genodermatoses such as Darier’s disease, pseudoxanthoma elasticum or Fabry’s disease may delay their onset until late childhood or adolescence. Adolescence is a time of establishing personal identity, autonomy and intimacy; teenagers seek simultaneously self-assertion and peer acceptance, demonstrate a high level of self-consciousness and give especial importance to their exterior aspect, so the skin achieves a great relevance as they interface with peers. However, their adaptation to cutaneous disease is highly variable, spanning from true indifference and disinterest for their condition to great worry and desperation, which may lead to auto-aggression and even suicide. The relationship with their physician may be difficult; at this age, adolescents tend to believe that no one else has ever experienced similar feelings and emotions and may not find a good way of communicating their problems. Additionally, parents may interfere in an already complicated relationship trying to influence some decisions or expressing criticism of the teenager. It is important that the physician tries to sympathize and listen to their concerns, assuring

Principles of diagnosis in pediatric dermatology

APPROACH TO DIFFICULT SITUATIONS Dealing with children usually challenges physicians’ role as healthcare professionals, because certain situations stir our deepest feelings of frustration, anxiety, and impotence. Approaching difficult situations must involve not only the affected child, but also the family members and the potentially strained relations that a childhood illness may impose.5 Promoting parents’ and patients’ satisfaction and adherence to treatment is also an important skill that should not be taken for granted.6–8 Pediatric dermatologists are consulted for diagnosing skin diseases in children with very severe underlying conditions such as cancer. The new skin condition might include drug and viral exanthems, graft-versus-host disease, candida infections, and many others. Often, the role of the pediatric dermatologist is to make a difficult diagnosis in a difficult patient, perhaps one long admitted to hospital and known by the caregivers. Very often, skin biopsies or other procedures are needed, and children and parents may react with anger against a new potentially painful test added to a great number of painful procedures performed in the past. It is the role of the pediatric dermatologist to explain the absolute need for the testing, as well as to treat both the child and parents with a mixture of proficiency, friendliness and compassion. Hundreds of genetic diseases can affect the skin, and the skin may be the only or main organ involved. In such situations, careful examination of the parents may be warranted, and the nature of a genetic disease must be explained. A correct clinical diagnosis is very important, and diagnostic accuracy may be increased by genetic tests. There are a lot of genetic tests available for hundreds of genetic skin disorders, and very often, parents demand a genetic test they think is readily available. The true expectations from genetic tests and their difficulties, drawbacks, and failures must be thoroughly explained to parents. Genetic tests are expensive and time-consuming, and sometimes may not

5. 6. 7.

Folkman S, Lazarus RS, Dunkel-Schetter C, et al. Dynamics of a stressful encounter: cognitive appraisal, coping, and encounter outcomes. J Pers Soc Psychol. 1986;50:992–1003. LaGreca AM, Schuman WB. Adherence to prescribed medical regimens. In: Roberts MC, ed. Handbook of pediatric psychology. 2nd edn. New York: Guildford Press; 1999:55–83. Renzi C, Abeni D, Picardi A, et al. Factors associated with patient satisfaction with care among dermatological outpatients. Br J Dermatol. 2001;145:617–623.

confirm a diagnosis. Genetic diseases are often not subject to any efficient treatment, and patients may experience feelings of surrender, which may lead to visit cancellations and loss of follow-up. Children with chronic, intractable diseases are troublesome in the office and also in daily family life; they create frustration and feelings of guilt in the parents. Chronic severe atopic dermatitis is a good example of this, and a sympathetic and instructive approach from the physician is desirable. Ideally, groups for patient or parent education are helpful, because they create a higher consciousness and personal autonomy, and show a way of dealing with chronic diseases which need daily care and routines. Physicians should provide information, both oral and in leaflets, that is easily understandable, and refer patients and parents to therapeutic education groups with the aim of improving quality of life.

HISTORY

confidentiality and treating the youngster as a free-thinking individual. It is many times rewarding trying to treat teenagers and speak to them as true adults. Teenagers tend to have an ‘act now’ approach of life, which can make it difficult for them to wait for the medication to take effect (typically, they try to fix quickly their acne pimples by squeezing them in spite of knowing the potential of scarring from manipulation). Adherence to treatments is difficult in this group of age, especially when there is no personal engagement or the therapy regimens interfere with lifestyle habits, have cosmetic side-effects or impede social interactions. Clinical examination of the adolescent is sometimes difficult because they may be reluctant to show certain parts of their bodies. A deep respect for teenagers’ concerns of shame and shyness should be kept.

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DOCUMENTATION It is always important to document significant psychosocial factors and unusual emotional overlay during a visit (see Ch. 2). Most infants and young children are seen by their primary physician at frequent, regular intervals; therefore, it is extremely important to communicate with the primary physician about any child with a chronic or unusual problem. The primary physician can also serve as a source of vital information about the unique aspects of the child and address concerns that have been raised in consultation.

HISTORY PRELIMINARY REMARKS The joint effort of patient and physician towards solving a medical problem usually begins with history-taking. However, in pediatric dermatology, there are two peculiarities. First, in younger children, the history has to be obtained from the parents or other caretakers. Of course, the older the children the more they will be able to participate in the review of the problem under consideration and the more they should be involved.9 This will also create a level of confidence which is useful for the following examination. Second, the pathology is easily accessible to the eyes. The pediatric dermatologist may take advantage of this fact since, for estimation of the scope of the history and for asking more tailored questions, it is often worthwhile to start with a brief look at the skin lesions. The history has two main parts, namely the special history focusing on the presenting complaint, and the general history giving information about other medical or personal problems that may be of influence on the current or future diseases. The more unclear or complex the problem, the more important is a detailed history. For instance, a full medical history is useless in

8. 9.

Friedman IM, Litt IF. Promoting adolescents’ compliance with therapeutic regimens. Pediatr Clin North Am. 1986;33:955–973. Levy ML. Principles of diagnosis. In: Schachner LA, Hansen RC, eds. Pediatric dermatology. 2nd edn. New York: Churchill Livingstone; 1995:139–163.

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Table 3.1  10 basic questions for a dermatological history

HISTORY

Special history

When, where and how did it start? Has it occurred anywhere else? How does it behave? What affects it? Does it itch, hurt, burn, or anything else?

General history

Do you/does your child suffer from any symptoms not related to the skin? Have you/has your child been ill recently or previously? Have you/has your child been treated topically or systemically, and if so how? Are there or have there been similar problems in other family members? What are your thoughts about the cause of the problem?

Modified from du Vivier.11

season of the year, cold, heat, physical activities, contact with animals or plants, or exposure to topical agents or chemicals. Symptoms are often reported by the parents or patients themselves. However, the severity and periodicity of itch, pain, burning, stinging, or other sensations have to be asked for. Information about the complaints is particularly helpful for confirmation of a suspected diagnosis, since subjective symptoms are often characteristic of specific dermatoses.13 Thus, for example, scabies, urticaria, atopic and contact dermatitis can be excluded in non-itching conditions. Previous therapies of the condition in question, whether topical or systemic, have to be recorded, including the duration of use, tolerance, and efficacy.13 They may grossly influence the actual presentation of a skin disease. In such cases, it may be inevitable to stop every kind of treatment and to make an appointment 1 or 2 weeks later. Furthermore, knowledge about previous treatments helps to avoid repeated prescription of ineffective agents.

GENERAL HISTORY a schoolboy with a single finger wart, whereas a detailed history is essential in a toddler with atopic dermatitis or an adolescent with systemic lupus erythematosus. These examples also show that the aim of the history is not only to arrive at a clear or suspected diagnosis but also to evaluate etiological or worsening factors. The skill of the pediatric dermatologist consists in asking all questions relevant to the problem and, because of time limitations, leaving out irrelevant ones. To avoid unintentional omissions, it is prudent to adapt to an orderly and logical framework in history-taking,10 as proposed in the following. (Some key questions are summarized in Table 3.1.)

SPECIAL HISTORY As the patient mostly presents or is presented with a concrete problem, it seems reasonable to start with the special history. First and foremost, the doctor should envision the age and sex of the patient. There are a number of conditions which are confined to or appear in the first year of life, whereas others rarely start before puberty. Many disorders have a clear sex preference. Time and site(s) of onset of the skin lesions should be accurately determined. Patients or parents should be asked to describe the initial lesions and whether they have changed in appearance or character.12 Further evolution of the lesions in terms of extension, exacerbations, remissions and recurrences should be recorded. In conditions limited to short episodes, their frequency and duration have to be ascertained. Assessment of the duration of individual lesions may be a valuable clue. Moreover, it is important to note whether the parents or the patient are aware of any provoking or aggravating factors, such as food, sunlight,

10. MacKie RM. The dermatological history: examination and investigations frequently used in dermatology. In: Clinical dermatology. An illustrated textbook. Oxford: Oxford Medical Publications; 1991:1–15. 11. Du Vivier A. The dermatological diagnosis. In: Dermatology in practice. Philadelphia: JB Lippincott; 1990:1–14. 12. Cox NH, Coulson IH. Diagnosis of skin disease. In: Burns T, Breathnach SM, Cox N, et al., eds. Rook/Wilkinson/Ebling Textbook of dermatology. 7th edn. Oxford: Blackwell; 2004:5.1–5.20.

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The skin disorder may be related to a prior or current systemic disease. Therefore, associated extracutaneous symptoms, such as fever, fatigue, sore throat, joint pain, diarrhea, or seizures, and previously diagnosed chronic illnesses, hospitalizations, or surgeries have to be precisely recorded. Of special importance are metabolic and endocrine disorders, chronic infections, and states of congenital or acquired immunodeficiency. Suspected syndromes, congenital anomalies or infections afford a detailed review of the prenatal history, the delivery and the postnatal mental and motor development. When considering a genetically determined dermatosis, examination of other family members and family history-taking including a diagram of the pedigree may support the suspected diagnosis and disclose the pattern of transmission. Contagion to family members may also serve as a clue for infectious conditions, such as scabies or tinea. The past history of skin and related disorders may be a great help for the classification of the actual problem. Of special importance is the recognition of an atopic diathesis (atopic dermatitis including cradle cap and flexural eczema, hay fever and bronchial asthma) in the background of the patient and the family.14 Since many systemic agents can cause diverse cutaneous side-effects, the current and previous drug therapies including over-the-counter medications have to be noted. Knowledge about the medication may also uncover a medical problem which was not otherwise mentioned by the parents.14 Immunosuppressive agents predispose to skin infections, especially viral diseases and mycoses. Vaccinations may provoke local or systemic skin reactions. Furthermore, information about known adverse reactions to drugs, such as an allergy to penicillin or to food, has to be obtained. A question about dietary and nutritional habits, whether on health, religious or other grounds,

13. Wolff HH. Introduction to the skin and dermatology. In: Burgdorf WHC, Plewig G, Wolff HH, et al., eds. Braun-Falco’s dermatology. 3rd edn. Heidelberg: Springer; 2009:3–16. 14. Lynch PJ. Principles of diagnosis. In: Sams WM, Lynch PJ, eds. Principles and practice of dermatology. 2nd edn. New York: Churchill Livingstone; 1996:23–32.

Principles of diagnosis in pediatric dermatology

DERMATOLOGICAL EXAMINATION PROCEDURE AND TECHNICAL CONSIDERATIONS Easy access to the organ involved is an essential advantage in pediatric dermatology. The first step in a dermatological exami15. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006;155:145–151.

nation is to gain a preliminary impression of the pattern of involvement by inspecting the skin lesions from a distance. The subsequent close examination aims at the analysis of the type and morphology of primary and secondary skin lesions, their arrangement, and involved sites, as explained in detail below. Afterwards, the distribution over the body has to be assessed. For this purpose, the entire skin surface should be examined, especially in all patients attending for the first time. Infants and toddlers should be totally undressed including removal of the diapers, whereas older children may keep their underwear on, except for inspection of the genito-anal area. The examination should be performed in an orderly sequence and include the scalp, scalp hair, eyebrows and eyelashes, nails, adjacent mucous membranes, and teeth as well as the palpation of the cervical, axillary and inguinal lymph nodes. The latter is particularly required if acute infections, chronic inflammations, and malignant conditions are suspected. Total skin examination may reveal unchanged lesions which are more characteristic than those primarily presented by the patient or parents but may also disclose potentially harmful findings, such as congenital abnormalities. The examination room should be well lit with natural light being best. Additional lighting by high-intensity examination lamps and magnification of skin lesions by hand-held magnifying glasses is very useful. The realization of the examination mainly depends on the age of the child. For example, special precautions have to be followed when examining newborn infants in hospital nurseries. Examination of toddlers and pre-school children may be facilitated by distracting them with small toys, keeping them seated on the parent’s lap, or the promise of a reward.9 In contrast, many adolescents will prefer to be examined in the absence of their parents.

DERMATOLOGICAL EXAMINATION

should not be missing when dealing with an unexplained skin disorder. The ethnic background of a child may provide information on a certain genetic predisposition and pattern of reaction.12 Asking about past holidays in foreign countries may disclose the decisive factor in uncommon skin infections. Contact with animals, particularly pets, is often more intense in children than in adults and may be the cause of certain infections, infestations or allergies. Occupational history plays an important role only in adult dermatological patients. However, enquiry about hobbies and other leisure activities may uncover exposure to sunlight, water, contact allergens, or irritant chemicals in older children and adolescents.12 The social history deals with the living conditions of the patient, the socioeconomic, nutritional and health status of the family, and includes knowledge about further persons of close relation. This kind of information is particularly helpful in children with chronic skin diseases, also in estimating the compliance and prognosis of a patient. Finally, the physician should try to get an idea about the psychological effects of the disease on the patient and family and about the patient’s or parents’ thoughts on its cause, respectively.10,11 Domestic conflicts caused or triggered by the disease and difficulties in coping with it may have extremely negative repercussions on the condition. On the other hand, a chronic skin disorder may not improve because the child is fearful of losing the increased attention and affection associated with it. The burden of disease may more precisely be evaluated by standardized questionnaires, such as the Children’s Dermatology Life Quality Index (CDLQI).15 The consequences on the quality of life have also to be considered for the choice of treatment. Inept worries about infectivity or malignancy may be easily dispelled, and exaggerated expectations have to be cautiously adjusted by the doctor. Fortunately, a time-consuming history comprising all of the items addressed above will rarely be necessary. However, in complex problems, such as inherited disorders with extracutaneous involvement, allergological questions and conditions related to physical or chemical agents, as well as in difficult patients or parents, a very detailed or even repeated enquiry may be indispensable. Patients and parents should feel as comfortable as possible in a clinical setting. The physician should mainly be seated, move cautiously within the examination room, speak to the child in an understandable language and be careful not to touch the patient early or to speak loudly, particularly with young children.9 This simple code of conduct will usually enable the physician to gain the child’s confidence, which is essential for the realization of the following examination.

3

DESCRIPTION AND TERMINOLOGY OF SKIN DISEASES Introductory remarks The majority of skin diseases can be diagnosed by appropriate history-taking and proper examination alone. Diagnostic accuracy may be further improved by repeated examination since the actual state represents only a snapshot of a dynamic process. In spite of the wealth of dermatological conditions considered in this textbook the pediatric dermatologist is usually dealing with a reasonable number of diagnoses only. Among them, atopic dermatitis, viral warts, impetigo, scabies, acquired melanocytic nevi, and alopecia areata may be the most common ones. Interestingly, Schachner et al.16 found 25 diagnoses to account for approximately 82% and 50 diagnoses for more than 91% of all skin disorders seen in a pediatric dermatology clinic. Correct recognition of the morphological features is an essential prerequisite to diagnosis of a given skin disorder and, for obvious reasons, a basic vocabulary of well-defined terms is indispensable for a proper description. However, differences in terminology become evident when comparing standard dermatological textbooks and noting continuing discussions in 16. Schachner L, Ling NS, Press S. A statistical analysis of a pediatric dermatology clinic. Pediatr Dermatol. 1983;1:157–164.

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dermatological journals.17,18 For example, there is considerable inconsistency with regard to the minimum or maximum size of some primary skin lesions. Exanthem and erythroderma are further examples of often-used but ill-defined expressions. The following definitions partly keep to the glossary of basic dermatology lesions that was published by the committee on nomenclature of the International League of Dermatological Societies in 1987,19 but also reflect recent recommendations.17,18 Dermatologists will be glad to confirm the Chinese proverb that a picture may be worth more than a thousand words. Therefore, photographic documentation of skin lesions is often expedient, especially if the diagnosis is unclear or unusual, if changes or courses are to be monitored, and for teaching and publication purposes. Skin tumors of uncertain origin should likewise be documented prior to excision or biopsy. Moreover, pictures offer the possibility to send them to expert colleagues via common or electronic mail (’teledermatology’) and seek their advice.

Figure 3.1  Macules. Multiple small hyperpigmentations on nose and cheeks (freckles).

Primary skin lesions Those fundamental morphological changes that appear first on formerly unchanged skin are called primary skin lesions. Secondary lesions usually do not develop on uninvolved skin but mostly arise from alteration of primary lesions. They can provide clues as to the primary lesions if these are absent.9 However, as secondary lesions, such as scales or excoriations, may also occur on clinically unchanged skin, the limits between primary and secondary lesions are somewhat blurred. Nonetheless, the following list of basic terms keeps this differentiation.

Figure 3.2  Patch. A large, red, flat area of irregular shape (port-wine stain). (Courtesy of Dr. Antonio Torrelo.)

Macule A flat, circumscribed area of skin different in color or texture from the surrounding (normal) skin (Fig. 3.1). By definition, a macule does not exceed 1 cm in greatest diameter. It cannot be recognized on palpation.

Patch A large macule, more than 1 cm in diameter (Fig. 3.2). A macule or patch can result from:

• Deposition of endogenous (hemosiderin, lipids, bile

• • • •

pigments) or exogenous products (tattooing, ingrained dirt, coal dust, smoke, gunpowder, metals, topical agents, carotene, systemic drugs) Extravasation of blood (petechiae, purpura, suggillations, ecchymoses, hematoma) Changes in melanin content of the epidermis or dermis (hyperpigmentation by increased, hypopigmentation by reduced, depigmentation by absent melanin) Active (erythema) and passive hyperemia (cyanosis) Diminished blood supply and vasoconstriction.13

Occasionally, macules and patches may be slightly depressed below the skin surface (atrophic macules) or show minor surface changes, such as scaling.

17. Lewis EJ, Dahl MV. On standard definitions: 33 years hence. Arch Dermatol. 1997;133:1169. 18. Reisfeld PL. On standard dermatologic definitions. Arch Dermatol. 1998;134:635–636.

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Papule A circumscribed solid elevation of the skin up to 1 cm in diameter. It is mostly caused by tissue proliferation or cell infiltration (Fig. 3.3). The following types of papules can be distinguished:

• An epidermal papule is composed of localized thickening of the epidermis (acanthosis) or of the stratum corneum (hyperkeratosis). • A dermal papule is composed of a localized, solid thickening of the upper dermis produced by accumulation of cells, such as lymphocytes or melanocytes, hyperplasia of fibers, proliferation of adnexal structures, vessels or neural tissues, deposition of metabolic products, or other pathologic changes. • Dermoepidermal papules are formed by a combination of epidermal and dermal abnormalities. Caused by an abundance of different pathological processes, papules may show a considerable variety of shapes, colors, consistency and surface qualities. For differential diagnosis purposes, it is important to note whether papules are associated

19. Winkelmann RK. Glossary of basic dermatology lesions. The International League of Dermatological Societies Committee on Nomenclature. Acta Derm Venereol Suppl. 1987;130:1–16.

Principles of diagnosis in pediatric dermatology

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DERMATOLOGICAL EXAMINATION

Figure 3.3  Papules. Multiple small red solid elevations on the left cheek (Gianotti–Crosti syndrome).

Figure 3.5  Nodule. A solid lobulated elevation >1 cm in size in the right auricle (pilomatricoma). (Courtesy of Dr. Antonio Torrelo.)

Figure 3.4  Plaque. A large, solid elevation from confluence of papules (psoriasis; note the peripheral white halo, the Woronoff halo). (Courtesy of Dr. Antonio Torrelo.)

Figure 3.6  Nodules. Nodules may be subcutaneous and more palpable than with hair follicles or other adnexal structures or whether they involve interfollicular skin.

Plaque A circumscribed, superficial, solid elevation of the skin >1 cm in diameter (Fig. 3.4). The geographic counterpart of a plaque is a mesa, a flat-topped mountain. Plaques may have a plane or uneven surface, they may be elevated only at the margin, as in granuloma annulare, and some intracutaneous plaques may not be visibly raised at all, as in morphea.14 Plaques may occur as primary lesions but may also result from coalescence of joining papules and then, strictly speaking, represent secondary lesions. Plaques may have the same subdivisions as papules.

Nodule A solid lesion of the skin with more than superficial height or palpable depth greater than 1 cm in diameter (Fig. 3.5).

visible. This is the case in this child with panniculitis (erythema nodosum). (Courtesy of Dr. Antonio Torrelo.)

A nodule usually results from tissue augmentation. It may not absolutely present as an elevation but can always be palpated. The distinction between papule and nodule depends on both size and extension. Nodules may be located deep-dermally, dermal-subdermally or solely in the subcutaneous fat (Fig. 3.6).

Tubercle A small, firm papule or nodule protruding from the cutaneous or mucosal surface.

Gumma A firm, nodular swelling with tendency to softening leading to perforation and ulceration, as seen in tertiary syphilis and tuberculosis cutis colliquativa. 77

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Basic Science and Principles of Diagnosis and Treatment

DERMATOLOGICAL EXAMINATION

Figure 3.7  Wheals. Multiple coalescing marginated lesions on the trunk (acute urticaria).

varying size (linear IgA disease). Some blisters are eroded.

Wheal

Vesicle (small blister)

An elevated, transient dermal edema, varied in size (Fig. 3.7). Wheals are characteristically evanescent, disappearing within up to 24 hours.20 The changeability is due to the fact that they are mostly made up of a circumscribed, rapidly resorbed accumulation of interstitial fluid in the upper dermis and hardly of cellular components. Their color is pale red if the capillaries are dilated, or whitish if the swelling is heavy enough to compress the blood vessels. Wheals typically cause itching, which is answered by rubbing. They are the characteristic lesion of urticaria. If individual lesions last more than 24 hours, urticarial vasculitis has to be considered. Whether a wheal should be regarded as a basic dermatologic lesion or better described as a type of papule or plaque is disputed.18

A circumscribed elevation of the skin up to 1 cm in diameter and containing a fluid (Fig. 3.8).

20. Fitzpatrick TB, Bernhard JD, Cropley TG. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al. eds.

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Figure 3.8  Vesicles and bullae (blisters). Multiple fluid-containing elevations of

Bulla (large blister) A circumscribed elevation of the skin >1 cm in diameter containing a fluid (Fig. 3.8). The distinction between vesicle and bulla depends only on size. The line is usually drawn at 5 mm. The term blister unites vesicles and bullae. The following types of vesicles and bullae can be distinguished:

• A subcorneal vesicle or bulla is formed by exudate beneath the stratum corneum, as in bullous impetigo.

Fitzpatrick’s dermatology in general medicine. 5th edn. New York: McGrawHill; 1999:13–41.

Principles of diagnosis in pediatric dermatology

3

• Intraepidermal vesicles or bullae are located within the

Blisters may house serum, blood, lymph, or a mixture of these fluids. Depending on their pathogenesis, they may consist of a single chamber (unilocular blister) or of multiple compartments (multilocular blister). Vesicles are almost always tense; bullae may be either tense or flaccid. Their stability towards physical forces allows some conclusions with regard to pathogenesis and plane of cleavage. Intraepidermal blisters caused by spon­ giosis and ballooning, and subepidermal blisters tend to be tense, whereas subcorneal and acantholytic blisters are mostly flaccid.21 Blisters can also contain cellular elements, such as keratino­ cytes or inflammatory cells. The microscopic proof of their nature may essentially help in establishing the diagnosis, such as detection of eosinophilic granulocytes in the vesicular stage of incontinentia pigmenti.

Pustule A circumscribed superficial elevation of the skin filled with pus (Fig. 3.9). Pus is composed of leukocytes, mostly neutrophils, with or without cellular debris. Pustules are white or yellow in color. They may occur within the epidermis, for example in intra­ corneal or subcorneal sites, within a pilosebaceous follicle or, much more rarely, in an eccrine duct.22 Important to differentiate, they may be sterile, as in pustular psoriasis, or contain microorganisms, as in ostiofolliculitis. They do not always occur primarily but may also develop from vesicles or bullae (secondary pustules).

Figure 3.9  Pustules. Multiple small elevations containing pus (impetigo neonatorum). (Courtesy of Dr. Antonio Torrelo.)

Secondary skin lesions Scale A perceptible flat plate or flake of stratum corneum. The abnormal shedding or accumulation of stratum corneum in perceptible flakes (scales) is called desquamation (scaling). Several types of scales can be distinguished, among them:

• Collarette scales: fine, ruff-like scales surrounding inflammatory lesions

• Exfoliative scales: large, sheet-like scales • Furfuraceous/pityriasiform scales: fine, loose, bran-like scales

• Ichthyosiform scales: large, polygonal, fish-like scales • Lamellar scales: thin, relatively large scales • Psoriasiform scales: coarse, non-adherent, silvery-white scales13,20

• Lichenoid scales: shiny, smooth, tightly adherent scales.

Cyst

Keratosis

Any closed cavity with an epithelial, endothelial or membranous lining containing fluid or soft material. True cysts with epithelial lining are differentiated from pseudocysts, the capsule of which is formed by compressed connective or granulation tissue, as in mucocele and digital mucous cyst. Most true cysts are derived from keratinizing (epidermis or hair follicle) or glandular (sweat glands) epithelium. Developmental cysts, the third subgroup of true cysts, originate from failed closure of embryologic fusion lines or misplacement of epithelial structures.

A horny thickening that firmly adheres to the skin. Keratoses may be epidermal or follicular; they may be arranged either horizontally, such as scales, or vertically, such as spines, spikes and horns.21

21. Cockerell CJ. How are abnormalities of the skin described? In: Arndt KA, Robinson JK, LeBoit PE, et al., eds. Cutaneous medicine and surgery. An integrated program in dermatology. Philadelphia: WB Saunders; 1996:84–110.

DERMATOLOGICAL EXAMINATION

epidermis. The three main pathogenetic principles include spongiosis (collection of fluid between individual keratinocytes, as in acute dermatitis), ballooning (collection of fluid within individual keratinocytes, as in herpes virus infections), and acantholysis (separation of keratinocytes by loss of intercellular adhesion, as in pemphigus diseases).21 • Subepidermal vesicles and bullae develop by cleavage of the dermo-epidermal junction, as in pemphigoid diseases. The roof of the bulla is composed of the entire epidermis. • A dermal vesicle or bulla is caused by separation of tissue components of the dermis, as in dystrophic epidermolysis bullosa.

Erosion A loss of the epidermis or a viable part of it that heals without scarring. It usually results from rupture of vesicles and bullae or from superficial trauma to the skin.

22. Ackerman AB, Chongchitnant N, Sanchez J, et al. Definition of terms. In: Histologic diagnosis of inflammatory skin diseases. An algorithmic method based on pattern analysis. 2nd edn. Baltimore: Williams & Wilkins; 1997:75–98.

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Excoriation

Abscess

Any loss of substance of skin produced by scratching. Usually, the papillary dermis is reached resulting in bleeding, crust formation, and healing with formation of a superficial scar. Excoriations often have a linear arrangement. They point to the severe pruritus associated with the skin disease.

A localized collection of pus in a dermal or subdermal cavity formed by inflammatory disintegration or necrosis of tissues.

Fissure, rhagades Any linear gap or slit in the skin surface reaching into the dermis. Fissures usually develop in hyperkeratotic or excessively dry skin over flexural creases, especially of hands and feet, and are painful. Other sites of predilection are onset of the external ear, angle of the mouth and perianal skin.

Absence or visible reduction of hair from normally hairy areas.

Angioedema Massive subcutaneous swelling caused by local confluence of interstitial fluid. Angioedema often occurs in combination with wheals, but is more deeply located and resolves less quickly.

DERMATOLOGICAL EXAMINATION

Ulcer

Aphtha

A deep defect or loss of the entire epidermis and at least the upper (papillary) dermis, which heals with scarring. Since dermal damage is present, ulcers are usually accompanied by vessel disruption, bleeding and the formation of hemorrhagic crusts which, by enrichment of fibrin, form dark-colored, difficult-to-remove, so-called eschars.14 The pathogenesis of ulcers is variform. Ulcers may result from the enlargement of erosions and excoriations; they may be due to venous insufficiency, occlusive arterial disease, vasculitis, infections, injuries, artifacts, or other causes. Moreover, nodules and tumors, especially malignant ones, may ulcerate.

A small, round or oval defect of the mucous membranes, usually surrounded by a narrow, inflammatory rim and covered with fibrin.

Wound In the acute sense, wound means an injury in which the skin is torn, pierced, cut, or otherwise broken. A chronic wound is a skin defect which does not heal by secondary intention within 3 months.

Crust An outer layer from the drying of exudate, secretion, pus, or hemorrhage. Correspondingly, the color of crusts can vary considerably. For example, yellow crusts are typical for impetigo; hemorrhagic crusts are the consequence of bleeding and often cover excoriations and ulcers.

Scar

Atrophy A diminution in the size of a tissue. This is a broadly used term applicable in pathology and many clinical disciplines. In dermatology, the following types of atrophy may be distinguished:20,21

• In superficial cutaneous atrophy, usually both epidermis and dermis are involved. The skin appears thinned and finely wrinkled, reminiscent of cigarette paper. Loss of skin markings and epidermal appendages produce a shiny appearance. Pigmentary disturbances and telangiectasias may be present. Deep veins and tendons are perceptible through the transparent skin. • Circumscribed, roundish to oval areas of dermal atrophy due to loss of elastic fibers that appear as soft, slightly depressed or outpouched lesions are called anetoderma. • Deep cutaneous atrophy is caused by the loss of connective tissue in the reticular dermis. The skin appears normal in color and markings, but is depressed. If extensive, eversion of the skin caused by herniations of fat may occur. • Lipoatrophy: Atrophy of the subcutaneous tissue usually results in deep depressions of the body surface without textural changes of the overlying skin.

The fibrous tissue replacing normal tissues destroyed by injury or disease. A scar is the irreversible end stage of many inflammatory and destructive processes. Clinically, the normal skin markings and appendages are lacking; hyper- or hypopigmentation may be evident. Scars may be smooth or sclerotic; they may lie in the level of the skin, be depressed and wrinkled (atrophic scar) or firm and elevated (hypertrophic scar).

Burrow

Glossary of common terms used in clinical dermatology

Comedo

The following list includes a number of specific terms which make a short, apt description of a dermatological condition much easier and help to avoid longwinded phrasings. 80

Alopecia

A narrow, elevated passage or tunnel in the skin produced by a parasite, particularly the scabies mite.

Callus Circumscribed thickening of epidermis and stratum corneum (hyperkeratosis) in response to persistent mechanical forces.

A plug of cornified cells, sebum, and microorganisms in a dilated infundibulum of a pilosebaceous follicle. The orifice may also be dilated (‘open’ comedo, blackhead) or narrowed (‘closed’ comedo, whitehead).

Principles of diagnosis in pediatric dermatology

Cord

Lichenification

A string- or rope-like structure in or beneath the surface of the skin.21 Most often, they represent thickened, indurated blood vessels or nerves.

Thickening of the skin with accentuation and coarsening of the skin markings usually induced by habitual rubbing.14

Large, flat extravasation.

Milium Tiny, white cyst containing lamellated keratin.

Enanthem

Petechia

See Exanthem.

An isolated punctate hemorrhagic spot.

Eruption

Poikiloderma

See Rash.

A combination of atrophy, telangiectasia, and variegated pigmentary changes (hyper- and hypopigmentation), typical for chronic radiation damage, but also characterizing some genodermatoses.

Erythema More or less transient redness of the skin produced by vascular congestion or increased perfusion.12

Erythroderma Generalized redness and inflammation of at least 90% of the body surface associated with infiltration and desquamation of the skin.

DERMATOLOGICAL EXAMINATION

Ecchymosis

3

Purpura An eruption of many small circumscribed extravasations of blood (petechiae). Vibices are streaky, suggillations are coinsized, and ecchymoses are extensive purpuric lesions.13 Petechiae and purpura are macular in nature. Elevated lesions point to vasculitis allergica (‘palpable purpura’).

Exanthem Generalized or widespread rash of similar skin lesions with a dynamic course (acute onset, temporary persistence, spontaneous regression). Enanthem is the corresponding term for mucosal lesions.

Fistula An abnormal passage from a deep structure to the skin surface or between two deep structures, often lined with squamous epithelium or endothelium.

Gangrene Severe necrotizing process resulting from arterial occlusion or infection.20

Hematoma Deep bleeding with swelling going through characteristic color changes from purple to blue to green-yellow.

Hypertrophy Increase in the size of a structure, tissue or organ.

Impetiginization Impetigo-like secondary infection of an initially non-bacterial skin disorder by bacteria.13

Infiltration Diffuse thickening of the skin by cellular elements over a relatively large area, generally associated with inflammation and redness.13

Rash In a broader sense, the totality of multiple skin lesions, corresponding to the term eruption. In the narrower sense, rash is applied to a widespread skin disease with red and only slightly elevated lesions,14 similar to an exanthem.

Scab A devitalized integral portion of the skin resulting from necrosis.

Sclerosis A circumscribed or diffuse induration or hardening of the skin often due to fibrosis. Due to loss of skin markings and reduction of hair follicles, the skin looks shiny and often ivory-colored. On palpation, it is hard and tight, often adheres to deeper structures and cannot be raised or folded. Sclerosis may develop primarily or after an inflammatory stage. Apart from circumscribed and systemic scleroderma, sclerosis of the skin may occur in further collagen-vascular disorders, some congenital and metabolic disorders, deposition diseases and chronic graft-versus-host disease. It may also be induced by exogenous factors, as medications and chemicals.

Sinus An epithelium-lined channel that permits, via an ostium, the escape of fluid or pus on to the skin surface.

Telangiectasia A visible dilation of small cutaneous blood vessels. 81

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Tumor Tumor is an unspecific generic term used for any larger mass in or beneath the skin irrespective of its inflammatory or noninflammatory, benign or malignant origin. If possible, it should be replaced by a more precise designation.

Vegetation

Table 3.2  Common colors and causes in dermatology COLOR

CAUSES

Red

Hyperemia, erythema Telangiectasia Recent extravasation of blood (purpura)

White

Absence of melanin Anemia Vascular spasm Hyperkeratosis Fibrosis of the upper dermis

Gray

Melanin in the dermis Early necrosis Arsenic, silver, mercury, exogenous pigments, some drugs

Brown

Melanin in the epidermis Hemosiderin Granulomas Serous crust

Black

Melanin in the epidermis Old blood crust Old necrosis

Blue

Cyanosis Stasis Hematoma Melanin in the dermis Arsenic, silver, mercury, exogenous pigments, some drugs

Yellow

Pus Carotene Lipids Bile pigments Infiltrates of mast cells Senile elastosis

Green

Old hemosiderin

A growth of pathologic tissue consisting of multiple closely set papillary elevations, often in intertriginous areas.

Further morphological characteristics DERMATOLOGICAL EXAMINATION

Size The size of individual lesions is already roughly determined by the description of the type of primary lesion. In most instances, particularly in tumors and ulcers, the size should be noted more exactly by indicating the greatest diameter and that at right angles. Metric measures are preferable to terms of comparable objects.

Color Skin lesions may take on a variety of colors, with red, brown and white being probably the most relevant ones in pediatric dermatology. However, just red and brown have many different shades which should be realized as exactly as possible, since many dermatoses have their own typical color. Of course, the influence of the patient’s complexion and intensity of circulation on the color of the lesional skin has to be taken into consideration. The darker the skin, the less informative is the color of the lesions. Common colors and causes are put together in Table 3.2.

Shape/configuration The shape of an individual lesion may be characteristic enough to inform about its evolution or even to make a diagnosis. Many lesions are roundish or oval and may be, for example, guttate (drop-shaped), nummular (coin-shaped) or discoid (disk-like). Others are polygonal (with several sides), polycyclic (several circles touching each other), stellate (star-shaped), digitate (finger-like) or serpiginous (wavy, snake-like). An annular (ringlike) or marginated (with accentuated borders) shape often emerges from peripheral extension and central healing of a lesion. If parts of the ring clear, a circinate/arcuate (arc-like) shape may result. The characteristic target lesion (iris lesion) of erythema multiforme is a cocardiform macule or small plaque that has a dusky center and an erythematous border with an eventual vesicle in the midst. Patches may have leaf-like, linear, whorled, phylloid (like large leafs), or checkerboard configurations. Linear and whorled patches may follow the lines of Blaschko representing the outgrowth of a different cell population during early embryogenesis.

23. Braun-Falco O, Plewig G, Wolff HH, et al. Principles of dermatological diagnosis. In: Dermatology. Berlin: Springer; 1991:1–12.

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Modified from Braun-Falco et al.23 and Fritsch.24

Contour This criterion only applies to solid elevated lesions. They may be flat-topped or dome-shaped, slightly elevated or acuminate, papillated/papillomatous (nipple-like), digitate (finger-like) or umbilicated.21

Surface characteristics If secondary lesions are lacking, the surface texture of a lesion should be checked for roughness or smoothness, shine or dullness, verrucous, papillomatous, and other changes of unevenness.

Margins Skin lesions may be regularly or irregularly, sharply or indistinctly bordered.

24. Fritsch P. Dermatologischer Untersuchungsgang. In: Dermatologie und Venerologie. Lehrbuch und Atlas. Berlin: Springer; 1998:99–115.

Principles of diagnosis in pediatric dermatology

In contrast to all other criteria mentioned above, the consistency of a lesion can only be assessed by palpation. Therefore, it is the last element in the description of an individual lesion. Terms suited for the description of the consistency of a lesion are soft, pasty, firm, hard, fluctuating, compressible, lobulated, and so on. Consistencies may also be compared with natural objects, such as velvety or rock-hard.

Number Low numbers of lesions, around up to 10, should be counted. Higher numbers may be estimated or called multiple, numerous, myriad, countless.

Arrangement Turning away from the individual lesion, the relationship of different lesions to each other has to be assessed. Sometimes, their arrangement is so characteristic, such as in herpes zoster, that a diagnosis is readily enabled. Table 3.3 summarizes the most relevant patterns in which skin lesions may be arranged. The terms circinate/arcuate, gyrate/ polycyclic, and serpiginous are applicable both to the shape of a single and the arrangement of multiple lesions. Individual lesions arranged in these irregular forms may occur. More often, however, a single lesion may take on this shape by extension, confluence and partial recession of several annular lesions.

Linearity of skin lesions is particularly ambiguous. Underlying causes may be:

• The contact with exogenous agents and artificial influences • Physical trigger factors, as defined by the Köbner phenomenon

• The course of blood vessels or lymphatics involved in a dis­ease process

• A genetic mosaic state visualizing the lines of Blaschko • Further factors not satisfactorily explained.12 Köbner phenomenon (isomorphic effect) A non-specific external or internal trauma, such as physical damage, infection, or irritant/allergic reactions, may provoke the occurrence of disease-specific new lesions in the traumatized skin after an average of 10–14 days.25,26 This observation is particularly striking when the lesions show a linear arrangement. The Köbner phenomenon is often seen in psoriasis (Fig. 3.10), lichen planus, and vitiligo but can also occur in many other dermatoses.

DERMATOLOGICAL EXAMINATION

Consistency

3

Distribution The distribution and sites of involvement of a skin disease can only be assessed if the entire integument and mucous membranes are inspected. Remote or hidden, untreated lesions may be more characteristic than those demonstrated by the patient or parents and may provide the decisive diagnostic clue.

Table 3.3  Types of arrangement of skin lesions TERM

EXPLANATION

EXAMPLES

Disseminated

Non-grouped, randomly distributed

Exanthemas

Grouped

Clustered, located close together

Viral warts

Herpetiform

Tightly grouped, touching, partly confluent

Herpes simplex, herpes zoster

Corymbiform

Central lesion or cluster of lesions surrounded by scattered smaller lesions

Melanoma with satellite metastases

Agminate

Grouped without touching

Multiple Spitz nevi

Linear

Following a line (see text)

Phytophotodermatitis, urticaria factitia

Blaschkoid

Following the lines of Blaschko

Linear nevi

Sporotrichoid

Separated but in line

Sporotrichosis

Segmental/zosteriform

Following a dermatome

Herpes zoster

Systematized

Following an overriding principle, such as the vascular system, the nervous system, or lines of embryonal development

Widespread linear nevi

Annular

Ring-like, active margin with clear center

Granuloma annulare

Circinate/arcuate

Arc-like, semicircular

Erythema arciforme et palpabile migrans

Gyrate/polycyclic

Winding, curved, joined annular and arcuate lesions

Erythema annulare centrifugum

Serpiginous

Wavy, snake-like

Creeping eruption

Follicular

Bound to openings of hair follicles

Folliculitis

Reticular

Net-like

Livedo reticularis

25. Fritsch P. Dermatologischer Untersuchungsgang. In: Dermatologie Venerologie. Grundlagen. Klinik. Atlas. 2nd edn. Berlin: Springer; 2004:115–132.

26. Boyd AS, Neldner KH. The isomorphic response of Koebner. Int J Dermatol. 1990;29:401–410.

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due to hypopigmentation and vasoconstriction (nevus anemicus), since the latter fail to redden intensively. After putting on gloves, it can be determined whether a secretion or pasty material can be expressed from a cyst or sinus.

Nikolsky sign

SIMPLE CLINICAL TESTS

Figure 3.10  Köbner phenomenon. Psoriatic lesions around the neck provoked by a necklace.

Furthermore, the distribution itself may be very informative with regard to the cause. It should be noted whether the skin lesions show a localized, regional, generalized, or universal, uni- or bilateral, symmetric or asymmetric distribution. Bilateral and symmetric rashes are often caused by endogenous or systemic agents via hematogenous spread.20 External influences may tend to provoke more focal, unilateral or asymmetrical findings. In most cases, the distribution is not random but certain areas are preferentially involved. These sites of predilection are characteristic of many dermatoses but their origin is often not understood. However, in a number of conditions, the pattern of distribution may be explained, for example, by exposure to sunlight, chemical agents, or mechanical forces, or the blood or nerve supply of the involved areas may be the underlying principle. The documentation of the distribution is often more accurate and rapid in standardized drawings of the body than in wordy records, especially in widespread conditions.

SIMPLE CLINICAL TESTS PALPATION AND MANIPULATION Palpation is quite important during dermatological examination. The palpating finger or fingers can prove the consistency of the lesion, serve to assess whether, for example, a lesion is slightly raised or in the level of the skin, whether the skin is foldable or sclerotic, whether a swelling is dentable (‘pitting edema’) or fluctuating (both pointing to fluids), whether the skin is movable over a nodule or a nodule is fixed to underlying structures, whether a swelling, nodule or tumor is painful on palpation, whether a patch is anesthetic, or whether arteries or cords are pulsatile. The skin temperature, which is cool in ischemia and cyanosis and warm in acute inflammation, is best perceived with the dorsa of the fingers. The vasal reaction after a short pressure exerted on the skin is different in erythemas and cyanosis from normal skin in that the pale macule is filled from the periphery to the center, similar to the aperture of a lens. Rubbing on the skin may help to differentiate between patches

27. Grando SA, Grando AA, Glukhenky BY, et al. History and clinical significance of mechanical symptoms in blistering dermatoses: a reappraisal. J Am Acad Dermatol. 2003;48:86–92.

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The Nikolsky sign was first described by Pyotr Vasilyevich Nikolsky.27 The Nikolsky sign, which shows active acantholysis, helps the clinician to determine if the skin cleavage is intraepidermal or sub-epidermal. Its presence is also indicative of active disease, whereas its disappearance heralds deceleration of the activity. The description of the Nikolsky sign is inconsistent in the dermatological literature and textbooks, yet in reality it is a characteristic sign of acantholytic disorders, namely pemphigus and staphylococcal scalded skin syndrome. Two types of Nikolsky signs are known. ‘Marginal’ Nikolsky sign is performed by rubbing the normal skin at the periphery of a lesion or pulling the remnant of a bulla, and positivity denotes the spread of the erosion to the surrounding normal-appearing skin. ‘Direct’ Nikolsky sign is the induction of a new erosion by rubbing the normal-appearing skin far from an existing lesion. Pseudo-Nikolsky sign is evidenced by peeling of the entire epidermis, which is observed in Stevens–Johnson’s syndrome and toxic epidermal necrolysis (Fig. 3.11). The cause of the peeling is apoptosis of keratinocytes rather than acantholysis, and it can only be elicited in erythematous areas.27 Asboe–Hansen sign, which is referred to as Nikolsky II or indirect Nikolsky sign by some, can be observed in both intraepidermal and subepidermal detachment. It is described as the extension of a bulla by direct pressure; however, the blister extension has a sharp angle in pemphigus vulgaris, whereas in bullous pemphigoid the advanced border is round.

Simple aids for clinical tests Apart from the indispensable magnifying glass, there are some simple and disposable diagnostic aids used in dermatology. The exact size of a lesion can be measured by dermatometers with millimeter scales. Some of them also have round punches of increasing diameters. With the help of a cotton bud, one can determine if a coating on the tongue can be wiped off, as is the case in oral candidiasis. It may also serve to test the fragility of tissues, such as the margins of an ulcer. A probe is used to check the length of a sinus or fistula and whether the margins of an ulcer are undermined. A wooden spatula serves to examine the oral mucosa and to remove or better visualize inconspicuous scaling, such as in pityriasis versicolor.

Dermographism Dermographism refers to pruritic linear wheals and erythema in response to a firm stroke or rubbing applied with a wooden spatula or the round back of a pen. It is usually performed on the back or the forearm of the patient. One study reported that the forearm is the most appropriate body region in testing dermographism.28 In normal subjects, stroking causes a bright-red

28. Tremklinchan V, Kulthanan K, Bunyaratavej S. Assessment of dermographism at different anatomical regions by dermographometer. J Med Assoc Thai. 2006;89:992–996.

3

SIMPLE CLINICAL TESTS

Principles of diagnosis in pediatric dermatology

Figure 3.11  Pseudo-Nikolsky sign. Induction of a small erosion by tangential pressure in a child with toxic epidermal necrolysis. (Courtesy of Dr. Antonio Torrelo.) non-raised line due to vasodilation after 3 to 15 s, known as red dermographism. In urticarial dermographism, due to the release of histamine, a wheal reaction following erythema occurs in the test area after a few to 10 min (Fig. 3.12). In most patients with atopic dermatitis and other atopic diseases, the vascular response to the stroke is paradoxically anemic, therefore it is referred to as white dermographism. White dermographism has a longer time to onset and shorter duration than red dermographism in non-atopic subjects.29 Interestingly, a marked age-dependent increase in the demonstrability of white dermographism in patients with infantile eczema was reported.30 Elicitation of dermographism is firmly dependent on the strength and site of the applied mechanical pressure, therefore, the use of dermographometers seems reasonable in controlled studies. Rarely, delayed urticarial dermographism occurring in pressure urticaria 3–6 h after the stroke and hemorrhagic dermographism in hemorrhagic diatheses can be observed.

Psoriasis phenomena The following three phenomena typical for psoriasis vulgaris can be identified with a wooden spatula in unclear cases:

• Candle sign. If the silvery-white scales are scraped off, they detach from the lesion as small flakes, similar to wax flakes scraped from a candle. • Last cuticle sign. With continuing scraping, one can remove a coherent moist sheet from the lesion, also called the Duncan Bulkley membrane that corresponds to the lowest layers of the epidermis. • Auspitz sign. After removal of the last cuticle, spotty bleeding (‘bloody dew’) occurs, indicating that the dilated capillaries in the papillary dermis are ruptured.31 29. Wong RC, Fairley JA, Ellis CN. Dermographism: a review. J Am Acad Dermatol. 1984;11:643–652. 30. Aizawa H, Tagami H. Inability to produce white dermographism in the early stage of infantile eczema. Pediatr Dermatol. 1989;6: 6–9.

Figure 3.12  Urticarial dermographism induced by firm strokes with a wooden spatula.

Although best known, the Auspitz sign is not sensitive or specific for psoriasis for which the last cuticle sign has the greatest diagnostic value.

Darier sign The Darier sign is elicitation of urtication and an erythematous halo in response to heavy rubbing of a lesion with a spatula or the round end of a pen. Occasionally, even a blister may occur. It is particularly positive in mast cell diseases such as mastocytoma (Fig. 3.13) and urticaria pigmentosa. The presence of the Darier sign in addition to typical lesions of mastocytosis substantiates the diagnosis; however, the Darier sign is not always present and it may be variably elicited. Therefore, histopathological examination is mandatory when there is clinical suspicion.32

Diascopy Firm pressure applied with a hard, transparent instrument, such as a plastic or glass spatula or two microscope slides, may be used to blanch the skin temporarily. With this simple procedure, it is possible to determine if a macule or a papule is due to dilatation of capillaries (erythema) or extravasation of blood (purpura). The erythema subsides whereas extravasations remain visible. Diascopy is key to diagnosing nevus anemicus which is due to vasoconstriction resulting from hypersensitivity to cate31. Christophers E, Mrowietz U. Psoriasis. In: Burgdorf WHC, Plewig G, Wolff HH, et al., eds. Braun-Falco’s dermatology, 3rd ed. Heidelberg: Springer; 2009:506–526. 32. Skrabs CC. Darier sign: A historical note. Arch Dermatol. 2002;138:1253–1254.

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A

B

Figure 3.14  Diascopy. (A) A purple papule showing (B) central bluish discoloration after pressure with a glass spatula corresponding to a broken cactus prickle.

Figure 3.13  Darier sign. Paleness and urticarial swelling with peripheral SIMPLE CLINICAL TESTS

redness after rubbing of a macule in urticaria pigmentosa. (Courtesy of Dr. Antonio Torrelo.)

cholamines.33 Moreover, the brownish apple jelly color elicited by diascopy in certain granulomatous infiltrates, such as in sarcoidosis, tuberculosis, and foreign body granulomas, is a valuable aid in diagnosis (Fig. 3.14). It was reported that diascopy can help discriminate between subtle macules of vitiligo and post-inflammatory hypopigmentation in oral mucosa, which appears white or uniformly hypomelanotic with convex margins in vitiligo and mottled to tan brown with uneven or jagged margins in the latter.34

DERMOSCOPY

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Figure 3.15  Both clinical and dermoscopic images of the same invasive melanoma. The clinical image (inset) lacks the ABCD criteria suggestive of a melanoma. With dermoscopy there is a great deal of asymmetry of colors and structures diagnostic of melanoma. (Image courtesy of Wilhelm Stolz, Regensburg, Germany.) (Reprinted from Dermoscopy of pigmented skin lesions. An atlas based on the Consensus Net Meeting on Dermoscopy 2000. EDRA Medical Publishing and New Media, Milan, 2001, with permission.)

Dermoscopy, the term used by most experts around the world, is also known as digital dermoscopy, dermatoscopy, epiluminescence microscopy (ELM) and skin surface microscopy. It is an in vivo non-invasive technique that magnifies the skin in such a way that colors and structures in the epidermis, dermo-epidermal junction and papillary dermis become visible. These are colors and structures that cannot be seen with the magnification clinicians typically use (Fig. 3.15). With training and experience, the analysis of this extra criterion has been shown to significantly improve the clinical diagnosis of melanocytic and non-melanocytic, benign and malignant skin lesions, especially melanoma, by as much as 30%.35 The technique is significantly more sensitive and specific to diagnose pigmented lesions vs hypo- or amelanotic pathology, both benign and malignant. It is easier to diagnose a heavily pigmented vs amelanotic melanoma.36 Some lesions may be feature-poor or featureless, making dermoscopy less helpful. There are no significant differences in what one sees in adults vs the pediatric population and the technique is helpful in people of all skin types, not only in lighter-skinned races.

Available instrumentation includes the hand-held dermatoscope (different models and manufacturers are available) with a ×10 magnification and digital computer systems. With the dermatoscope, some type of oil or fluid (mineral oil, immersion oil, K-Y jelly, alcohol, ultrasound gel, hand cleaning gels, or water) is placed over the lesion to be examined. Liquid eliminates reflection of light from the surface of the skin and renders the stratum corneum transparent, allowing visualization of subsurface colors and structures. The dermatoscope is then placed directly over the lesion to be examined. The DermLite (different models are available from 3GEN Inc.) utilizes a polarizing system and fluid is no longer needed.

33. Ahkami RN, Schwarz RA. Nevus anemicus. Dermatology. 1999;198:327–329. 34. Tolat SN, Gharpuray MB. Diascopy, the lips and vitiligo. Arch Dermatol. 1995;131:228–229.

35. Kittler H, Pehamburger H, Wolff K, et al. Diagnostic accuracy of dermoscopy. Lancet Oncol. 2002;3:159–165. 36. Menzies S, Kreusch J, Byth K, et al. Dermoscopic evaluation of amelanotic and hypomelanotic melanoma. Arch Dermatol. 2008;144:1120–1127.

Principles of diagnosis in pediatric dermatology

BOX 3.1 HIGH-RISK CRITERIA (MELANOMASPECIFIC CRITERIA)

Table 3.4  Differentiation of a melanocytic from non-melanocytic lesion Pigment network, globules, homogeneous blue color, parallel patterns, by default

Criteria for a seborrheic keratosis

Milia-like cysts, comedo-like openings, fissures and ridges, fat fingers, finger-print pattern, hairpin vessels

Criteria for a basal cell carcinoma

Absence of pigment network, arborizing vessels, pigmentation, ulceration, spoke-wheel structures

Criteria for a vascular lesion

Lacunae

Criteria for a dermatofibroma

Pigment network, central white patch

By default

When there is an absence of all of the above criteria the lesion should be considered to be melanocytic

Some criteria are better visualized with contact dermoscopy using fluid vs non-contact dermoscopy with polarized instrumentation.37 For example, one can better visualize milia like cysts with contact dermoscopy, whereas small vessels are better seen with non-contact polarizing equipment. Minimal pressure is essential when one wants to study small vessels with dermo­ scopy. These differences are not significant when it comes to making a dermoscopic diagnosis. Polarized instruments are by far more practical when one has to examine a patient with many suspicious skin lesions, since fluid is not needed. Dermoscopic analysis is a two-step process.31 Step One is to determine if a lesion is melanocytic or non-melanocytic (Table 3.4). Step Two is to determine if a melanocytic lesion is benign or malignant. There are five well-studied algorithms used around the world. These include: pattern analysis,38 Menzies 11-point scoring system,39 the ABCD rule of dermatoscopy,40 the 7-41 and newest 3-point checklists.42 Whereas most experienced dermoscopists prefer pattern analysis, the 3-point checklist can be used by less experienced clinicians.

Trunk and extremities

>> Asymmetry of color and structure >> Multicomponent (three different areas with a lesion) and non-specific global patterns

>> Irregular pigment network >> Irregular dots and globules >> Irregular streaks (pseudopods, radial streaming) >> Irregular blotches >> Blue-white color >> Regression (bony white color of scarring) >> 5–6 colors >> Irregular vessels (pinpoint, linear, corkscrew, hairpin, milky red areas)

Head and neck

>> Asymmetrical pigmentation around follicular openings >> Annular granular structures >> Rhomboid structures Acral

>> Parallel ridge pattern >> Multicomponent pattern >> Variegate pigmentation

With pattern analysis, one has to identify global patterns and local criteria (Box 3.1). The identified criteria are put into patterns, and patterns correlate with specific pathology. For example, there are patterns of criteria suggestive of different types of melanoma (e.g. superficial spreading, nodular, lentigo maligna, lentigo-maligna melanoma, sub-ungual, acrolentiginous, hypoand amelanotic melanoma), and of different types of melanocytic nevi (e.g. congenital, acquired, halo, recurrent, blue, combined, dysplastic or Spitz).

All of the important criteria have histopathologic correlates. For example, pigment network represents elongated and hyperpigmented rete ridges. Brown globules represent nests of melanocytes at the dermo-epidermal junction and streaks can represent the radial growth phase of melanoma. The skin on the head and neck is thinner than the skin on the trunk and extremities, as compared with the even thicker skin of the palms and soles. As a result, there are criteria and patterns specific (site specific) for these areas of the body. If a pigment network is identified, then the next step is to determine if it is regular or irregular, low- or high-risk, good or bad. A regular pigment network has uniform thin line segments, uniform color and regular holes vs an atypical pigment network in which the line segments are thickened, branched, broken up and/or irregularly pigmented (Fig. 3.16) The more prominent and irregular the pigment network is, the greater the chance that the lesion is high-risk (e.g. dysplastic nevus or melanoma). If dots and globules are present, are they regular, or irregular in size, shape and distribution in the lesion? All of the criteria in a lesion should be identified and analyzed in this manner before making a dermoscopic diagnosis. Potentially disastrous mistakes can be made if one does not try to identify everything within a lesion before making a dermoscopic diagnosis. For example, there might be milia-like cysts in a melanoma. If one stops with

37. Pan Y, Gareau D, Scope A, et al. Polarized and non-polarized dermoscopy. Arch Dermatol. 2008;144:828–829. 38. Johr RH, Soyer HP, Argenziano G, et al. Dermoscopy: the essentials. Edinburgh: Mosby; 2004. 39. Menzies S, Ingvar C, McCarthy W. An atlas of surface microscopy of pigmented skin lesions. Sydney: McGraw-Hill; 1996.

40. Stolz W, Braun-Falco O, Bilek P, et al. Color atlas of dermatoscopy. 2nd edn. Berlin: Blackwell; 2002. 41. Marghoob AA, Braun RP, Kopf AW, eds. Atlas of dermoscopy. London: Taylor and Francis; 2005. 42. Zalaudek I, Argenziano G, Soyer HP, et al. Three point checklist: an open internet study. Br J Dermatol. 2006;154:431–437.

Pattern analysis

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Criteria for a melanocytic lesion

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Atypical pigment network Typical pigment network SIMPLE CLINICAL TESTS

Figure 3.16  A typical/regular pigment network is characterized by regularly meshed and narrowly spaced line segments that gradually thin at the periphery. The atypical pigment network is thickened and branched, usually ending abruptly at the periphery. (Reprinted from Dermoscopy of pigmented skin lesions. An atlas based on the Consensus Net Meeting on Dermoscopy 2000. EDRA Medical Publishing and New Media, Milan, 2001, with permission.)

the identification of milia-like cysts and diagnoses a seborrheic keratosis, the melanoma-specific criteria found elsewhere in the lesion will be missed. It is important to learn the definitions and see images of all of the global patterns and local criteria.43 While one may see classic criteria in a given lesion, not uncommonly there may be variations of the classic patterns, often leading to the need for the development of a dermoscopic differential diagnosis. As a general rule, symmetrical and uniform criteria favor a benign diagnosis, and asymmetry of colors and structures, plus the presence of melanoma-specific criteria, are suggestive but not 100% diagnostic of melanoma. The worst clinical and dermoscopic picture can still turn out not to be melanoma. All of the high-risk global patterns and criteria can be seen in benign as well as malignant pathology (Fig. 3.17).

Menzies 11-point scoring method Menzies scoring method is a variation of pattern analysis. If a lesion demonstrates symmetry of pattern within the lesion (not necessarily symmetry of contour) and the presence of a single color, then in most cases it would not be a melanoma. On the other hand, if a lesion demonstrates asymmetry of pattern and more than one color, and if one or more of nine positive features can be identified, then the lesion should be considered a melanoma (Box 3.2, Fig. 3.18).

ABCD rule of dermatoscopy With the ABCD rule of dermatoscopy, four criteria were found to be significant co-factors for diagnosing melanoma and they

43. Malvehy J, Puig S, Argenziano G, et al. Dermoscopy report: proposal for standardization. Results of a consensus meeting of the International Dermoscopy Society. J Am Acad Dermatol. 2007;57:84–95.

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Figure 3.17  Using pattern analysis asymmetry of color and structure (+), irregular dots and globules (boxes) and blue–white color (arrows) differentiated this superficial spreading melanoma from many seborrheic keratosis that looked similar clinically and surrounded it.

BOX 3.2 MENZIES 11-POINT SCORING METHOD

>> Symmetry of pattern or presence of a single color = benign >> Asymmetry of pattern, more than one color plus 1 to 9 positive features = melanoma

Positive features

>> Blue-white veil >> Multiple brown dots >> Pseudopods >> Radial streaming >> Scar-like depigmentation >> Peripheral black dots/globules >> Multiple colors (5 or 6) >> Multiple blue/gray dots >> Broad pigment network

include: asymmetry (A), borders (B), colors (C) and the presence of different structural components (D). It is a semi-quantitative mathematical approach that gives points for the criteria identified in a lesion and a formula to determine the total dermato­ scopy score (TDS) for each lesion. A TDS 5.45 is highly suspicious but not 100% diagnostic of melanoma (Fig. 3.18). Keep in mind that ‘false positives’, represented by a high TDS, are possible, even in a benign lesion. By definition, there are some lesions that always have a pattern recognition diagnosis, and the ABCD rule of dermatoscopy

Figure 3.18  Asymmetry of color and structure, more than one color, plus

Figure 3.20  This is the classic cobblestone pattern of a banal nevus with large

brown globules (boxes) diagnose this melanoma using Menzies method. There is a total dermatoscopy score (TDS) of 6.6 using the ABCD rule of dermoscopy which is clearly in the melanoma range.

angulated brown globules (arrows) and foci of smaller dots and globules (boxes).

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Principles of diagnosis in pediatric dermatology

Figure 3.21  The starburst pattern in a Spitz nevus demonstrating a Figure 3.19  The saccular pattern diagnostic of a hemangioma. (Reprinted from Dermoscopy of pigmented skin lesions. An atlas based on the Consensus Net Meeting on Dermoscopy 2000. EDRA Medical Publishing and New Media, Milan, 2001, with permission.)

should not be applied. Hemangiomas (Fig. 3.19), compound nevi (Fig. 3.20), and Spitz nevi (Fig. 3.21) are examples of this dermoscopic concept. Asymmetry (A) of contour, color, or structural components is determined by visually dividing the lesion into two 90° rightangle axes, then assigning a score ranging from zero for a lesion that is completely symmetrical in contour, color or structure in both axis, to one point for a lesion that is asymmetrical in one axis and a maximum of two points for a lesion that is asymmetrical in both axes. The mirror image approach is used to judge symmetry or asymmetry within a lesion. This is the only algorithm in which the contour has significance. To determine the border score (B), the lesion is visually divided into eight pieshaped segments, and then the number of segments in which there is an abrupt cutoff at the margins of identifiable criteria (pigment network, branched streaks, dots, globules or diffuse

symmetrical lesion with a rim of pseudopods radially oriented at the periphery of the lesion. (Reprinted from Dermoscopy of pigmented skin lesions. An atlas based on the Consensus Net Meeting on Dermoscopy 2000. EDRA Medical Publishing and New Media, Milan, 2001, with permission.)

pigmentation) is counted. The score can range from zero to eight. Colors (C) to look for include: red, white, light and dark brown, blue-gray and black. White color should be lighter than the surrounding skin and one should not confuse the bony white, scar-like color of regression with hypopigmentation commonly seen in melanocytic lesions. Each color gets a point and the total score ranges from one to six. A lesion with 5 or 6 bright and distinct colors is a significant clue that it might be a melanoma. Different structural components (D) are pigment network, branched streaks (thickened and branched pigment network), structureless areas (color, but no structures such as pigment network, branched streaks, dots or globules), dots and globules. The total different structural component score ranges from one to five. After all of the criteria have been identified, the total dermatoscopy score (TDS) is calculated by multiplying the points by conversion factors (A × 1.3 + B × 0.1 + C × 0.5 + D × 0.5 = TDS). With experience, the TDS can be rapidly calculated. 89

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Table 3.5  Seven-point checklist CRITERIA Major criteria   1. Atypical pigment network   2. Atypical vascular pattern (irregular linear and/or dotted)   3. Blue-whitish veil (blue and/or white color)

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Minor criteria   4. Irregular streaks (pseudopods/radial streaming)   5. Irregular pigmentation (irregular blotches)   6. Irregular dots/globules   7. Regression areas

7-POINT SCORE 2 2 2

1 1 1 1

7-point total score: 3 = melanoma.

The 7-point checklist This is another variation of pattern analysis with a point system that is simpler than the ABCD rule of dermatoscopy, in which major and minor criteria within a lesion are identified. Major criteria receive two points each and minor criteria receive one point. A score of ≥3 has a 95% sensitivity of being a melanoma (Table 3.5, Fig. 3.22).

(boxes, 2 points), irregular brown globules (circle, 1 point) and irregular pigmentation (arrows, 1 point), giving this in situ melanoma a score of 4. Asymmetry of color and structure plus irregular pigment network are 2 out of 3 of the 3-point checklist criteria needed to raise a red flag of concern of high risk pathology.

This is the newest algorithm geared for the less experienced clinician. Asymmetry of color and structure, atypical pigment network and blue-white color are especially high-risk criteria that can be seen in melanoma. With very little training this simplified algorithm can be learned and used by inexperienced clinicians as a highly sensitive way to diagnose melanoma. If two or three of the criteria are identified, the lesion should be considered for excision or referral to an experienced dermoscopist for further evaluation. This algorithm does not differentiate melanocytic from non-melanocytic lesions and a high score can also be seen in a dysplastic nevus or basal cell carcinoma (Fig. 3.22). There are pigmented skin lesions that are not high-risk enough to warrant immediate histopathologic diagnosis, yet not so banal that there is no need for concern. In these situations, sequential digital dermoscopic monitoring can be used. A small percentage of melanomas do not look high-risk clinically or with dermoscopy and are only diagnosed after monitoring for dermoscopic changes over time when comparing baseline with subsequent digital images. Short-term monitoring is performed every 3–4 months44 and long-term monitoring45 is done at 6 months to yearly intervals. Single or multiple suspicious lesions can be chosen for sequential digital monitoring. This approach is very

helpful for pediatric patients with multiple banal or mildly atypically pigmented skin lesions in which the vast majority do not need histopathologic diagnosis (Table 3.6). No patient, especially children, should ever have a skin lesion removed before dermoscopic examination. With this cutting-edge clinical approach, unnecessary surgery can often be avoided. Dermoscopy is an excellent non-invasive way to help diagnose inflammatory and infectious diseases.46,47 Tracts and small gray triangular delta structures representing the scabies mite can be seen, potentially eliminating the need for a scabies scraping (Fig. 3.23). One can diagnose the nits of head lice without a hair pull and microscopic examination and use the technique to track the success of treatment. Viable nits filled with lice embryos can be differentiated from empty nit shells seen after successful therapy. The absence of red and black dots indicates successful wart therapy, while delled, clear papules are seen with molluscum contagiosum. Pinpoint vessels in red scaly plaques are found in psoriasis and bony white reticular structures seen in violaceous papules reflect the Wickham’s striae of lichen planus. Pubic lice and blood-filled ticks are dramatic and confirm the diagnosis. Abnormal capillary loops and sclerotic cotton ball structures help diagnose scleroderma. Trichoscopy is the use of dermoscopy to study hair shafts, follicular openings and perifollicular skin.48 The non-invasive diagnosis of genetic hair shaft abnormalities such as monilethrix, trichorrhexis invaginata and pili annulati are facilitated. Hyperkeratotic plugs in hair follicles appearing as yellow dots along with micro-exclamation point hairs and cadaverized black dot hairs diagnose alopecia areata. Bony white color of scarring

44. Altamura D, Avramidis M, Menzies SW. Assessment of the optimal interval for and sensitivity of short term sequential digital dermoscopy monitoring for the diagnosis of melanoma. Arch Dermatol. 2008;144:502–506. 45. Kittler H, Guitera P, Riedl E, et al. Identification of clinically featureless incipient melanoma using sequential dermoscopy imaging. Arch Dermatol. 2006;142:1113–1119.

46. Zalaudek I, Argenziano G, DiStefani A, et al. Dermoscopy in general dermatology. Dermatology. 2006;212:7–18. 47. Zalaudek I, Giacomel J, Cabo H, et al. Entodermoscopy: a new tool for diagnosing skin infections and infestations. Dermatology. 2008;216:14–23. 48. Rudnicka L, Olszewska M, Rakowska A, et al. Trichoscopy: a new method for diagnosing hair loss. J Drugs Dermatol. 2008;7:651–654.

The 3-point checklist

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Figure 3.22  Using the 7-point checklist one finds irregular pigment network

Principles of diagnosis in pediatric dermatology

3

Congenital nevus

Islands of normal skin, islands of criteria, perifollicular hypopigmentation (Fig. 3.24)

Acquired nevus

The globular or cobblestone pattern with regular dots and globules is the most common pattern seen in children

Halo nevus

Central brown or pink papule can have regular dots and globules or be featureless with surrounding depigmented macule, single or multiple lesions, rarely can be seen with melanoma

Actively changing nevus

Peripheral dots and globules, invariably will enlarge over time, commonly seen in children (Fig. 3.25)

Blue nevi

Homogeneous blue color

Recurrent nevi

Criteria centrally located within a scar

Dysplastic nevi

Looks more benign than malignant, asymmetry of color and structure, irregular network, dots and globules, multifocal hypopigmentation (Fig. 3.26)

Spitz nevi

Starburst pattern with dots, globules and or streaks at the periphery with a homogeneous brown, blue color, can also have a globular pattern or black network, reticular depigmentation or white pigment network can be seen

Superficial spreading melanoma

Variable number of melanoma specific criteria (see Figs 3.17, 3.18)

Nodular melanoma

Intense pigmentation, blue white color, atypical vessels, decreased number to absent local criteria

Amelanotic melanoma

More commonly seen in pediatric population, feature poor or featureless, different shades of pink color, atypical vessels especially centrally located

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Table 3.6  Common dermoscopic patterns

Figure 3.23  Tracts (arrows) and the triangular delta structure (box) characterize this scabies-complex.

Figure 3.24  Perifollicular hypopigmentation (boxes), pigment network (circles) plus dots and globules (arrows) characterize this small congenital melanocytic nevus.

and the absence of hair follicles characterize the broad category of scarring alopecia (Box 3.3).

WOOD’S LIGHT EXAMINATION Wood’s lamp, also known as black light, is a high-pressure mercury lamp. It has a special filter, which allows only the passage of ultraviolet A light (320–400 nm) with a peak wavelength of 365 nm. In a pediatric setting, it is quite valuable in diagnosing cutaneous infections, pigmentary disorders and porphyrias given the safe, non-invasive, simple, convenient and cost-effective nature of the test. Ideally, during examination, the room must be completely dark and the patient must be totally undressed. It is important to note that Wood’s light examination is not sufficiently accurate for use in darker skin types.49 Clinicians must also be aware of the possible fluorescence of topical

A

B

Figure 3.25  Peripheral dots and globules are (A) a dermoscopic clue that (B) this nevus will change over time. This pattern is commonly seen in children and is a red flag of concern if found in an adult. Short-term monitoring was advised but the patient returned 2 years later. The significant change led to an excision and diagnosis of a severely dysplastic nevus.

49. Asawanonda P, Taylor CR. Wood’s light in dermatology. Int J Dermatol. 1999;38:801–807.

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Figure 3.26  Irregular dark blotches (black arrows), multifocal hypopigmentation (red arrows) and irregular globules (boxes) characterize this dysplastic nevus.

yellow-white or copper-orange hue. Wood’s light examination permits early recognition of Pseudomonas infection, which produces the pigment called pyoverdin or fluorescein and gives rise to green fluorescence. Erythrasma, which is a cutaneous infection caused by Corynebacterium minutissimum, shows coral-red fluorescence due to porphyrins produced by the organism.50 Hypopigmentation, or depigmentation in light-colored skin types can be very difficult to assess. Wood’s light examination can be very useful in diagnosing and locating these lesions. In particular, the ash leaf macules of tuberous sclerosis, hypopigmented patches in hypomelanosis of Ito, vitiligo, and piebaldism, can be more easily detected with the aid of the Wood’s lamp.51 In vitiligo, enhancement of the lesion with Wood’s light is nearly diagnostic. Subtle areas of hyperpigmentation can also be highlighted. Compared with normal skin, differences in pigmentation are enhanced to a greater degree in epidermal than in dermal melanocytoses.20 Lastly, urine, stool, teeth and red blood cells of patients suspected of having porphyria can be screened with the Wood’s lamp examination, which produces a characteristic orange-red fluorescence.

TZANCK TEST BOX 3.3 DERMOSCOPY PEARLS

>> Put in the time to learn the basics – there is a significant learning curve

>> Identify all of the criteria in a lesion before making a diagnosis >> Do not only examine atypical lesions to avoid missing high-risk incognito pathology

>> There should be a good dermoscopic pathologic correlation >> High-risk criteria are not always easy to see – focus one’s attention at all times

>> There are exceptions to every rule >> Use the area with the most high-risk criteria to biopsy if an excision is not possible

>> The clinical and dermoscopic ‘ugly duckling’ could be high-risk >> Digital dermoscopy to follow lesions over time >> If it’s pink, stop and think >> Gut feelings should not be ignored >> Dermoscopic evaluation before excision without exception >> If in doubt, cut it out

medications, lint, fibers and soap residue. Some fungal and bacterial infections produce pigments that fluoresce under Wood’s light. Pteridine causes the fluorescence observed in fungal infections. Lesions caused by Microsporum audouinii, M. canis and M. ferrugineum can be recognized by their bright blue-green fluorescence. Trichophyton schoenleinii may show a faint blue color.49 Otherwise inapparent tinea versicolor may be identified by a

50. Jillson OF. Wood’s light: an incredibly important diagnostic tool. Cutis. 1981;28:620–626. 51. Ducharme EE, Silverberg NB. Selected applications of technology in the pediatric dermatology office. Semin Cutan Med Surg. 2008;27:94–100. 52. Tzanck A. Le cytodiagnostic immediate en dermatologie. Bull Soc Fr Dermatol Syph. 1947;7:68.

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Cytology investigates individual cells and their intrinsic characteristics. In cutaneous disorders, cytology was first used by Tzanck,52 and hence, the cytologic examination of skin diseases is referred to as Tzanck test. Tzanck test is a valuable adjunct for diagnosing skin disorders; although it is inexpensive, easy and rapid, it is not widely used in dermatology. Samples for examination are taken by scraping the lesion. In bullous disorders, the roof of an intact blister is removed with a scissors. Excess blister fluid is cautiously absorbed with a gauze or cotton bud. Subsequently, the blister base is gently scraped with a round scalpel blade. The specimen is smeared on a microscope slide, allowed to air-dry for some minutes, stained with Giemsa or another rapid stain used in hematological cytodiagnosis (e.g. Wright stain), and is then examined under the light microscope.53 The Tzanck test is often used for infections induced by herpes simplex viruses and in autoimmune bullous diseases of the pemphigus group. In all forms of pemphigus, many rounded acantholytic cells, the so-called Tzanck cells, are seen (Fig. 3.27A). They have small amounts of basophilic or dark-staining, peripherally concentrated cytoplasm and are not attached to one another. In contrast, normal keratinocytes are polygonal in shape and often aggregate in clumps. In subepidermal bullous diseases such as bullous pemphigoid, acantholytic cells are absent and an abundance of eosinophils is observed. More­over, toxic epidermal necrolysis (TEN) and staphylococcal scalded skin syndrome (SSSS) can be differentiated by using the Tzanck test. In TEN, necrotic basal cells with scattered leukocytes and fibroblasts predominate, whereas SSSS is characterized by dyskeratotic acantholytic cells and few inflammatory cells.54 Diagnostic Tzanck smear findings of herpes simplex, herpes zoster, and varicella infections are multinucleated giant cells and

53. Pariser DM, Caserio RJ, Eaglstein WH. Techniques for diagnosing skin and hair disease. 2nd edn. New York: Thieme; 1986. 54. Ruocco V, Ruocco E. Tzanck smear, an old test for the new millennium: when and how. Int J Dermatol. 1999;38:830–834.

Principles of diagnosis in pediatric dermatology

A

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B SIMPLE CLINICAL TESTS

Figure 3.27  Tzanck test. (A) Rounded acantholytic keratinocytes in pemphigus vulgaris (courtesy of D. Zillikens, Würzburg). (B) Multinucleated giant cells in herpes zoster. Giemsa ×200.

some acantholytic epidermal cells; however, these infections cannot be further differentiated with the Tzanck test (Fig. 3.27B).53 The possibility of positivity in Tzanck smears is higher in early herpetic lesions, particularly in vesicles 5/cm2 or >5/hpf Demodex mites is required.

DIAGNOSTIC METHODS FOR DETECTION OF OTHER MICROORGANISMS

SKIN TESTS

In suspected cases of pediculosis capitis, the diagnosis can be confirmed by observation of a live organism on the scalp. When the parasite is not directly noticeable, ova or nits firmly attached to the hair shaft are looked for (Fig. 3.34). Affected hairs should be cut with scissors and placed on glass slides. It may be useful to apply some plastic mounting medium such as Permount to stabilize the hair. A coverslip is then applied and the hair is examined under the light microscope. For suspected scabies lesions, whether crusted papules, vesicles, pustules, or linear burrows, dermatoscopy of the skin with a drop of immersion oil is very useful. Most mites are identified in the typical burrows of finger webs, flexor aspects of the wrists, and the penis. Parasites, ova, and scybala of scabies mites can also be seen when the burrow is scraped off with a scalpel blade or lancet and the sample is placed on a microscope slide. A drop of immersion oil is placed on the scraping, which is then covered with a coverslip. The scraping material is examined microscopically under low power. In Demodex infestations (rosacea-like demodicidosis, pityriasis folliculorum and granulomatous rosacea) Demodex mites can be detected with standardized skin surface micro­scopy.67 Initially, cyanoacrylate glue – which can penetrate deep into the sebaceous glands and follicles – is applied over the selected area (1 cm2). Subsequently, a glass slide is placed over it and after

66. Bauer JH, Miller OF, Peckham SJ. Medical pearl: confirming the diagnosis of molluscum contagiosum using 10% potassium hydroxide. J Am Acad Dermatol. 2007;56:s104–s105. 67. Forton F, Germoux MA, Brasseur T, et al. Demodicosis and rosacea: epidemiology and significance in daily dermatologic practice. J Am Acad Dermatol. 2005;52:74–87.

SIMPLE CLINICAL TESTS

Figure 3.33  Detection of herpes simplex virus type 2 (HSV-2) in clinical

3

In dermatology, various simple but indispensable tests are utilized such as allergic skin tests and pathergy test. Skin tests in allergic skin disorders are valuable adjuncts in identifying the causative agents. They are primarily employed in immediatetype allergies such as urticaria, angioedema, and anaphylactic shock, as well as in delayed type hypersensitivity allergies such as allergic contact dermatitis. Techniques include the prick test (scratch test), intradermal test, rub test, and patch test. In chronic idiopathic urticaria, an autologous serum test is an aid in confirming the presence of circulating autoantibodies.

PATCH TEST The patch test is a valuable diagnostic tool for determining delayed-type hypersensitivity in patients with allergic contact dermatitis. The patch test should be performed in all children with persistent undifferentiated eczema, as well as difficult-tocontrol or worsening atopic eczema. The prevalence rate of patch test positivity in children ranges from 14.5% to 83%.68,69 Most allergens are diluted in petrolatum, whereas watery allergen solutions must be absorbed on to filter paper. In children, the same concentrations are used as in adults; however, some advocate that in children 10 mg of prednisolone    Short-term use, equivalent to ≤50 mg of prednisolone    Short-term use, equivalent to >50 mg of prednisolone    Topical corticosteroids in the test area Non-immediate drug reactions   Glucocorticoids    Long-term use, equivalent to >10 mg of prednisolone    Short-term use, equivalent to ≥50 mg of prednisolone    Short-term use, equivalent to 90% of hair shafts show oval or round shapes.120

SWEAT TESTING

Scanning electron microscopic evaluation of hair shafts Scanning electron microscopy of hair shafts allows a more accurate three-dimensional view of abnormalities of the configuration and the cuticula of individual hair shafts. It is reserved for scientific uncertainties.

Trichoscopy Trichoscopy is a novel imaging technique for the diagnosis of hair disorders. By utilizing a videodermoscope, it allows high magnification (20–70-fold) of hair, and captures the viewed images digitally and stores them.121 It has been used in the evaluation of many acquired and genetic hair disorders, namely androgenetic alopecia and alopecia areata,121,122 The method rapidly identifies hair shaft abnormalities without the need of hair sampling.123 In alopecia areata, the presence of yellow dots is considered diagnostic, which enables one to differentiate between trichotillomania and telogen effluvium. In the late stages of androgenetic alopecia, yellow dots may also be observed; however, at that stage the diagnosis can easily be made by clinical means.121 Videodermoscopy allows examination of normal and diseased scalp and hair, and shows promise for more fully elucidating these diseases.

120. Hamm H, Traupe H. Loose anagen hair of childhood: The phenomenon of easily pluckable hair. J Am Acad Dermatol. 1989;20:242–248. 121. Ross EK, Vincenzi C, Tosti A. Videodermoscopy in the evaluation of hair and scalp disorders. J Am Acad Dermatol. 2006;55:799–806. 122. Lacarrubba F, Dall’Oglio F, Rita Nasca M, et al. Videodermatoscopy enhances diagnostic capability in some forms of hair loss. Am J Clin Dermatol. 2004;5:205–208.

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Figure 3.43  Minor iodine-starch test for detection of sweat glands.

show triangular shapes, as typical for uncombable hair syndrome. (×50.)

The Minor iodine-starch test is used to visualize an area of hyperhidrosis, or to prove the absence or abnormal distribution of sweat glands. After cleaning the skin a solution containing 2 g of iodine in 10 mL of castor oil and 90 mL of ethanol is applied to the test area with large cotton wool swabs. After the solution dries, potato starch powder is uniformly sprinkled on to the area with a fine sieve. Sweat causes the mixture to turn dark blue. The same test can be performed with iodinated starch powder, which is prepared with 500 g of soluble starch powder and 0.5–1 g of iodine crystals. This method is superior because sweat droplets are visualized as discrete dark purple dots that can be easily cleaned without staining the skin.124 For quantification, sweat production in a defined time interval is assessed gravimetrically. For this purpose, a filter paper is weighed on an electronic precision scale, placed on the dried test area, and then is re-weighed immediately after the test period (usually 1–5 min). The weight difference is taken as the amount of sweat secreted during the collection period. In females affected with X-linked hypohidrotic ectodermal dysplasia, sweat testing on the back identifies, alternately, sweating and non-sweating areas, following the lines of Blaschko (Fig. 3.43).

IMMUNOHISTOCHEMISTRY Immunohistochemistry has been used in the histopathological diagnosis of dermatological disorders for a long time. The technique is based on staining tissue samples with specific antibodies. It is relatively cheap, fast, and can be applied in

123. Olszewska M, Rudnicka L, Rakowska A, et al. Trichoscopy. Arch Dermatol. 2008;144:1007. 124. Sato KT, Richardson A, Timm DE, et al. One-step iodine starch method for direct visualization of sweating. Am J Med Sci. 1988;295:528–531.

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SIMPLE CLINICAL TESTS

Principles of diagnosis in pediatric dermatology

Figure 3.44  Note positive Melan-A staining of melanocytes at the dermoepidermal junction. (×100.)

paraffin-embedded tissues. Its weakest point is that there is no single antibody pathognomic for a particular disease. Many antibodies are required to improve diagnostic accuracy and make a differential diagnosis; however, accurate diagnosis is not always possible. The most common uses of immunohistochemistry in dermatology are for the differentiation of lymphomas, the diagnosis of benign and malignant tumors, and as an aid for the diagnosis of inflammatory and genetic disorders. Immunohistochemistry should be utilized if conventional histopathological examination cannot provide a diagnosis. Additionally, the number of stainings should be restricted and diagnosis should not be based exclusively on immunohistochemical findings.125 Before examination, sections should be mounted on specially coated glass slides prior to incubation with the antibodies. Techniques used include avidin-biotin-peroxidase complex, alkaline phosphatase/anti-alkaline phosphatase, and streptavidin peroxidase or alkaline phosphatase, in which the antibody is used to localize an enzyme to antigen-expressed sites in tissue sections. Consequently, a reagent that develops a color (chromogranin) at the enzyme-antigen-antibody complex site is added (Figs 3.44, 3.45). The alkaline phosphatase-streptavidin method has the greatest sensitivity of all immunohistochemical methods.126 Table 3.12 summarizes the most common antibodies used in immunohistochemistry.

IMMUNOFLUORESCENCE MICROSCOPY Immunofluorescence (IF) microscopy is a laboratory technique for demonstrating the presence of antibodies in tissues or body fluids.128 It has become indispensable in the diagnosis of auto­

125. Braun-Falco M, Schempp W, Weyers W. Molecular diagnosis in dermatopathology: what makes sense, and what doesn’t. Exp Dermatol Epub 2008 Oct 22. 126. Elenitsas R, Nousari CH, Ayli E, et al. Laboratory methods. In: Elder DE, Elenitsas R, Johnson BL, et al., eds. Lever’s histopathology of the skin. 10th edn. Lippincott Williams and Wilkins; 2008:67–81. 127. Kim HJ, Lee JY, Kim SH, et al. Stromelysin-3 expression in the differential diagnosis of dermatofibroma and dermatofibrosarcoma protuberans:

Figure 3.45  Anti-CD3 staining of lymphocytes within the hair follicle in follicular mycosis fungoides. (×200.)

immune diseases, especially bullous dermatoses. There are two basic types of IF technique: direct IF and indirect IF microscopy.

Direct immunofluorescence microscopy This one-step procedure is used to detect antibodies bound to tissue in vivo.128,129 The substrate of the test is a patient’s skin biopsy. The most suitable site of the biopsy depends on the disease being evaluated. For example, the biopsy should be taken from normal-appearing skin adjacent to a blister in autoimmune bullous dermatoses, such as pemphigus vulgaris, and from an early erythematous or purpuric lesion in Henoch–Schönlein purpura. If direct IF microscopy is performed at the same institution where the biopsy is taken, it should be immediately snapfrozen in liquid nitrogen and stored at 270°C until used. Otherwise, it is placed in a special liquid fixative (Michel’s

comparison with factor XIIIa and CD34. Br J Dermatol. 2007;157:319– 324. Epub 2007 Jun 26. 128. Dahl MV. Immunofluorescence in dermatology. In: Clinical immunodermatology. St Louis: Mosby; 1996:417–445. 129. Bhogal BS, Black MM. Diagnosis, diagnostic and research techniques. In: Wojnarowska F, Briggaman RA, eds. Management of blistering diseases. London: Chapman and Hall; 1990:15–34.

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Table 3.12  Common antigens used in immunohistochemistry125

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ANTIGENS

LOCATION

Cytokeratins (Type 1 and 2 IF)

Epidermis and appendages

Vimentin (Type 3 IF)

Mesenchymal cells and melanocytes Lymphomas, sarcomas, melanomas

Desmin (Type 3 IF)

Muscle cells Muscle tumors

Keratin (AE1, AE 3, CAM 5.2)

Epithelial cells Epithelial tumors

Differentiate melanocytic, hematopoietic and mesenchymal tumors

Cytokeratin (CK) 20

Epidermis and its appendages Merkel cell carcinoma

Specific for Merkel cell carcinoma

CEA (carcinoembryonic antigen)

Eccrine and apocrine cells Benign sweat gland tumors, extramammary Paget’s disease

Typically stains adenocarcinomas

Epithelial membrane antigen (EMA)

Sweat and sebaceous glands Squamous cell carcinoma, epithelioid sarcoma

Neuron-specific enolase (NSE)

Neuroendocrine cell, neurons Merkel cell carcinoma, malignant melanoma, neuroendocrine tumors

Chromogranin (A, B, C)

Neuroendocrine cells, eccrine gland cells Merkel cell carcinoma

Synaptophysin

Neuroendocrine cells Merkel cell carcinoma

Normal Merkel cells do not express this antigen

S100 protein

Melanocytes, Langerhans cells, eccrine and apocrine gland cells, nerves, muscles, Schwann cells, myoepithelial cells, chondrocytes, adipocytes Langerhans cell histiocytosis, melanoma, liposarcoma, etc.

Highly sensitive but has low specificity

HMB 45

Nevus cells Some types of melanoma and nevi

Spindle cell and desmoplastic melanomas are negative

Lysozyme

Macrophages, granulocytes, myeloid cells

α1 antitrypsin

Macrophages Carcinoma, melanoma, fibrohistiocytic neoplasms

MART-1/Melan A

Melanocytes, nevi, Spitz nevi, melanoma

Leukocyte common antigen (LCA, CD45)

Granulocytes, lymphocytes, monocytes, macrophages, mast cells, Langerhans cells Lymphoma, leukemia T lymphocytes B lymphocytes Endothelial cells

CD45-RO CD20 CD31

Vascular tumors

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CD34

Endothelial cells, bone marrow progenitor cells Dermatofibrosarcoma protuberans, fibrous tumor, neurofibroma, fibrous papule of the nose etc.

Factor XIIIa

Fibroblast-like mesenchymal cells, dermal dendrocytes, platelets, megakaryocytes, peritoneal and alveolar macrophages, adipose tissue, monocytes, placenta, uterus and prostate

NOTES

It is a non-specific antibody, yet it is used to differentiate melanocytic and mesenchymal tumors

Has low specificity

Helpful in differentiating pigmented actinic keratosis from lentigo maligna, diagnosing spindle cell and desmoplastic melanoma

Negative staining in desmoplastic melanomas

Sensitive marker for vascular tumors except Kaposi’s sarcoma In diagnosis of cutaneous angiosarcoma, more sensitive marker than factor VIII-related antigen Helpful in differentiating dermatofibrosarcoma protuberans from dermatofibroma (CD34 negative)

Principles of diagnosis in pediatric dermatology

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Table 3.12  Common antigens used in immunohistochemistry (continued) ANTIGENS

LOCATION

NOTES

C-kit (CD117)

Mast cells, melanocytes, hematopoietic stem cells, immature myeloid cells, myeloid and lymphoid progenitors Systemic mastocytosis, melanoma, leukemia, some solid tumors

CD1a

Langerhans cells, thymocytes Langerhans cell histiocytosis

Factor VIII-related antigen (von Willebrand factor)

Endothelial cells Angiosarcoma, Kaposi’s sarcoma

Ulex europaeus agglutinin I

Endothelial cells, keratinocytes, eccrine glands Benign vascular tumors, angiosarcoma, Kaposi’s sarcoma

Smooth muscle actin

Smooth muscle cells, myofibroblastic cells Smooth muscle tumors

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Dermatofibroma, fibrous papule of the nose, atypical fibroxanthoma, multinucleate cell angiohistiocytoma, epithelioid cell histiocytoma

Less specific than factor VIII-related antigen

Ki 67

Proliferation marker

Helps to differentiate benign versus malignant

Stromelysin 3127

Stroma Dermatofibroma, basal cell carcinoma, wound healing

More reliable if combined with CD34 in differentiating dermatofibroma from dermatofibrosarcoma protuberans

IF, intermediate filament; MART, melanoma antigen recognized by T cells. Modified from Braun-Falco et al.125

medium), which prevents degradation of tissue, including immunoreactants,130 and sent at ambient temperature to a specialized laboratory. Upon processing, cryostat sections of the biopsy specimen are incubated with fluorescein-labeled antibodies against human immunoglobulins G, A, and M, complement C3, and fibrinogen. Sections are evaluated under a fluorescent microscope with which the antigen sites can be identified by the apple-green color of the fluorescein (Fig. 3.46).128,129 Table 3.13 gives some examples of typical direct IF microscopy patterns in various dermatoses.

Indirect immunofluorescence microscopy Unlike direct IF microscopy, indirect IF microscopy is a two-step serologic test for the detection of circulating autoantibodies in serum or other fluid.128,129 Sera to be analyzed by indirect IF microscopy can be sent by regular mail without freezing or special preservatives; they are stored at 14°C until examined. Normal tissue, preferably monkey esophagus and normal human skin, is used as substrate. Frozen sections of tissue substrate are placed on microscope slides and incubated with serially diluted patient’s serum so that the antibodies can bind to the normal tissue components of the substrate. Subsequently, specimens are

130. Mutasim DF, Pelc NJ, Supapannachart N. Established methods in the investigation of bullous diseases. Dermatol Clin. 1993;11:399–418. 131. Stummvoll GH, Fritsch RD, Meyer B, et al. Characterisation of cellular and humoral autoimmune responses to histone H1 and core histones in human systemic lupus erythematosus. Ann Rheum Dis. 2009;68:110–116.

washed to remove excess antibodies that are not specifically bound, re-incubated with fluorescein-labeled antihuman immunoglobulin or complement, and washed again. The binding sites are identified under a fluorescence microscope. Typical findings are summarized in Table 3.13. Typically, antibody reactivity is expressed as serum titers. The titer is the highest dilution of serum that results in detectable labeling of the antibody.128 With the help of immunoblotting, the antigen responsible for the antibody production can be further specified. Immunoblotting is a method which assesses the antigen specificity of circulating antibodies. It is a reliable technique to discriminate between diseases which have similar immunofluorescence findings, although the real antigens are different.132

Complement indirect immunofluorescence microscopy This three-step technique is a modification of indirect IF microscopy and is suited to determining whether circulating antibodies in a patient’s serum are capable of binding to the complement.128,129 It may be more sensitive than common indirect IF and is used particularly in the diagnosis of pemphigoid gestationis.

132. Pas HH. Immunoblot assay in differential diagnosis of autoimmune blistering skin diseases. Clin Dermatol. 2001;19:622–630.

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Table 3.13  Typical patterns of direct and indirect immunofluorescence microscopy in some important dermatoses

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DISEASE

DIRECT IMMUNOFLUORESCENCE

INDIRECT IMMUNOFLUORESCENCE

TARGETED ANTIGENS

Pemphigus vulgaris

Intercellular IgG and C3

Intercellular IgG

Dsg I, III

Bullous pemphigoid

Linear IgG and C3 at the DEJ

Epidermal IgG (SSS)

BP 180, BP 230

Dermatitis herpetiformis

Granular IgA at dermal papillae

Anti-endomysium IgA

Transglutaminase

Linear IgA disease

Linear IgA and C3 at the DEJ

Epidermal and dermal IgA (SSS)

LAD-1, BP 180, BP 230, collagen type VII

Epidermolysis bullosa acquisita

Linear IgG, lgA and C3 at the DEJ

Dermal IgG (SSS)

Collagen type VII

Henoch–Schönlein purpura

IgA, C3 and fibrinogen at superficial and deep dermal vessels

Negative

Not known

Lichen planus

Colloid bodies coated with IgM; fibrinogen at BMZ

Negative

Not known

Discoid lupus erythematosus

Granular or linear IgG, IgM, IgA, or C3 at BMZ

Negative

Not known

Subacute cutaneous lupus erythematosus

Granular IgG, IgM, C3, fibrinogen at BMZ

Ro/SSA, La/SSB

Ro/SSA, La/SSB

Systemic lupus erythematosus

Linear IgG, IgM, C3 at BMZ

High titer of antinuclear antibodies

Histone H1,131 Double-stranded DNA, Ro/SSA, La/SSB

SSS, salt-split skin; DEJ, dermo-epidermal junction. Modified from Stummwoll et al.131

Figure 3.46  Direct immunofluorescence demonstrating linear IgA deposits in linear IgA disease (Courtesy of D Zillikens, Würzburg). (×160.)

Split-skin indirect immunofluorescence microscopy technique This indirect IF microscopy method is used for differentiation of acquired bullous dermatoses with circulating IgG antibodies against antigens of the basement membrane zone. Split skin with the plane of cleavage in the lamina lucida is produced by incubation with cold 1 M NaCl solution and then used as a substrate for the indirect IF technique (Fig. 3.47). Antibodies in bullous pemphigoid, pemphigoid gestations, and in a subgroup of cicatricial pemphigoid bind to the epidermal roof of the split, whereas antibodies to type VII collagen or laminin 5 in epider110

Figure 3.47  Indirect immunofluorescence visualizing binding of circulating IgA antibodies of the patient to the epidermal roof of a split-skin cleavage in linear IgA disease (Courtesy of D Zillikens, Würzburg). (×400.)

molysis bullosa acquisita, or in another subgroup of cicatricial pemphigoid, bind to the dermal side.129

Antigen mapping This rapid, elegant IF microscopy method is used to assign an inherited bullous disease to one of the three main types of epidermolysis bullosa (EB), namely: EB simplex, junctional EB, and dystrophic EB. Sections of an excisional skin biopsy of a freshly induced blister are stained with mono- or polyclonal antibodies against bullous pemphigoid antigen, laminin 5, and

Principles of diagnosis in pediatric dermatology

3

Table 3.14  Staining patterns of antibodies to bullous pemphigoid antigen 180 (BP 180) and type IV collagen in the three major types of epidermolysis bullosa (EB) BINDING PATTERN OF ANTIBODY TO EB type

BP 180

Type IV collagen

EB simplex Junctional EB Dystrophic EB

Floor Roof Roof

Floor Floor Roof

SIMPLE CLINICAL TESTS

type IV collagen. The level of blister formation and, thus, the EB type can be determined by evaluation of whether a given reagent stains the roof or the floor of the blister (Table 3.14).128

ELECTRON MICROSCOPY Electron microscopic examination is an elegant method requiring great expertise in preparation and evaluation. It is not available in most dermatology departments and, therefore, is not suited for routine use. Electron microscopy allows the structures in the cells to be observed in detail. Two types of electron microscope are used: the transmission electron microscope (TEM) and the scanning electron microscope (SEM). TEM has a higher resolution than SEM, but SEM provides three-dimensional viewing of the surfaces. Therefore, SEM is widely used in the diagnosis of hair disorders. Electron microscopy aids in:

Figure 3.48  Electron microscopy. Detection of Birbeck granules in the cytoplasm of a Langerhans cell in Langerhans cell histiocytosis. (×18 000.)

• The rapid diagnosis of infections by herpes, parapox, and orthopox viruses through negative-contrast staining

In vivo reflectance confocal microscopy is a novel imaging method with high resolution and contrast, which is used for non-invasive in vivo skin imaging. It has many advantages over conventional histology. It is painless, non-invasive, rapid, and does not alter tissue. Additionally, the same skin site can be imaged repeatedly. In short, a point source of light illuminates a small spot within the tissue. The light passess through a pinpoint hole; therefore, only the region that is in focus is detected.

The reflected light is imaged on to a detector. Generally, a ×30 objective lens with a lateral resolution of 0.5–1 µm and an axial resolution of 2–5 µm is used. This system permits imaging of skin to a depth of 250–300 µm (epidermis, papillary, and reticular dermis). For even better imaging, a water-based gel and a skin contact device are used.134 Confocal imaging of skin in vivo correlates well with conventional histology.135 In contrast to conventional histology, grayscale horizontal images are obtained.134 In confocal imaging of normal skin, the stratum corneum appears as a brightly refractive first layer. The granular layer has cells with bright grainy cytoplasm and large dark oval nucleus. The spinous layer looks like a honeycomb with small cells. The basal layer appears as bright cell clusters at the dermo-epidermal junction. In the papillary dermis, reticular fibers and blood vessels can be viewed. The reticular dermis shows matrix fibers, hair follicles, and sweat ducts (Fig. 3.49).135 In vivo confocal microscopy in the diagnosis of psoriasis,136 contact dermatitis,137 infections,138,139 basal cell carcinoma,140 actinic keratosis, and squamous cell carcinoma has

133. Schaller M, Korting HC. Elektronenmikroskopie. In: Korting HC, Sterry W, eds. Diagnostische Verfahren in der Dermatologie, Berlin: Blackwell; 1997:177–181. 134. Gonzalez S, Swindells K, Rajadhyaksha M, et al. Changing paradigms in dermatology: Confocal microscopy in clinical and surgical dermatology. Clin Dermatol. 2003;21:359–369. 135. Nehal KS, Gareau D, Rajadhyaksha M. Skin imaging with reflectance confocal microscopy. Semin Cutan Med Surg. 2008;27:37–43. 136. González S, Rajadhyaksha M, Rubinstein G, et al. Characterization of psoriasis in vivo by reflectance confocal microscopy. J Med. 1999;30:337–356.

137. Astner S, González E, Cheung AC, et al. Non-invasive evaluation of the kinetics of allergic and irritant contact dermatitis. J Invest Dermatol. 2005;124:351–359. 138. González S, Rajadhyaksha M, González-Serva A, et al. Confocal reflectance imaging of folliculitis in vivo: correlation with routine histology. J Cutan Pathol. 1999;26:201–205. 139. Hongcharu W, Dwyer P, Gonzalez S, et al. Confirmation of onychomycosis by in vivo confocal microscopy. J Am Acad Dermatol. 2000;42:214–216. 140. González S, Tannous Z. Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma. J Am Acad Dermatol. 2002;47:869–874.

• The definitive diagnosis of Langerhans cell histiocytosis by proving the existence of Birbeck granules in the cytoplasm of histiocytic cells (Fig. 3.48) • The diagnosis of many genodermatoses, such as epidermolysis bullosa, ichthyoses, and collagen and storage diseases.133

IN VIVO REFLECTANCE-MODE CONFOCAL MICROSCOPY

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Figure 3.49  Sequential images of normal human

A

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B

C

D

E

112

skin taken with in vivo reflectance-mode confocal microscopy (RCM). From epidermal level (A) to reticular dermis (E), in vivo RCM shows a sequence of virtual and parallel optical sections in the transverse plane. These RCM images have histological resolution, showing cytological details such as nuclei or cellular morphology, which have been correlated with conventional histology features. From upper to deeper, virtual optical sections show the normal epidermal pattern constituted by polygonal-shaped cells (keratinocytes) with an oval to round dark central area (cellular nucleus) surrounded by a bright cytoplasm with well demarcated and brighter cell borders forming a honeycomb pattern (A). The following RCM virtual optical sections (B) are composed of small bright cells grouped in oval structures, which are correlated with pigmented basal keratinocytes covering upper level of dermal papillae (DP). Cellular bright is due, principally, to refractivity of melanin contained in pigmented basal keratinocytes (red arrows in C). These structures show bright cellular rings (yellow arrows in C) surrounding dark dermal papillae (DP), with grey thin collagen bundles and dark central spaces of capillary vessels (asterisks), at the level of dermalepidermal junction (C and D). The deepest level we can see with RCM is superficial reticular dermis, where we can see grey thick collagen bundles (yellow arrows in E) and adnexal structures such as hair follicles (HF) with their central bright hair shaft (red arrows in E). (Courtesy of Dr. JL Santiago Sánchez-Mateos. Department of Dermatology, Hospital General Universitario de Ciudad Real, Spain.)

Principles of diagnosis in pediatric dermatology

MOLECULAR METHODS In situ hybridization In situ hybridization techniques allow specific nucleic acid sequences to be detected in morphologically preserved chromosomes, cells, or tissue sections.144,145 In combination with immunocytochemistry, in situ hybridization can provide microscopic topological information about gene activity at the DNA, mRNA, and protein level. The technique is based on hybridization of a complementary DNA probe to the DNA sequence of interest. First, the tissue is incubated with a labeled probe. The specimen is then coated with a photographic emulsion or chromogenic substance that shows the location of the hybridization of the labeled probe and the target DNA.146 Fluorescence in situ hybridization (FISH) is a newer technique, which is more rapid and it allows the use of multiple probes in a single procedure. It is performed with fluorescent-labeled DNA probes that are complementary to the DNA sequence of interest. If hybridization occurs, fluorescence is generated, which is detected with a fluorescence microscope. FISH is used in cancer research, gene mapping, prenatal research, and infectious diseases studies. It is also used in the detection of genetic alterations in melanoma, as well as diagnosis of X-linked ichthyosis.147

Polymerase chain reaction (PCR) PCR is an in vitro technique for enzymatically synthesizing defined sequences of DNA. It is superior to other detection techniques because it is fast, sensitive, and works with small quantities of DNA. For example, it can be used to find very low quantities of an infectious agent present in clinical samples, by exponentially increasing the quantity of a specific nucleotide sequence of a pathogen.148 The patented PCR technology uses two primers that hybridize to opposite strands and flank the target DNA sequence to be amplified. The primer pair consists of short oligonucleotides (15–25 bases) chosen from known nucleic acid sequences of the target and corresponding to com-

141. Aghassi D, Anderson RR, González S. Confocal laser microscopic imaging of actinic keratoses in vivo: a preliminary report. J Am Acad Dermatol. 2000;43:42–48. 142. Ulrich M, Stockfleth E, Roewert-Huber J, et al. Noninvasive diagnostic tools for nonmelanoma skin cancer. Br J Dermatol. 2007;157(suppl 2):56–58. 143. Langley RG, Rajadhyaksha M, Dwyer PJ, et al. Confocal scanning laser microscopy of benign and malignant melanocytic skin lesions in vivo. J Am Acad Dermatol. 2001;45:365–376. 144. Reischl U, Wolf H. The use of molecular methods in infectious diseases. Biotest Bulletin. 1998;6:3–20.

5‘

3‘ primer

5‘

3‘

5‘

3‘

5‘

5‘

3‘

3‘

annealing 3‘ 5‘ target sequence

3‘

5‘

3‘

5‘

3‘

5‘

3‘

3‘

5‘

3‘

5‘

5‘

repeat process

In PCR to replicate a target sequence of DNA, primers, nucleotides and DNA polymerase are used

Figure 3.50  Polymerase chain reaction (PCR). PCR uses a thermostable DNA polymerase to amplify a specific target segment of the DNA defined at each end by a specific primer.

SIMPLE CLINICAL TESTS

been previously used and is reported to be very beneficial.141,142 It has also been used for the diagnosis of melanocytic lesions. Because melanocytes have high contrast, melanocytic lesions can be viewed and differentiated easily with confocal microscopy. In the light of recent studies, it appears that in vivo reflectance confocal microscopy has great potential in the diagnosis of melanocytic lesions, eliminating unnecessary excision of benign melanocytic lesions.143 Current limitations are limited depth of imaging and a lack of details of the ultrastructure of the tissues in grayscale images.

3

plementary DNA strands. Elongation of the primers is catalyzed by a heat-stable DNA polymerase, such as Taq DNA polymerase. The reaction is accomplished by a series of temperature changes, consisting mainly of three steps (Fig. 3.50):

• Denaturation (DNA strand separation at 95°C) • Annealing (primer attachment to a complementary strand at 55–60°C)

• Extension (3′-DNA strand synthesis starting at the 5′-3′-end of each primer molecule at 72°C). Because the primer extension products synthesized in a given cycle can serve as a template for the next cycle, the number of target DNA copies approximately doubles every cycle. Thus, 20 cycles of PCR yield about a million copies (220) of the target DNA. Detection of the amplificate is typically performed by hybridization with labeled probes. Recently, ultra-rapid realtime cycling techniques, such as the LightCycler System (Roche Molecular Biochemicals), have been developed to complete PCR in 20 min, by way of very rapid air heating and cooling. Realtime PCR is a new PCR method in which target amplification and detection occur simultaneously. Yet, the time required to complete the assay is shorter. Additionally, real-time PCR allows quantification applications.

Ligase chain reaction (LCR) LCR is another technique for detecting or amplifying a target sequence. Unlike PCR, LCR uses a thermostable DNA ligase to link two adjacent oligonucleotide probes on each strand of the target DNA.144,148 After ligation and denaturation, the joined fragments serve as templates for further rounds of thermocyclic

145. Pardue ML, Gall JG. Molecular hybridisation of radioactive DNA to the DNA of cytological preparations. Proc Natl Acad Sci USA. 1969;64:600–604. 146. Parslow TG. Molecular genetic techniques for clinical analysis of the immune system. In: Parslow TG, Stites DP, Terr AI, et al., eds. Medical immunology. 10th edn. New York: McGraw-Hill; 2001:260–269. 147. Sra KK, Babb-Tarbox M, Aboutalebi S, et al. Molecular diagnosis of cutaneous diseases. Arch Dermatol. 2005;141:225–241. 148. Reischl U, Mayer J. Modern methods in nucleic acid-based diagnostics. Lab Med. 1993;17:456–464.

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5‘

3‘ Denatured DNA

3‘

5‘ probe annealing

5‘

3‘

3‘

5‘ probes are ligated by DNA ligone

5‘

3‘

3‘

5‘ probes anneal and amplify both original target and duplicate

SIMPLE CLINICAL TESTS

Figure 3.51  Ligase chain reaction (LCR). LCR uses a thermostable DNA ligase to link two adjacent oligonucleotide probes on each strand of the target DNA.

amplification, which, as in PCR, proceeds exponentially (Fig. 3.51). In clinical tests (e.g., Abbott LCx Probe System), capture and detection ligands are attached to the opposite ends of probe fragments so that only ligated products are both captured and detected. Current applications include the direct detection of Mycobacterium tuberculosis, Neisseria gonorrhoeae, and Chlamydia trachomatis in clinical specimens.

G banding G banding is a widely used technique, especially for the detection of chromosomal abnormalities in cutaneous T cell lymphomas.149 With this method, histone proteins, which hold chromosomes together, are digested with trypsin. Following this process, which unfolds the chromosomes, Giemsa staining is performed. A distinctive banding pattern on the chromosome is observed, which shows any numeric or structural chromosomal abnormality. Major limitations are the requirement of a high rate of cell division and cells in metaphase, as well as its inability to detect subtle translocations, deletions, or insertions.147

DNA microarray DNA microarray is another in situ hybridization technique that allows simultaneous evaluation of multiple probes within one

149. Karenko L, Hyytinen E, Sarna S, et al. Chromosomal abnormalities in cutaneous T-cell lymphoma and in its premalignant conditions as detected by G-banding and interphase cytogenetic methods. J Invest Dermatol. 1997;108:22–29. 150. Kunz M. DNA microarray technology in dermatology. Semin Cutan Med Surg. 2008;27:16–24. 151. Lowell C. Clinical laboratory methods for detection of cellular immunity. In: Parslow TG, Stites DP, Terr AI, et al., eds. Medical immunology. 10th edn. New York: McGraw-Hill; 2001:234–249.

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sample. It is widely used in gene-expression analysis, as well as for single nucleotide polymorphism and point mutation detection. The DNA microarray technique has been used to detect gene alterations or gene expression patterns in tumors, such as malignant melanoma, and basal cell and squamous cell carcinomas, as well as in psoriasis, lupus erythematosus, and systemic sclerosis.150 DNA probes are arranged in a specific order on a plastic support (microarray). The microarray can be formed of either complementary DNA or oligonucleotides. After reverse transcribing the RNA from tissues to DNA, it is fluorescently labeled and then hybridized to the slide. When hybridization occurs, fluorescent spots can be visualized on the platform.

Flow cytometry Flow cytometry is a commonly used method to measure and analyze features of single cells. It is an instrument that measures the light scattered by cells as they pass through an orifice at high velocity. The cells are labeled with fluorescent-tagged antibodies and the light they emit is measured as well. The light-scattering properties of cells are affected by their size and intracellular structure. For analysis, samples should be a single-cell suspension. With the increase in the available monoclonal antibodies that recognize more surface markers, flow cytometry will discriminate more cells.151

PRENATAL DIAGNOSIS Prenatal diagnosis in pregnancies with a particular risk for the recurrence of severe hereditary skin diseases, such as severe types of epidermolysis bullosa and ichthyosis, began in the early 1980s by submitting mid-trimester fetal skin biopsies for ultrastructural and immunohistological evaluation. In the last decade, remarkable progress has been made in elucidating the molecular basis of many genodermatoses. As a result, DNAbased prenatal diagnosis in chorionic villus samples during the first trimester of pregnancy has become available for more and more inherited conditions.152,153 More recently, pre-implantation diagnosis has become possible using in vitro fertilization techniques. In this case, DNA analysis is performed with a blasto­ mere biopsy of a 6–10-cell embryo, thereby avoiding the need for later termination of a fetus determined by conventional methods to be affected.152 Of course, the severity of the clinical phenotype has to justify the effort of prenatal diagnosis, and the parents should be willing to bear the consequences of positive results. The current status of prenatal diagnosis is discussed in greater detail in Chapter 6 on neonatal skin disorders.

152. Shimizu H, Suzumori K. Prenatal diagnosis as a test for genodermatoses: its past, present and future. J Dermatol Sci. 1999;19:1–8. 153. Ashton GH, Eady RA, McGrath JA. Prenatal diagnosis for inherited skin diseases. Clin Dermatol. 2000;18:643–648.

Mandi L. Maronn, Alanna F. Bree, Elaine C. Siegfried, Alex Zvulunov, Orith Waisbourd-Zinman, Dan Ben-Amitai, Ayelet Adir-Shani, Antonio Martorell, Antonio Torrelo, Zoe D. Draelos and Howard B. Pride

INTRODUCTION Mandi L. Maronn, Alanna F. Bree and Elaine C. Siegfried Each physician’s approach to therapy is tailored to the individual patient based on collective experience and accumulated research data. Unfortunately, accumulated research data have been less than adequate for pediatric patients. Children have been referred to as ‘therapeutic orphans’ because the majority of commercially available medications have never been studied in pediatric patients, and clinical trials for new drugs are also limited in this age group.1,2 This chapter is an introduction to the basic principles of dermatologic treatment for children, intrinsically biased by the personal experiences of the authors. For hundreds of years, until more specific pharmacologic agents became available, variations of salicylic acid, zinc oxide, tar, sulfur, phenol, mercury, boric acid and iodine were the mainstays of therapy for a wide variety of skin problems. The therapeutic and safety profiles of many of these older drugs have not been subjected to the rigorous scrutiny required for today’s approval by the United States Food & Drug Administration (FDA). Long-term and widespread use confer a degree of confidence for a few of these compounds, but many have been responsible for under-appreciated toxicity in vulnerable infants.3 Newer approaches to treatment are so much more effective and specific that old clichés have lost their meanings: ‘If it’s wet, dry it …’ is still true, but the improved dermatologic armamentarium now includes a variety of topical and systemic antibacterials, antifungals, antivirals, retinoids, vitamin D analogs, corticosteroids and a host of non-steroidal biologic immune response modifiers. Making the correct diagnosis is the most important step in prescribing effective treatment. The wrong treatment will not only fail to improve the primary problem but may also cause side-effects that can further complicate the process.

1.

Blumer JL (ed.) The therapeutic orphan. A Joint Conference of the Pediatric Pharmacology Research Unit Network, the European Society of Developmental Pharmacology, and the National Institute of Child Health and Human Development, held in Washington DC, May 2, 1997. Pediatrics. 1999;104:581–645.

4



PRESCRIBING PEARLS

Principles of treatment in pediatric dermatology

PRESCRIBING PEARLS Escalating costs of healthcare are a major concern for everyone. The cost of medication is a significant out-of-pocket expense that can be prohibitive. Walmart, Sam’s Club, and Neighborhood Market recently started a $4 drug program. A large number of both prescription and over-the-counter generic medications can be obtained for $4 in a 30-day supply and $10 for a 90-day supply. Prescriptions must initially be filled in person and refills must be picked up at the store. For particular brand-name drugs, the price of different forms (e.g., liquid versus tablet) may vary greatly. The prices are similar for 1-, 2.5-, 5-, and 10-mg tablets of prednisone. Per milligram, 10-mg capsules of 13-cis-retinoic acid (Accutane) cost two to three times as much as 40-mg tablets. In general, liquid and chewable forms of medication are more costly than equivalent doses in capsule or tablet form. Liquid medication may also have altered bioavailability, significantly shortened shelf-life and require refrigeration. Milligram for milligram, cimetidine syrup and griseofulvin suspension cost almost three times more than equivalent doses in tablet form. However, cefadroxil (Duricef) liquid, 500 mg/5 mL, is one-half the price of 500-mg tablets. Generic medications are almost always less costly and in many cases can be substituted for brand-name drugs. Benadryl (diphenhydramine hydrochloride) costs 10 times more than its generic equivalent. An affordable mid-potency topical steroid may be compounded by adding 5 mL (200 mg) of generic triamcinolone acetonide, 40 mg/mL, to 1 lb of white petrolatum or vegetable shortening. It is mixed in a bowl and kept in the refrigerator. This is a 0.045% triamcinolone ointment and is intermediate to the commercially available 0.1% and 0.025% preparations. Keep in mind, generic preparations may not perform as consistently as the brand-name equivalent, particularly in the category of topical corticosteroids.4 Costs also vary greatly for over-the-counter products, including dressing materials, cleansers, emollients, sunscreens, topical wart therapies and antiseborrheic shampoos. Simple soap-and-

2. 3. 4.

Rowell M, Zlotkin S. The ethical boundaries of drug research in pediatrics. Pediatr Clin North Am. 1997;44:27–40. Spray A, Siegfried E. Dermatologic toxicology in children. Pediatr Ann. 2001;30:197–202. Jackson D, Thompson C, McCormack J, et al. Bioequivalence of generic corticosteroids. J Am Acad Dermatol. 1989;20:791.

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water baths will sanitize, wet and gently debride the skin just as well as a host of more expensive chemical baths. Discarded, clean towels can fulfill the need for dressings just as well as any commercially available dry gauze material. White petrolatum is the least irritating and most cost-effective emollient available. When the cost of medication is a family burden, or if more convenient, readily available therapy has failed, the use of time-honored preparations may be considered. Many of these compounds have predated requirements for rigorous testing of safety and efficacy but have survived decades, or even centuries, of use with good reputations. Salicylic acid is a good example. This agent has recently enjoyed a renaissance in popularity and is commercially available in a variety of non-prescription topical products. However, simple formulations may also be compounded. An amount of 3–6% salicylic acid in isopropyl alcohol is inexpensive and useful for the treatment of acne, seborrheic dermatitis and tinea. If this mixture is too drying, glycerin may be added to the solution as follows: 10% in the summer, 15% in the winter and 20–40% for xerotic skin. In an effort to stop itching, 0.25% menthol can be added if desired. This mixture can also be used to treat itchy, scaly, dry skin; however, it burns when applied to open wounds, cuts, or scrotal skin. An amount of 40–70% salicylic acid is an effective agent for debriding warts. Salicylic acid may be systemically absorbed and could lead to salicylism; therefore, it should not be used on infants or extensively on children with widespread skin disease. Topical phenol, at a concentration of 0.5–2%, has been popular since the early twentieth century. It has been an active ingredient in many widely used over-the-counter preparations (e.g., Noxzema, Ungentine, Sarna Carmex and Chloraseptic) for its bacteriostatic and anesthetic properties. Other phenolic compounds include hexachlorophene (pHisoHex), triclosan (the active ingredient in many liquid deodorant soaps) and resorcinol. In addition to its antimicrobial properties, application of a phenolated material for 1 hour is believed to augment the antipruritic and anti-inflammatory effects of a subsequently applied topical corticosteroid. In concentrations above 5%, phenol may be a tumor promoter. Use in infants under 6 months of age should be avoided due to associated neonatal hyperbilirubin­ emia, seizures and death.5,6 Phenol has been eliminated from Sarna and Chloraseptic preparations because of concerns about toxicity. A very effective swish-and-swallow oral preparation can be custom-compounded for patients with extensive oral erosions from a variety of non-infectious diseases such as Stevens– Johnson syndrome, epidermolysis bullosa, lichen planus and aphthous stomatitis. Given the name Magic Mouthwash, it is administered up to four times a day in divided doses of up to 4 mL/kg per day. It contains 120 mL nystatin suspension (100 000 U/mL), 480 mL diphenhydramine elixir (12.5 mg/ 5 mL) and 240 mg hydrocortisone powder (USP) mixed in 720 mL of 2% sodium carboxymethylcellulose. A total of 240 mL (125 mg/mL) of either erythromycin (for children

Successful topical therapy depends not only on the selection of the most appropriate pharmacologically active ingredient but also on the most optimal vehicle for delivery. Vehicles include water-soluble liquids, gels and foams, powders and lipid-based ointments, creams and lotions. A variety of other ingredients are added to improve the odor, texture, color, and shelf life. Liquid bases include water, alcohol, glycerin and propylene glycol. Glycerin is hygroscopic, humectant and soluble in water and alcohol. Propylene glycol is more widely used than glycerin. It is not only miscible with water, alcohol, acetone and essential oils, but it is also a preservative and possesses in vivo antimicrobial activity against certain bacteria, dermatophytes and Pityrosporum. Propylene glycol in concentrations of >5% may irritate the skin; allergic contact dermatitis is uncommon, but important to recognize because of its prevalence in foods, medications, industrial products and a wide variety of topical preparations.7 Used as a vehicle for orally administered vitamins or intravenous medications, propylene glycol has been associated with central nervous system (CNS) toxicity in premature infants.8 Adverse reactions to glycerin are much less common.9 A popular line of emollient products (Biersdorf) illustrates the relationship between ointment, cream and lotion: Aquaphor is petrolatum, mineral oil, mineral wax and wool wax alcohols; Eucerin Creme is Aquaphor with water, emulsifiers and preservatives; Nivea Creme is Eucerin with more water, glycerin plus additional emulsifiers, stabilizers, solvents and fragrance. The preservative used in the cream and lotion products (methylisochlorothiazolinone/isothiazolinone or Kathon CG) is a common cause of allergic contact dermatitis in adults and children.10 Propellants are rapid but less cost-effective vehicles for topical medication. Sprays require extra effort to avoid the eyes and direct the medication to where it is needed. Alcohol-based vehicles can cause stinging and irritation when applied to compromised skin. Commercially available petrolatum-based emollient sprays include Dermamist (Ferndale Laboratories), with 10% petrolatum in a mineral oil, coconut oil, butane, isobutane, propane vehicle, and Diaper Rash with Vitamins A&D Spray (Touchless Care Concepts, LLC), with 50% mineral oil, 15% petrolatum, cyclomethicone, cod liver oil, lanolin, microcrystalline wax, lemon oil. Moisture Barrier Spray with Zinc Oxide (Touchless Care Concepts, LLC) is a similar product that also

5.

8.

6. 7.

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West DP, Worobec S, Solomon LM. Pharmacology and toxicology of infant skin. J Invest Dermatol. 1994;76:147. Adams R. Principles in practice of topical therapy. Pediatr Clin North Am. 1971;18:685. Catanzaro J, Smith J. Propylene glycol dermatitis. J Am Acad Dermatol. 1991;24:90.

under age 8) or tetracycline suspension (for older children) may be added. An amount of 2% viscous lidocaine may also be added with caution. Another commonly used version of Magic Mouthwash is viscous lidocaine, simethicone, and diphenhydramine mixed in equal parts.

GENERAL PRINCIPLES OF SKIN CARE IN CHILDREN VEHICLES

MacDonald MG, Getson PR, Glaogow AM, et al. Propylene glycol: increased incidence of seizures in low birth weight infants. Pediatrics. 1987;79:622. 9. Fischer AA. Contact dermatitis. Ch. 17, 3rd ed. Philadelphia: Lea & Febiger; 1986. 10. Manzini BM, Fewrdani G, Simonetti V, et al. Contact sensitization in children. Pediatr Dermatol. 1998;15:12.

Principles of treatment in pediatric dermatology

for maintaining stratum corneum hydration or promoting penetration of an active ingredient. Ointments are water-insoluble occlusive mixtures of animal, vegetable or mineral lipids. White petrolatum, a mineral-based hydrocarbon, is a purified and bleached or more often synthetic mixture of high-molecular-weight alkanes. This inexpensive ointment is widely used because it is odorless, colorless and rarely sensitizing. Anhydrous lanolin is a natural product derived from sheep’s wool. It contains sterols (cholesterol, lanosterol), fatty alcohols (steryl and cetyl alcohol) and fatty acids with varying composition. Lanolin is rarely sensitizing in people with normal skin, but it is a cause of allergic contact dermatitis in those with chronic skin problems. Ointments impart a greasy– tacky feel to the skin and can exacerbate miliaria, acne and folliculitis in some patients. The commercial division separating ointments from creams is blurred, and the nomenclature can be confusing. Many prescription ‘ointment’ vehicles are greasy water-in-oil creams (e.g., Westcort, hydrocortisone valerate ointment). ‘Hydrophilic ointment’ is an oil-in-water cream that contains a high pro­ portion of water to make it washable and easily spreadable. While plain white petrolatum is a pure hydrocarbon grease, hydrophilic petrolatum (e.g., Aquaphor, Beiersdorf) is a mixture of pure petrolatum, beeswax, alcohols, cholesterol and a little water, formulated to facilitate compounding with hydrophilic ingredients. Powders are finely pulverized, hygroscopic agents that dry and minimize friction of the skin surface. Examples include zinc oxide, zinc stearate, magnesium stearate, talc, cornstarch, and precipitated calcium carbonate. Applied to intertriginous areas, powders absorb body fluids to prevent maceration and irritation, but caking is often a problem. Powder should be administered gently and directly to the skin, not shaken or dusted so as to avoid inhalation of the material. Contrary to popular belief, cornstarch does not encourage bacterial, yeast, or fungal overgrowth. Some commercially available powders contain other active ingredients (e.g., antimicrobial agents) for use in the treatment of tinea pedis or as deodorants/antiperspirants. Pastes are a mixture of powder and ointment. They are used as protectants against external irritants and sunlight. Lassar’s Plain Zinc Paste is a historically compounded 1 : 1 : 4 mixture of zinc oxide, starch and white petrolatum. Variants of this recipe are useful for diaper dermatitis and intertrigo. Pastes are opaque and are best applied liberally, obscuring the underlying skin from inspection. However, ointment-based pastes are easily removed with mineral oil and gentle wiping. Zinc oxide-based pastes may be used as broad-spectrum sunscreen. Opaque products were popularized by the addition of day-glo coloring. Micronized zinc oxide is a more cosmetically acceptable alter­ native, transparent to visible light, but effectively blocks UVA and UVB.

GENERAL PRINCIPLES OF SKIN CARE IN CHILDREN

contains 25% zinc oxide. Sprays are a fast and effective means of applying sunscreen to children. Foam is another rapid and well-accepted vehicle that is more easily directed to the application site. Alcohol-based foams (e.g., Luxiq, Connetics) are especially useful to treat hair-bearing areas. Gels are popular astringent vehicles for people with oily skin and are well suited for acne medications and sunscreens. They are colloidal dispersions in a semi-solid base that liquify on contact and dry to a greaseless film. Most gels are composed primarily of water, acetone, alcohol or propylene glycol suspended with organic polymers such as agar, gelatin, hydroxypropyl cellulose, carbomer methylcellulose, pectin and polyethylene glycol. Gels also enhance penetration through the epidermis, so they are useful for the delivery of corticosteroids, especially in hair-bearing areas. In some cases, initial treatment with a gelbased exfoliant will thin psoriatic plaques prior to topical corticosteroid therapy and allow increased absorption. Disadvantages of gels include lack of emollient properties, burning and stinging on application and, in some cases, ready dissolution after washing or perspiring. Lotions are suspensions of powder or other material in liquid. They offer the convenience of easy spreadability over large areas. They can be rubbed into almost any surface, even hair-bearing and intertriginous areas. Lotions containing alcohols are cooling, antiseptic and astringent, but they often sting or burn when applied to compromised skin, which limits their use in eczematous conditions. A ‘shake lotion’ is a powder-in-water suspension that requires mixing immediately before application. Shake lotions have been historically useful as protective, drying and soothing treatments for subacute inflammatory processes. Basic shake lotion contains zinc oxide, talc, glycerin and water. Calamine lotion is basic shake lotion plus ferric oxide, bentonite magma and calcium hydroxide. ’Soapless cleansers’ are lotions primarily composed of either glycerin (Aquanil) or propylene glycol (Cetaphil) and fatty alcohols. These products were originally designed to limit skin drying from frequent bathing with hot water and harsh soaps. When applied to dry skin, these products produce a foamy film that can be wiped off, leaving a humectant lubricating residue. However, frequent, short, tepid water baths with limited use of gentle cleansing products have many benefits including skin debridement, fun, and relaxation. Immediately after bathing, application of a bland emollient will limit evaporative desiccation and enhance skin hydration. Creams are emulsions of oil (hydrophobic hydrocarbons, animal or vegetable fats) and water; the ratio of these ingredients determines the texture, emollient and occlusive properties of the product. The less greasy, washable oil-in-water emulsions have been referred to as ‘hydrophilic ointment’ or ‘vanishing cream.’ The more lubricating, occlusive products are also known as ‘cold cream.’ Formulation of creams requires the addition of emulsifiers, stabilizers and preservatives. Humectants, perfumes, and coloring agents are often added. Cream is the most popular vehicle for topical medications. As a generalization, the number of ingredients in a cream is proportional to the risk of contact irritation or sensitization, but specific ingredients such as wool wax alcohols, formaldehyde, formaldehyde releasers, parabens and Kathon CG are particularly common sensitizers. Other limitations of creams are poor retention on oozing surfaces, matting of hairy areas and diminished efficacy compared with ointments

4

SOAPS AND CLEANSERS The skin of infants and children does not differ significantly from that of adults in regard to cleaning. Skin thickness and epidermal barrier function are mature by 32 weeks’ gestation. The skin surface lipids of neonates are similar to those of adults, with an increased ratio of sebum lipids (triglycerides, wax esters and squalene) to lipids derived from keratinocytes (cholesterol, ceramides and fatty acids). By comparison, sebum lipids are 117

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proportionately diminished in children.11 Similar to its role in adolescent acne, the increased ratio of sebum in infants may influence the pathogenesis of neonatal acne. Otherwise, the presence or absence of sebum has not been shown to significantly contribute to basic skin integrity or cutaneous disease in pediatric patients.12 Cleansing agents lower the surface tension of water emulsifying (combining of two liquids that do not easily mix) and trapping oil and dirt. Classic soaps are derived from animal fat (tallow) or vegetable fat (e.g., coconut oil) processed with lye (sodium or potassium hydroxide) to yield alkali or metallic salts of fatty acids. They are by nature alkaline in solution (pH 9.5– 10.5), with superfatted soaps at the lower end of this range; in comparison, the pH value of normal skin is approximately 4–5.5. Synthetic detergents, or ‘syndets,’ are synthetically derived organic quaternary ammonium compounds or fatty acids that have been polymerized or sulfonated. Syndets can be buffered to a neutral or slightly acidic pH.13 Many claims have been made about the importance of using neutral or cationic cleansers to avoid interruption of epidermal barrier function and to prevent skin irritation. However, the pathogenesis of skin irritation is complex, and pH alone probably does not play the primary role.14 Bar soaps tend to be more irritating than liquid cleansers, but liquids can be easily over-dispensed. Excessive amounts of cleanser, scrubbing and incomplete rinsing will contribute to irritation. Hundreds of millions of dollars are spent annually on the products manufactured and marketed for the care of infants’ skin. These products have more stringent standards for purity, potential toxicity and irritancy. However, for infants and children with normal skin, there is no need to use special cleansing products. The best soap for normal skin is the one the buyer likes best. ’Soapless cleansers’ are lotions that are primarily composed of either glycerin (Aquanil) or propylene glycol (Cetaphil) and cetyl/steryl alcohols. They are hygroscopic, lubricating agents that work by hydrating insoluble molecules. When applied to skin, they produce a foam that can be wiped off with a humectant residue. A wide variety of ‘medicated soaps’ are available. Those containing antimicrobial agents are used as deodorants, antiseptics and to augment therapy for bacterial folliculitis. Other types of additives (e.g., benzoyl peroxide, tar, salicylic acid, sulfa) probably do not stay on the skin long enough to have a therapeutic effect. These, as well as fragrances and dyes, may act as primary irritants or allergens in susceptible individuals. A self-cleansing mechanism is inherent in skin; thus, daily bathing is more a pleasurable ritual than a necessity. Regular cleansing is necessary only in areas that accumulate waste and dirt, such as the groin and underarms. Frequent bathing in tepid water can be helpful in debriding wounds, controlling pruritus and hydrating xerotic skin. Colloidal oatmeal or cornstarch

11. Ramassastry P, Downing D, Pochi P, et al. Chemical composition of human skin surface lipids from birth to puberty. J Invest Dermatol. 1970;54:139. 12. Pochi P. The sebaceous gland. In: Maibach H, Boisits EK, eds. Neonatal skin: structure and function. New York: Marcel Dekker; 1982:Ch. 3. 13. Strube D, Nicoll G. The irritancy of soaps and syndets. Cutis. 1987;39: 544. 14. Murahata R, Toton-Quinn R, Finkey M. Effect of pH on the production of irritation in a chamber irritation test. J Am Acad Dermatol. 1988;18:62.

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added to bathwater can also be soothing. The addition of oil to bath water does not effectively moisturize skin, but it can transform the bathtub into a slippery hazard.15 Immediate application of an ointment or cream emollient after bathing is a safe and effective method to maintain skin hydration. Percutaneous penetration is enhanced through warm, wet skin. Emollients and topical corticosteroids are best applied immediately after bathing while skin is damp. It is important to pat the skin, rather than aggressively rubbing it completely dry with a towel, in order to maintain a small amount of water on the skin’s surface. Irritating or potentially toxic topical medications (e.g., topical retinoids, vitamin D analogs, DEET and lindane) should not be applied until at least 20 min after bathing when the skin has thoroughly dried.

SHAMPOOS Shampoos are liquid soaps or detergents. Baby shampoos are more tolerable for infants and children because they are isotonic to tears and less irritating to the eye. Baby shampoos generally contain fragrances and dyes, but trigger allergic contact dermatitis only in very susceptible individuals. Shampoo can be an effective vehicle for applying anti-inflammatory and antimicrobial agents to the scalp, for the treatment of conditions such as seborrheic dermatitis and psoriasis. A variety of medicated shampoos are available. Coal tar shampoo is relatively inexpensive and effective, but its odor can be offensive and repeated use can discolor blonde hair. Shampoos containing fluocinolone acetonide (Dermasmoothe) or clobetasol (Clobex) are more cosmetically acceptable anti-inflammatory alternatives. A 15-min daily application of Clobex shampoo was compared with daily application of clobetasol gel in subjects >12 years old. Both were effective in the treatment of psoriasis, but hypothalamic pituitary adrenal (HPA) axis suppression and thinning of the skin were seen in patients treated with the gel and not those treated with the shampoo. Shampoos that contain anti-Pityrosporum agents, including salicylic acid, urea, ketoconazole, zinc pyrithione, selenium sulfide and ciclopirox, are also effective in the treatment of psoriasis and seborrheic dermatitis.16 Many active ingredients in medicated shampoos are substantive (with residual adherence to the scalp after rinsing). To maximize efficacy, shampoos should be applied before a bath and left on for 10–20 min under a towel before washing and rinsing. Shampooing 2–3 times weekly is enough to control normal flaking but there is no harm in daily shampooing.17

EMOLLIENTS Dry skin is manifest by diminished pliability, scaling and mechanical cracking. Appropriate water balance, neither undernor overhydration, is the most important factor in maintaining

15. Hills RJ, Unsworth A, Ive FA. A comparative study of the frictional properties of emollient bath additives using porcine skin. Br J Dermatol. 1994;130:37. 16. Ward RM. Children, drugs and the Food & Drug Administration: studies of pediatric drugs are beginning to catch up. Pediatr Ann. 2001;30:189–194. 17. Abeck D. Rationale of frequency of use of ciclopirox 1% shampoo in the treatment of seborrheic dermatitis: results of a double-blind, placebocontrolled study comparing the efficacy of once, twice, and three times weekly usage. Int J Dermatol. 2004;43:13–16.

Principles of treatment in pediatric dermatology

INGREDIENT TYPE

MECHANISM OF ACTION

EXAMPLES

Lubricating agents

Occlusion

Petrolatum Mineral oil Lanolin Silicones

Humectants

Absorption of moisture from the air

Glycerin Propylene glycol Ethylene glycol Sorbitol

Tissue-derived

Unclear

Hyaluronic acid compounds Collagens Elastin Lecithins Polycationic resins

Keratin softeners

Alters keratin to produce a softening effect

Urea Lactic acida Glycolic acidsa

Polyamino sugar

Binds keratin

Pen-Kera Creme condensate (keratinbinding factor)

a

alpha-hydroxy acids have both exfoliant and humectant properties. Modified from Grove GL. The effects of moisturizers on skin surface hydration as measured in vivo by electrical conductivity. Curr Ther Res 1991; 50:712, with permission.

barrier homeostasis. Several humidity-dependent enzymatic catabolic pathways mediate normal stratum corneum development.15 Balanced ratios of ceramide, fatty acids and cholesterol (the three major stratum corneum lipids) also play an important role in barrier function. Emollients are lipid-containing substances that soften the skin and influence epidermal homeostasis by preventing transepidermal water loss and facilitating corneocyte sloughing at the level of the stratum corneum. Evidence suggests that changes in hydration and corneocyte adhesion at the stratum corneum affect the growth and development of the entire epidermis.18 Ointment emollients are primarily occlusive (see above). Cream emollients often contain hygroscopic agents that attract environmental moisture to the skin. A wide variety of skin moisturizers are available (Table 4.1). Petrolatum, a nonphysiologic mineral lipid, is an ointment that consists of longchain aliphatic hydrocarbons. It has been considered the gold standard of emollients. It is non-sensitizing and provides an effective barrier to transepidermal water loss for 4–6 h. Other non-physiologic lipids from animals (e.g., lanolin) or plants (e.g., vegetable shortening) may be more sensitizing. Unfortunately, many people have a tactile aversion to the thick, sticky texture of ointments. Occlusive ointments may exacerbate atopic dermatitis in hot or humid environments, and may exacerbate pruritus especially in children with atopic dermatitis or miliaria.

18. Imayame S, Ueda S, Isoda M. Histologic changes in the skin of hairless mice following peeling with salicylic acid. Arch Dermatol. 2000;136:1390–1395.

The use of ointments may also exacerbate acne and folliculitis. Mineral oil is a similar product with a lower melting point that provides a less effective artificial barrier, but it may be more cosmetically acceptable. In attempts to create products that spread more easily and that feel and smell better, the cosmaceutical industry continues to develop cream and lotion formulations. These oil-and-water emulsions contain many other active and inactive ingredients. Inactive ingredients, including preservatives, emulsifiers, dyes and fragrances, are common causes of allergic contact dermatitis in susceptible children. Active ingredients include humectants, exfoliants and physiologic lipids. Humectants, such as propylene glycol and glycerin, are hygroscopic compounds. Exfoliants decrease corneocyte adhesion and result in superficial sloughing. α- and β-hydroxy acids have both humectant and exfoliant properties. Many emollients containing α-hydroxy acids (e.g., lactic acid or glycolic acid) and β-hydroxy acids (e.g., salicylic acid) are currently marketed. Exfoliants are useful in the treatment of scaling conditions; however, these compounds can be quite irritating in higher concentrations. Excessive absorption can lead to systemic acidosis after topical application to large surface areas on infants or on compromised skin (e.g., ichthyoses).16 Topical application of an optimized ratio of exogenous physiologic stratum corneum lipids (cholesterol, free fatty acids and ceramide) offers a safe, new approach to barrier repair for xerosis and atopic dermatitis.19 For children with normal skin, the best moisturizer is the one that the patient prefers. For children with xerosis and/or a tendency toward atopic, irritant or allergic dermatitis, ointment or simple (fragrance and preservative-free) cream emollients are the most effective, safest and usually least costly. The efficacy of any emollient can be optimized by applying it to damp skin immediately after bathing (see the Soaks and Bathing section below for additional details).

GENERAL PRINCIPLES OF SKIN CARE IN CHILDREN

Table 4.1  Classification of moisturizing ingredients

4

ANTIPRURITICS The pathophysiology of pruritus is complex and is not well understood.20 Histamine is the primary stimulus of the pruritus associated with urticaria. Other chemical stimuli that provoke itch include opioids and enkephalins. Pruritus may be associated with a wide variety of skin disease, or it may be ‘essential’ – a nagging primary symptom without obvious skin lesions. Everyone’s itch threshold is different, so the presence or absence of pruritus may not be a diagnostic clue. The most important steps in relieving itch are to find and treat the underlying cause. Several non-specific measures can also be helpful to all patients who itch: avoiding physical stimuli such as vigorous scratching and rubbing, heat, hot water, wool and tight-fitting clothing. Scratching, in particular, will induce skin changes that itch and perpetuate a vicious ‘itch–scratch’ cycle. A behavior modification technique that works well for some children is to teach them to squeeze or pat the area rather than scratch, and to use the fingerpad rather than fingernail, in an attempt to avoid breaking the skin and an increased risk of bacterial infections. Tepid to

19. Chamlin SL, Frieden IJ, Fowler A, et al. Ceramide-dominant, barrier-repair lipids improve childhood atopic dermatitis. Arch Dermatol. 2001;137:1110–1112. 20. Denman S. Review of pruritus. J Am Acad Dermatol. 1986;14:375.

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cool bath water with colloidal oatmeal added may be soothing. It is important to follow the above recommendations for moisturizing in all patients with a tendency toward xerosis. Application of emollients or topical medications that have been refrigerated provides a cooling sensation to the skin and may limit pruritus via the gating theory of nerve conduction. Topical antipruritic agents include anesthetics and products that mask itch. Pramoxine hydrochloride is a non-irritating, rarely sensitizing, topically applied anesthetic agent, commercially available over-the-counter with or without hydrocortisone in cream, lotion and gel formulations. Topical 5% doxepin hydrochloride cream (Zonalon) is FDA-approved for the shortterm management of pruritus in adults.21 It has been associated with allergic contact dermatitis, which should be kept in mind if a patient fails to improve or worsens while using the cream.22 Excessive absorption can cause drowsiness. Other antipruritic ingredients are potentially irritating and/or sensitizing and should be avoided. Topically applied diphenhydramine has been such a common cause of allergic contact dermatitis that it is no longer the active ingredient in topical Benadryl. Given the popularity of oral diphenhydramine, it has surprisingly not been reported to provoke systemic contact dermatitis. Camphor and menthol are over-the-counter agents that mask itch by promoting a cooling or tingling sensation. Coal tar has anti-inflammatory properties. These agents are minimally irritating, have a low potential for sensitization and are available as gels, lotions, creams, foams and ointments. Menthol and gel vehicles are only appropriate for use on intact skin. Phenol has anesthetic properties, but carries a risk of percutaneous toxicity and should be avoided in infants and small children. Systemic antihistamines are widely used as a non-specific treatment for pruritus in infants and children. Even at therapeutic doses, they carry the adverse CNS effects of idiosyncratic agitation, dyskinesia and even anticholinergic syndrome. Longacting, non-sedating antihistamines have been available since 1990. The first of these, astemizole and terbinafine, were associated with the development of hemodynamically significant cardiac tachyarrhythmias in adults. An overdose of astemizole resulted in multiple cardiac arrhythmias in a 3-year-old.23 These medications are no longer marketed. Newer agents have not been associated with similar adverse effects. FDA approval for safety and efficacy has been demonstrated for non-sedating antihistamines, fexofenadine (down to age 12), loratadine (to age 3), and cetirizine to age 2. Systemic antihistamines are the drugs of choice for treating itch associated with urticaria and dermatographism. For patients

with these histamine-mediated conditions, non-sedating agents are an effective but expensive option24 that will interfere with skin allergy testing for up to 1 month after discontinuation. For other types of pruritus, antihistamines are used primarily for their sedative effects. Non-sedating antihistamines are widely used to help control the pruritus associated with atopic dermatitis, but only a few small randomized, double-blind, placebocontrolled (RDBPC) clinical studies have evaluated their efficacy.24 Of these, only cetirizine yielded a marginally significant improvement compared with placebo at the highest, sedating dose (40 mg/day).25 Data support a possible adverse effect of H1 blockade, and beneficial effect of H2 blockade on the atopic immune response. This information should give pause to clinicians who routinely prescribe diphenhydramine and hydroxyzine for children with atopic dermatitis.26

21. Drake L, Breneman D, Phillips S, et al. Topical doxepin hydrochloride provides an increased clinical benefit when added to topical corticosteroid treatment for atopic dermatitis. Presented at the AAD Annual Meeting, Washington DC, December 1993. 22. Bonnel RA, La Grenade L, Karwoski CB, et al. Allergic contact dermatitis from topical doxepin: Food & Drug Administration’s postmarketing surveillance experience. J Am Acad Dermatol. 2003;48:294–296. 23. Tobin J, Doyle T, Ackerman A, et al. Astemizole-induced cardiac conduction disturbances in a child. JAMA. 1991;266:2727. 24. Wahlgren C, Hagermark O, Bergstrom R. The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis. Br J Dermatol. 1990;122:545. 25. Klein PA, Clark RA. An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol. 1999;135:1522.

26. Jutel M, Watanabe T, Klunkel S, et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature. 2001;413:420. 27. Overgaard Olsen L, Jemec GB. The influence of water, glycerin, paraffin oil and ethanol on skin mechanics. Acta Dermat-Venereol. 1993;73:404. 28. Jordan W, Blaney T. Factors influencing infant diaper dermatitis. In: Maibach H, Boisits EK, eds. Neonatal skin: predisposition, structure and function. Vol 1. New York: Marcel Dekker; 1982. 29. Leyden J, Katz S, Stewart R, et al. Urinary ammonia and ammoniaproducing microorganisms in infants with and without diaper dermatitis. Arch Dermatol. 1977;113:1678. 30. Elias M, Feingold KR. Does the tail wag the dog? Role of the barrier in the pathogenesis of inflammatory dermatoses and therapeutic implications. Arch Dermatol. 2001;137:1079–1081. 31. Adalat S, Wall D, Goodyear H. Diaper dermatitis-frequency and contributory factors in hospital attending children. Pediatr Dermatol. 2007;24:484–488.

CARE OF THE DIAPER AREA Many aspects of this common condition have been studied for well over a century, but the etiology, true prevalence and optimal treatment of diaper dermatitis are still issues of debate. Diaper dermatitis typically occurs at 6–12 months of age.27 The condition was once attributed to the effects of ammonia; however, objective studies did not support this theory.28,29 Many factors contribute to the pathogenesis of diaper dermatitis, but the nidus of the problem begins with excessive hydration, maceration and friction.30 Four factors shown to be associated with the development of diaper dermatitis are: oral thrush, high number of previous episodes, frequency of diaper changes and diarrhea.31 Once skin barrier function has been compromised, irritants (e.g., urine, fecal lipases, proteases, bile salts) and microorganisms (urease-splitting bacteria, Staphylococcus aureus, β-hemolytic streptococcus, Pseudomonas spp., Candida albicans) can exacerbate the problem. Exogenous irritants or potential allergens in cleansers, commercial diaper wipes and a myriad of over-thecounter topical products can perpetuate the process in susceptible infants. The most important steps in preventing diaper dermatitis are maintaining good hygiene, preserving skin barrier function and preventing irritation. Traditionally, an effective but laborintensive approach has been frequent diaper changes with gentle cleansing, thorough drying and limited use of vaporimpermeable plastic or rubber diaper covers. This practice has been greatly simplified by the introduction of disposable diapers. The first disposable diapers (Pampers; Proctor & Gamble Co., Cincinatti, OH, USA) were marketed in 1963. For 20 years, the

Principles of treatment in pediatric dermatology

32. Lane A, Rehder P, Helm K. Evaluation of diapers containing absorbent gelling material with conventional disposable diapers in new-born infants. Am J Dis Child. 1990;144:315. 33. Rory V, Wun C, Morrow A, et al. The effect of diaper type and overclothing on fecal contamination in day-care centers. JAMA. 1991;265:1840. 34. Odio MR, O’Connor RJ, Sarbaugh F, et al. Continuous topical administration of a petroleum formulation by a novel disposable diaper. 1. Effect on skin surface microtopography. 2. Effect on skin condition. Dermatology. 2000;200:232–234.

BOX 4.1 UNCOMMON CAUSES OF DIAPER DERMATITIS

>> Acrodermatitis enteropathica >> Bullous pemphigoid >> Cutaneous signs of child abuse – ecchymoses, scald injury >> Chronic bullous dermatosis of childhood >> Congenital syphilis >> Cystic fibrosis >> Dermatitis herpetiformis >> Ecthyma gangrenosum >> Enterobius (pinworm) infestation >> Epidermolysis bullosa >> Granuloma gluteale infantum >> Herpes simplex >> Langerhans cells histiocytosis >> Immunodeficiency syndromes >> Inborn errors of metabolism >> Incontinentia pigmenti >> Kawasaki disease >> Papular urticaria >> Perianal streptococcal dermatitis >> Post-scarlet fever desquamation >> Psoriasis >> Scabies >> Staphylococcal scalded skin syndrome >> Tinea inguinalis >> Wiskott–Aldrich syndrome.

GENERAL PRINCIPLES OF SKIN CARE IN CHILDREN

absorbent core was composed primarily of cellulose fluff. During that time, several conflicting studies compared the incidence of diaper dermatitis in infants using cloth diapers versus infants using disposable diapers.32 In the mid-1980s, a superabsorbent core material was developed. It was composed of a cross-linked sodium polyacrylate that transforms to hold a proportionately large amount of fluid within a gel substance. Several studies have concluded that superabsorbent diapers are superior to cloth diapers in preventing diaper dermatitis.32 In addition, super­ absorbent diapers may prevent occult fecal contamination of clothing and fomites in daycare settings.33 Another diaper innovation was first marketed in 2000 as Pampers Rash Care diapers. An incorporated inner layer continuously deposits a petroleumbased barrier product to the skin. Limited trials with normal infants demonstrated a reduction in skin microtopography and erythema when compared with controls.34 These diapers can be quite effective at preventing and helping to heal diaper rashes, but the downside is they are expensive when compared with other diapers on the market. There have been reports of allergic contact dermatitis to various blue, pink, and green dyes used in the production of diapers. Dye-free diapers should be used for allergen avoidance if necessary.35 Routine use of topical preparations to prevent diaper dermatitis is not necessary for infants with normal skin. Some of these products have additional risks. Additives have the potential to cause contact sensitization, irritation and/or percutaneous toxicity. Powders applied vigorously enough to aerosolize pose an aspiration risk. This is especially true for talc (mainly hydrous magnesium silicate) powders which can cause irritant pneumonitis. Talc may also cause granulomatous reactions when applied to wounds. Contrary to previous theory, cornstarch does not enhance the growth of C. albicans on the skin.36 Boric acid, once popular as a diaper rash treatment and still an ingredient in some diaper care products, is a cause of diarrhea, erythroderma and failure to thrive.3 A new product containing a combination of miconazole, zinc oxide, and white petrolatum was recently released on the market, Vusion (Barrier Therapeutics, Inc. Princeton, NJ). It is indicated for the treatment of candida diaper dermatitis, but is costly. It also contains fragrance, a potential allergen. Appropriate treatment of diaper dermatitis begins with correct diagnosis of the underlying cause. Most infants develop acute diaper dermatitis as a result of the factors described above. However, other primary pathologic processes must be considered for any infant with chronic, severe and/or recurrent diaper rash. Primary cutaneous diseases that may present with diaper rash include contact dermatitis, seborrheic dermatitis, psoriasis and candidiasis. Infants with atopic dermatitis may be more susceptible to irritants, and diaper dermatitis was common in this group prior to the availability of superabsorbent diapers. Since that time, the diaper area of atopic infants is most often dramatically spared, an important diagnostic and therapeutic

4

Modified from Schaad et al. (1991)38 with permission.

sign. Several uncommon causes of diaper dermatitis have serious, or even life-threatening, implications37 (Box 4.1). These conditions should always be considered in infants presenting in the first month of life, in immunocompromised patients and in those who are not otherwise thriving. Mild to moderate irritant diaper dermatitis should be treated initially by reminding caregivers of the importance of avoiding excessive wetness and exposure to feces. This can be achieved with traditional frequent diaper changes and the use of superabsorbent diapers. Leaving the area open is impractical and use of a hair dryer may cause inadvertent injury. All potential irritants or sensitizers, including often-overlooked commercial diaper wipes, should be discontinued. Water-dampened soft cloths or paper towels, or mineral-oil-soaked cotton pledgettes are safe

35. Alberta L, Sweeney SM, Wiss K. Diaper dye dermatitis. Pediatrics. 2005;116:e450–e452. 36. Leyden J. Corn starch, Candida albicans, and diaper rash. Pediatr Dermatol. 1984;1:322. 37. Lane A. Diaper rash: causes and cures. Patient Care. 1988;22:167–173. 38. Schaad UB, Stoupis C, Wedgwood J, et al. Clinical, radiologic and magnetic resonance monitoring for skeletal toxicity in pediatric patients with cystic fibrosis receiving a three-month course of ciprofloxacin. Pediatr Infect Dis. 1991;10:723.

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alternatives. Zinc oxide, in ointment or paste formulation, is an inexpensive, bland protective agent with antiseptic and astringent properties. Zinc may also play a role in wound healing.39–41 This is an ideal first-line therapy for diaper dermatitis, applied liberally with each diaper change. Adherent zinc oxide need not be removed, but it wipes away easily with mineral oil to allow skin examination. If there is no objective evidence of candidiasis, a short course of a topical low-potency corticosteroid or topical immunomodulator may be beneficial. When potassium hydro­ xide (KOH) preparation or culture supports the diagnosis of a yeast infection, treatment should be initiated with a topical antiyeast agent. However, the majority of topical antifungals are inherently irritating and may exacerbate the dermatitis. Nystatin ointment and ciclopirox olamine cream are the least irritating products. Gentian violet is another effective alternative that requires only one to two applications. Combination products containing potent topical corticosteroids and antifungal agents are less effective than an antifungal agent used alone.42 One such product that combines the potent class I topical steroid of 0.05% betamethasone dipropionate with 1% clotrimazole (Lotrisone, Schering-Plough, Kenilworth, NJ) has resulted in reports of skin atrophy, striae and even adrenal suppression when applied under the occlusion of a diaper.43 Lotrisone as well as the similar product combining 0.1% triamcinolone acetonide and nystatin (Mycolog II, Bristol-Myers Squibb, Princeton, NJ, USA) are contraindicated for diaper dermatitis.

COSMETICS Many cosmetics and personal grooming products are now produced and marketed specifically for children and adolescents. In many cases, only the packaging distinguishes these products from those marketed for adults. Products marketed specifically for infants may contain minimally irritating ingredients or feature safety packaging. Adverse reactions from these products have not been reported, but cosmetics should be considered as a possible cause in children with dermatitis.44 Contrary to popular belief, cosmetics do not cause or exacerbate acne. Many cosmetologists and dermatologists recommend the use of specific ‘non-comedogenic’ products in their patients with acne. This practice is based on the concept of comedogenesis as a primary process in the pathogenesis of acne. The rabbit ear assay has been a widely used test to evaluate comedogenicity. The predictive value of this model is not necessarily a reliable model for humans, and the association between acne and cosmetics is currently overmarketed.45 Therefore, it is difficult to predict whether a cosmetic will exacerbate acne for a given patient based on industry standards for product testing.

39. Maitra A, Dorani B. Role of zinc in post-injury wound healing. Arch Emerg Med. 1992;9:122. 40. Okada A, Takagi Y, Nezu R, et al. Zinc in clinical surgery – a research review. Surg Today. 1990;20:635. 41. Rackett S, Rothe M, Grant-Kels J. Diet and dermatology – the role of dietary manipulation in the prevention and treatment of cutaneous disorders. J Am Acad Dermatol. 1993;29:447. 42. Gange RW, Soparkar A, Matzinger E, et al. Efficacy of a sunscreen containing butylmethoxydibenzoylmethane against ultraviolet a radiation in photosensitized subjects. J Am Acad Dermatol. 1986;15:494.

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Rarely, cosmetic products are associated with two distinct types of adverse cutaneous reactions in people with acne. One is a rapid-onset irritant folliculitis. The other develops slowly following chronic use of a truly comedogenic product and is known as acneigenesis. There are industrial acneigens that cause occupational acne, but most cosmetics available today do not promote the formation of comedones. With few exceptions, notably hair pomades and some petrolatum products, it is not necessary to recommend restricted cosmetic products for patients with acne.

SUNLESS TANNING PRODUCTS For adolescents who insist on a tanned appearance, sunless tanning is a safe and often cosmetically acceptable alternative. The active ingredient in self-tanning or sunless products is dihydroxyacetone (DHA).46 DHA is a three-carbon sugar and is a white, crystalline powder that is stable between a pH of 4–6. It reacts with the free amino acid group of amino acids, peptides and proteins found in sweat and stratum corneum keratinocytes to form melanoidin, the brown substance that mimics a suntan. Most over-the-counter products contain 3–5% DHA. Some also contain sunscreen. Higher concentrations of DHA and body areas with increased keratin (e.g., elbows, knees) will stain a darker color. Patients should be informed that skin coloration from sunless tanners provides only minimal, unsubstantial sun protection. Recent studies have demonstrated that DHA-treated skin produced 180% more free radicals than untreated skin when exposed to the sun.47 Patients using sunless tanners should be counseled to avoid excessive sun exposure.

SUN PROTECTION The overall density of melanocytes in skin is greater in children than in adults, but melanin production in infants is probably limited (see Ch. 1). In addition, infants and children have not had the gradual ultraviolet (UV) exposure that stimulates fac­ ultative pigmentation. For these reasons, pediatric patients are more susceptible to the damaging effects of excessive exposure to sunlight. The adverse consequences of excessive doses of UV light are acute and cumulative. Acute overexposure results in erythema and skin necrosis. Acute photoallergic and phototoxic reactions occur in susceptible individuals. The effects of longterm excessive exposure may not become apparent for decades. The skin changes that were previously believed to be due to chronologic aging are now referred to as ‘dermatoheliosis’ because UV exposure plays a primary role in their pathogenesis. These changes include mottled pigmentation, coarseness,

43. Barkley W. Striae and persistent tinea corporis related to prolonged use of betamethasone dipropionate. J Am Acad Dermatol. 1987;17:518. 44. Draelos Z. Preadolescent cosmetics may cause dermatologic problems and misconceptions. Cosmet Dermatol. 1992;5:14. 45. Nelson F, Rumsfield J. Cosmetics: content and function. Int J Dermatol. 1988;27:665. 46. Levy SB. Dihydroxyacetone-containing sunless or self-tanning lotions. J Am Acad Dermatol. 1992;27:989–993. 47. Jung K, Seifert M, Herrling M, et al. UV-generated free radicals in skin: their prevention by sunscreens and their induction by self-tanning agents. Spectrochim Acta. 2008;69:1423–1428.

wrinkling, telangiectasia and purpura, as well as the development of premalignant and malignant neoplasms.48 Some 80% of lifetime sun exposure occurs during the first 18 years of life.49 More than 500 000 new cases of skin cancer are diagnosed in the USA every year. Among these is melanoma, the incidence of which is increasing more rapidly than any other type of cancer. A child born in 1935 had a one in 1500 chance of developing a melanoma. A child born today has a projected risk of one in 71. An estimated 116 500 new cases of melanoma were diagnosed in the USA in 2008.50 Factors that significantly increase that risk include red or blonde hair, marked freckling on the upper back, multiple nevi, blistering sunburns in childhood, an outdoor summer job for at least 3 years during adolescence and a family history of melanoma. A routine visit to the dermatologist is a perfect opportunity to provide parents, children and adolescents with this information, as well as strategies to minimize the risks of excessive sun exposure (Box 4.2). A sunscreen is a compound that absorbs, reflects or scatters the harmful spectrum of ultraviolet light (290–400 nm). An increasingly wide variety of sunscreen products are available. Marketing claims have been a source of confusion for consumers. In 1999, the FDA reviewed sunscreens and published a final monograph, Final Rule. This was implemented in May 2001 to define conditions under which over-the-counter sunscreens are deemed safe and effective and are not misbranded.51 Relative sunscreen efficacy, as originally defined, is the ability to prevent UVB-induced erythema and is expressed as a number known as the ‘sun protection factor’ (SPF). SPF is measured and calculated under standardized conditions using a solar simulator (290– 400 nm) to determine the minimal dose of UVB needed to

produce the minimal erythema dose (MED) with protection compared to the MED without protection. Prior to the Final Rule, sunscreens labeled with SPF values >30 overemphasized the benefits of using these products. Under the new regulations, labeling may indicate a qualitative degree of protection against sunburn: minimal (SPF 2–12), moderate (SPF 12–30) or high (≥30). Products are considered ‘water-resistant’ and ‘waterproof’ if the SPF is maintained after 40 and 80 min of water exposure, respectively. Ingredients that reflect and scatter a large portion of the solar spectrum, including UVB, UVA and visible light, are zinc oxide and titanium dioxide. In an attempt to make these physical blockers (zinc oxide and titanium oxide) more cosmetically elegant, products incorporating nanoparticle technology have been developed. However, there has been some concern over their potential safety due to systemic absorption and subsequent complications. A recent study showed > Keep infants and young children out of the sun >> Avoid exposure between 10.00 a.m. and 2.00 p.m.; be aware that clouds scatter only 20% of the UV light

>> Use protective clothing and hats >> Use the appropriate sunscreen >> Beware of reflected light from water, sand, snow, and cement >> Use extra protection at high altitudes and low latitudes >> Avoid artificial tanning devices >> Be aware of photosensitizing medications and diseases >> Do regular skin self-examination >> Set an example for children Modified from Hurwitz S, Rhodes A, Wiley H. For every child under the sun. New York: Skin Cancer Foundation; 1986, with permission.

4

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by the use of appropriate clothing and/or zinc oxide-containing sunscreens. In general, the best sunscreens for recreational use are those labeled ‘waterproof’ with a ‘high level’ of protection. For optimal efficacy, sunscreens must be applied liberally according to package directions and reapplied every 40 min if swimming or perspiring. An oral photoprotectant is now being marketed. Heliocare contains an oral natural antioxidant called Polypodium leuco­ tomos, which is a fern extract. In a small study of nine patients, 24 h after sun exposure there was less erythema, sunburn cells, cyclobutane pyrimidine dimers, proliferating epidermal cells, and dermal mast cells. The recommended daily dose is 240 mg, and it reportedly begins working in 30 min.67,68

spectrum can minimize the disfigurement associated with these conditions.60 Individuals exposed to excessive sunlight while using UVB-absorbing sunscreens or those who frequent tanning booths will receive large doses of UVA. The role of UVA in the development of skin cancers is controversial. However, UVA exposure (e.g., from tanning booths) probably increases the risk of skin cancer in people with a history of excessive exposure to UVB.61 There are two new sunscreens on the market in the USA which do provide UVA protection. Multiple Neutrogena pro­ ducts (Neutrogena Ultra Sheer Dry-Touch Sunblock SPF 55 and 70) now contain helioplex, which is a combination of two previously FDA-approved products, avobenzone and oxybenzone. Avobenzone has excellent UVA coverage, but alone is unstable when exposed to UV light. Combining it with oxybenzone offers greater stabilization and protection.62 Ecamsule (Mexoryl) is a sunscreen agent that was approved by the FDA (July 24, 2006), after being widely used in Europe and Canada for the past two decades.63 Mexoryl is marketed in two different forms: SX and XL. Mexoryl SX contains terephthalylidene dicamphor sulfonic acid and is hydrophilic, with peak UV absorption at 345 nm. Mexoryl XL contains drometrizole trisiloxane and is lipophilic, with peak UV absorptions at 303 nm and 345 nm. Mexoryl is marketed in the USA as Anthelios and is only approved as a daily moisturizer at SPF 15. The selection of an appropriate vehicle is just as important as the active ingredient. Variables include degree of water resistance, ease of application, emollient versus drying properties and the number of potentially irritating or sensitizing additives. Frequent application of most topical sunscreens is a difficult task for caregivers of active children. Products in the form of sprays and solid sticks with incorporated colors have been developed and are fun for children to apply. Adverse reactions developed in 19% of patients in one longitudinal prospective study,64 including subjective irritation, irritant and allergic contact dermatitis, contact urticaria, photosensitivity and acne.65 Patients with acne usually prefer liquid or gel preparations; those with dry skin prefer an emollient base. Individuals susceptible to allergic and/or irritant reactions should be aware of the spectrum of active and inactive ingredients in the products they choose. For infants under 6 months of age, the safety of topically applied sunscreens has not been established, but the theoretical risk of toxicity is low. The American Academy of Pediatrics recommends using sunscreen on small areas of the body in infants 14 days), high-dose glucocorticoid therapy (2  mg/kg per day) should not receive live attenuated vaccines (varicella-zoster, measles, mumps, rubella, rotavirus, influenza). The American Academy of Pediatrics recommends that the administration of live-virus vaccines be avoided while an infant is receiving GCS at these doses and until they have been discontinued for at least 1 month.483 If a child receiving long-term therapy with GCS is exposed to varicella, prophylactic therapy with varicella zoster immunoglobulin (VZIG) should be promptly administered and treatment with acyclovir should be initiated if cutaneous manifestations of varicella develop.483

483. Pickering L. American Academy of Pediatrics. RedBook. Active and passive immunization: Immunocompromised children. 2006. Online. Available: http://aapredbook.aappublications.org/cgi/content/full/2006 484. Lemaire CM, Browning JC, Hsu S. Medical Pearl: Pneumocystis pneumonia prophylaxis for patients on chronic systemic corticosteroids. J Am Acad Dermatol. 2006;55:124–125. 485. Kelly EJ, Brownlee KG, Ng PC, et al. The prophylactic use of ranitidine in babies treated with dexamethasone. Arch Dis Child. 1992;67:491.

Table 4.14  Preventive measures for long-term GCS therapy Monitor patient for: Baseline PPD skin test Interval urine test Interval blood sugars Blood pressure Growth parameters Weight gain Ophthalmologic examinations (every 6–12 months) Osteoporosis: consider bone mineral density (DEXA) scan every 6–12 months Osteonecrosis: MRI if suspect Treat: Certain adverse sequelae (diabetes, high blood pressure) H2 blockers/proton pump inhibitor TMP-SMX for PCP prophylaxis Upon cessation of long-term GCS therapy: ACTH stimulation test

IMMUNOSUPPRESSANTS

Table 4.13  Side-effects of long-term GCS therapy

4

Modified after Trikudanathan and McMahon (2008).482

PCP prophylaxis with trimethoprim-sulfamethoxazole or Dapsone is warranted in patients receiving long-term high-dose GCS, unless contraindicated.484 In adults with risk factors for peptic disease, concomitant treatment with H2-blockers is recommended.482 Although there is consensus regarding prophylactic treatment with H2-blockers in children treated with GCS, it is the authors’ practice to adopt prophylactic ranitidine 2 mg/kg per day in infants receiving prolonged high-dose GCS therapy.485 Upon cessation of GCS therapy, HPA axis response will recover promptly following short-term therapy ( TPMT testing (preferably phenotype – enzyme activity) >> Baseline complete blood count >> Baseline liver function tests >> Baseline renal function tests >> Pregnancy tests >> Urinalysis >> Repeat laboratory tests every 1–2 weeks in the first 1–2 months, then monthly

>> Follow-up for malignancies (in long-term use)

malignancies observed more commonly in patients with solid organ transplants treated with azathioprine include Kaposi’s sarcoma, lymphoproliferative disorders, carcinoma of the cervix, and non-melanoma skin cancers.525,526 Noteworthy is that a study including 358 patients diagnosed with systemic lupus erythematosus who were treated with azathioprine for a minimum of 6 months did not find an increased risk of malignancies.527 Azathioprine appears to be safe in pediatric patients, and the side-effect profile is similar to that for adults.528 There is a well-described hypersensitivity syndrome associated with azathioprine, but the mechanism by which this reaction occurs is not well understood. This syndrome manifests with multiorgan system involvement and signs and symptoms may include hypotension, fever, shock, maculopapular skin eruption, nephritis, pneumonitis, hepatitis, pancreatitis, and rarely, rhabdomyolysis.518 This rare syndrome usually occurs within 4 weeks after initiation, but was also reported to occur within a few hours after initiation of the therapy.520

Monitoring Recently published recommendations for monitoring during the treatment with azathioprine are summarized in Box 4.4. Evaluating the TPMT status in patients prior to initiating therapy is recommended.519,520 Furthermore, TPMT testing does not replace continuous blood count monitoring because bone marrow suppression can develop at any time during treatment from a few weeks to several years later. These tests, excluding TPMT levels, should be repeated every 1–2 weeks for the first 1–2 months and then monthly if stable. The dose should be decreased or azathioprine withdrawn completely if signs of bone marrow suppression appear.376 In addition, in such circumstances a patient should be managed jointly with a hematologist.

526. Maddox JS, Soltani K. Risk of non-melanoma skin cancer with azathioprine use. Inflamm Bowel Dis. 2008;14:1425–1431. 527. Nero P, Rahman A, Isenberg DA. Does long term treatment with azathioprine predispose to malignancy and death in patients with systemic lupus erythematosus? Ann Rheum Dis. 2004;63:325–326. 528. Markowitz JF. Therapeutic efficacy and safety of 6-mercaptopurine and azathioprine in patients with Crohn’s disease. Rev Gastroenterol Disord. 2003;1(suppl):S23–S29.

Principles of treatment in pediatric dermatology

Methotrexate (MTX) is a folic acid analog that acts by inhibiting dihydrofolate reductase (DHFR) and subsequently interfering with DNA, RNA, and protein synthesis. Actively proliferating tissues are more sensitive to this effect of MTX. The high turnover of epidermal cells was the rationale for use of MTX in psoriasis. MTX is generally well absorbed with peak serum levels reached within 1–2 h and with a half-life of 3–10 h. The bioavailability of MTX is reduced by the concurrent intake of food. The active metabolites of MTX as well as the parent drug are readily excreted in urine. MTX use in pediatric dermatology has been more limited due to the potential for systemic toxicity; however, there is extensive experience in the pediatric rheumatologic population in the treatment of juvenile rheumatoid arthritis (JRA). There is also considerable experience with MTX in the treatment of pediatric malignancies, especially acute lymphocytic leukemia.

Mechanism of action MTX is a folic acid analog that is metabolized to a polyglutamate form after absorption from the gastrointestinal tract. The polyglutamate form of the drug has a long intracellular half-life, allowing for once-weekly dosing of the drug. MTX is a competitive inhibitor of DHFR and acts to reduce de novo synthesis of purines, pyrimidines and polyamines; in addition, trans-methylation of phospholipids and proteins is inhibited.529 Cumulatively, inhibition of these various metabolic pathways is thought to reduce the ability of various cells, e.g., T cells and B cells, to mediate a continued inflammatory response. How MTX can be therapeutic even when given with folate supplements is poorly understood. An alternative mechanism for the anti-inflammatory effects of MTX involves inhibition of AICAR transformylase, an enzyme that catalyzes an early step in de novo purine synthesis.529 It has been shown that this inhibition leads to an increase in production and secretion of adenosine, a potent immunomodulator. Adenosine has at least four receptors and exerts multiple effects in different cell types. In vitro studies have shown that increased adenosine levels can result in a decrease in the production of reactive oxygen species, leukotriene B4 production and TNF-α as well as increases in IL-1 receptor antagonist protein and IL-10; each of these would be expected to have anti-inflammatory effects in vivo.

Indications MTX is approved for treatment of adults with psoriasis, Sezary syndrome, rheumatoid arthritis and in polyarticular JRA. MTX therapy in childhood psoriasis should be reserved for the most recalcitrant of cases including patients with erythrodermic

529. Bangert CA, Costner MI. Methotrexate in dermatology. Dermatol Ther. 2007;20:216–228. 530. Kaur I, Dogra S, De D, Kanwar AJ. Systemic methotrexate treatment in childhood psoriasis: further experience in 24 children from India. Pediatr Dermatol. 2008;25:184–188. 531. Weibel L, Sampaio MC, Visentin MT, et al. Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphoea) in children. Br J Dermatol. 2006;155:1013–1020.

Table 4.20  Potential uses for methotrexate in pediatric dermatology

Atopic dermatitis Behçet’s disease Bullous pemphigoid Cutaneous polyarteritis nodosa Juvenile dermatomyositis Leukocytoclastic vasculitis Morphea Pemphigus vulgaris Pityriasis lichenoides

Pityriasis rubra pilaris Psoriasis/psoriatic arteritis Pyoderma gangrenosum Reiter’s disease Sarcoidosis Scleroderma Sezary syndrome/mycosis fungoides Systemic lupus erythematosus

IMMUNOSUPPRESSANTS

METHOTREXATE

4

psoriasis, psoriatic arthritis non-responsive to traditional therapy, pustular psoriasis, or in patients with extensive plaque psoriasis non-responsive to more conservative therapy.376 A recent retrospective study on MTX therapy in 24 children and adolescents with recalcitrant psoriasis (including chronic plaque, erythrodermic and pustular types) reported rapid control (>50% PASI reduction) within 3–10 weeks in all patients and excellent overall results (>75% PASI reduction) in about 90% of the patients.530 MTX has been used also for a growing number of other inflammatory skin diseases (Table 4.20), including atopic dermatitis, pityriasis rubra pilaris, pityriasis lichenoides, autoimmune bullous and connective tissue diseases, vasculitides and neutrophilic dermatoses, as well as sarcoidosis and lymphomatoid papulosis. There have been recent reports advocating the combination of MTX therapy and pulsed corticosteroids in the treatment of widespread morphea/localized scleroderma.531,532 Yet to date there are no prospective double-blind placebo-controlled studies to evaluate its efficacy.

Dosage and administration MTX may be administered either orally, intramuscularly, or intravenously. Dosage and its schedule in children are mostly derived from studies in JRA. In children, it is appropriate to start with a lower dose of 0.2 mg/kg or 10–15 mg/m2 per week.533 If toxicity is not detected, the dose can be gradually increased, to achieve therapeutic efficacy, up to 0.7 mg/kg per week. MTX is available as a 2.5 mg scored tablet that can be divided, crushed, and mixed in a non-milk food.438 Alternatively, the injectable preparation can be given orally, at a fraction of the cost (available in 2 mL vials in concentrations of 2.5 mg/mL or 25 mg/ mL). Concomitant supplementation of folic acid on MTX-off days (1–5 mg/week) reduces the incidence and severity of MTXinduced adverse effects (Box 4.5).534

532. Uziel Y, Feldman BM, Krafchik BR, et al. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;136:91–95. 533. Niehues T, Horneff G, Michels H, et al. Evidence-based use of methotrexate in children with rheumatic diseases: a consensus statement of the Working Groups Pediatric Rheumatology Germany (AGKJR) and Pediatric Rheumatology Austria. Rheumatol Int. 2005;25:169–178. 534. Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. Br J Dermatol. 2008;160:622–628.

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BOX 4.5 SUGGESTED PHYSICIAN’S CHECKLIST FOR MTX

>> CBC with differential and platelets (monthly) >> Liver function, renal function (every 1–2 months) or serum procollagen III aminopeptide (every 2–3 months)

>> Serology for hepatitis A, B, and C antibodies >> Chest X-ray in the setting of pulmonary symptoms >> Signs and symptoms of skin reaction >> Pulmonary function if MTX-induced lung disease is suspected >> Liver biopsy? >> Pregnancy tests >> Avoid other medication with potential for liver toxicity IMMUNOSUPPRESSANTS

Drug interactions Non-steroidal anti-inflammatory agents (NSAIDs) reduce the tubular secretion of MTX and may enhance its toxicity. In addition, phenylbutazone, phenytoin, and sulfonamides may increase serum level of MTX and subsequent potential toxicity. Renal tubular transport is also diminished by probenecid that may interfere with renal secretion of MTX. In general, oral antibiotics may decrease intestinal absorption of MTX. Concomitant therapy with trimethoprim/sulfamethoxazole (TMP/SFX) may increase the risk for pancytopenia. Concomitant use of systemic retinoids is contraindicated in patients treated with MTX due to potential hepatotoxicity. Nevertheless, this combination therapy had been successfully used in selected adult patients with psoriasis that did not experience any new or unusual adverse effects.535

Monitoring

The toxicity of MTX to normal tissues is more related to the duration of exposure to the drug rather than the peak level achieved. The majority of safety data in children can be found in the rheumatology literature pertaining to treatment of JRA.533 However, occurrence and severity of adverse effects may be different in patients with psoriasis as compared to those with rheumatoid arthritis. Some potential risk of adverse effects can be reduced with administration of folic acid at doses of 1–5 mg/ day while MTX efficacy is not adversely affected.534 Nausea, anorexia, and fatigue are the most commonly observed side-effects of MTX therapy, while diarrhea, vomiting, and stomatitis are seen less frequently. Alopecia may be seen in as many as 6% of treated patients. Other rare cutaneous effects include acral erythema, vasculitis, epidermal necrosis, and an unusual ‘recall’ reaction that may follow preceding sunburn or radiation therapy. Hepatotoxicity resulting from long-term MTX therapy is the adverse effect of most concern. There are minimal data on the incidence of fibrosis and cirrhosis in children, but it appears to

Baseline evaluation should include a careful history and physical examination as well as laboratory studies: CBC with differential and platelet count, liver function tests including transaminases, serology for hepatitis A, B, and C antibodies, and renal function tests. Patients should be counseled on the importance of avoiding other medications with the potential for liver toxicity including alcohol consumption. In female patients of childbearing age, pregnancy should be ruled out before initiating therapy, and conception should be avoided for at least 4 months after discontinuation.529 Male patients should also be counseled not to impregnate their female partners until 3 months after MTX therapy is discontinued.529 Follow-up laboratory tests should include CBC with differential and platelets monthly. In patients with evidence of MTXinduced hematotoxicity, leucovorin (folinic acid) should be administered. Renal function and liver function tests should be done every 1–2 months. MTX should be discontinued or dosage should be reduced when leukocyte counts drop below 3500/ mm3 or platelets fall below 100 000/mm3. Chest radiographs should be obtained in the setting of pulmonary symptoms. The necessity of baseline and follow-up liver biopsy remains controversial and no standard recommendations exist for the pediatric population. Serum liver function tests may be normal even in the setting of significant hepatic fibrosis and/or cirrhosis and are not highly sensitive screening measures. The American Academy of Dermatology (AAD) guidelines from 1998 advocate liver biopsy after cumulative dose of 1.5 g of MTX.538 More recently, monitoring of serum procollagen III aminopeptide has

535. Lowenthal KE, Horn PJ, Kalb RE. Concurrent use of methotrexate and acitretin revisited. J Dermatol Treat. 2008;19:22–26. 536. Aithal GP, Haugk B, Das S, et al. Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified? Aliment Pharmacol Ther. 2004;19:391–399.

537. Berends MA, Snoek J, de Jong EM, et al. Liver injury in long-term methotrexate treatment in psoriasis is relatively infrequent. Aliment Pharmacol Ther. 2006;24:805–811. 538. Roenigk HH Jr, Auerbach R, Maibach H, et al. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol. 1998;38:478–485.

Adverse effects

172

be less commonly reported as compared to the adult population. Furthermore, more recent studies indicate that frequency of hepatic fibrosis is much lower than previously thought.536,537 Known risk factors for the development of MTX-associated hepatotoxicity in adults include diabetes, obesity, and alcoholism. Pulmonary toxicity is a rare adverse effect reported with MTX therapy. Pulmonary effects are idiosyncratic, may be either acute or chronic in nature, and are potentially life-threatening. A prevalence of up to 5% has been reported in the adult rheumatologic literature but may be less frequent in children. Hematologic side-effects include megaloblastic anemia and leukemia. Pancytopenia represents the adverse effect with greatest potential for increased mortality. This risk is reported more commonly in the rheumatologic literature than in dermatology. This toxicity is observed more frequently in elderly patients, in individuals with impaired renal function and in patients receiving concomitant therapy with TMP/SFX or NSAIDs. Other potential toxicities include renal impairment due to precipitation of MTX in renal tubules with high dose therapy, potential induction of malignancy, and rare neurologic sideeffects including acute chemical arachnoiditis, which can be observed in 5–50% of patients within hours of intrathecal MTX injections.

Principles of treatment in pediatric dermatology

MYCOPHENOLATE MOFETIL Mycophenolic acid (MPA), the parent compound of mycophenolate mofetil (MMF), is a weak organic acid formed during fermentation by several Penicillium species. The compound was initially found to have antifungal, antibacterial and antiviral activities, while MPA’s anti-inflammatory activity was demonstrated in the 1970s in the treatment of moderate to severe recalcitrant psoriasis. Concerns of potential immunosuppression and carcinogenicity led to a decline in its clinical use until 1995 when MMF was approved by the FDA for prevention of renal allograft rejection. Currently, MMF is available commercially as CellCept or Myfortic. After oral ingestion of MMF, over 90% is readily absorbed from the GI tract and plasma peak concentration is reached within 0.5–1 h. MMF is metabolized in the liver to MPA and subsequently to phenolic glucuronide of MPA (MPAG), which is secreted into the bile and recycled to the liver via enterohepatic recirculation. MPAG is unable to penetrate cell walls and is therefore inactive until it is converted back to MPA by the enzyme β-glucuronidase. High levels of β-glucuronidase are found primarily in the epidermis and gastrointestinal tract. The major route of elimination of the drug occurs through kidneys as MPAG.541

Mechanism of action MPA inhibits de novo purine synthesis by selective and reversible inhibition of inosine monophosphate dehydrogenase (IMPDH). It preferentially affects cells which rely upon de novo purine synthesis rather than the purine salvage pathway and results in cytostatic effect on proliferating T and B lymphocytes, as well as smooth muscle cells and fibroblasts.541 Beyond this cytostatic effect, MMF may affect inflammatory reaction by induction of

539. Chalmers RJ, Kirby B, Smith A, et al. Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate: a multicentre audit and health economic analysis. Br J Dermatol. 2005;152:444–450. 540. Chédeville G, Scuccimarri R, Duffy CM. Survey on the use of methotrexate by pediatric rheumatologists in Canada. J Rheumatol. 2007;34:818–822. 541. Zwerner J, Fiorentino D. Mycophenolate mofetil. Dermatol Ther. 2007;20:229–238. 542. Orvis AK, Wesson SK, Breza TS Jr, et al. Mycophenolate mofetil in dermatology. J Am Acad Dermatol. 2009;60:183–199. 543. Beissert S, Werfel T, Frieling U, et al. A comparison of oral methylprednisone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Arch Dermatol. 2006;142:1447–1454. 544. Beissert S, Werfel T, Frieling U, et al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of bullous pemphigoid. Arch Dermatol. 2007;143: 1536–1542. 545. Farley-Li J, Mancini AJ. Treatment of linear IgA bullous dermatosis of childhood with mycophenolate mofetil. Arch Dermatol. 2003;139:1121–1124.

T-cell apoptosis, modification of expression of cytokines and adhesion molecules and by suppressing the production of inducible nitric oxide synthase.541

Indications MMF is approved for prevention of graft rejection in patients with renal, liver, and heart transplants. Although MMF beneficial effect had been repeatedly reported in the therapy of autoimmune bullous disorders and atopic dermatitis, it is not officially licensed for any dermatologic use. Autoimmune bullous diseases constitute the most common indication for off-label use of MMF documented in numerous case reports, mostly in adults.542 In comparative studies, MMF had similar efficacy, corticosteroid-sparing effects, and safety profiles as azathioprine in the treatment of pemphigus and bullous pemphigoid in adults.543,544 MMF had been reported occasionally as efficacious adjuvant therapy in few children with linear IgA bullous dermatosis, pemphigus vulgaris and bullous pemphigoid.545–547 Efficacy of MMF had been also demonstrated in several case series of severe recalcitrant atopic dermatitis in adults and children. Improvement may be expected on average 4 weeks after the start of the therapy with maximal effect within 8–12 weeks.548 Few open-label studies demonstrated MMF efficacy as monotherapy in adults with chronic plaque-type psoriasis with PASI50 reduction ranging from 47–70% within 6–12 weeks.549,550 Beneficial effects were also reported in case reports and small series in a long list of other inflammatory skin diseases.542 MMF is relatively contraindicated in pregnant or nursing women and carries a class D pharmacologic rating.551 MMF is also relatively contraindicated in patients with peptic ulcer disease, hepatic and cardiopulmonary disease. Intravenous MMF (CellCept) is contraindicated in patients who are allergic to Polysorbate-80 (TWEEN).552

IMMUNOSUPPRESSANTS

been shown as a more reliable marker of hepatic fibrosis that allows substantial reduction in liver biopsies as compared to AAD guidelines.539 In this regard, standards of care are not well established in the pediatric dermatology setting. Until substantial evidence for the need of liver biopsy in MTX-treated children with psoriasis is available, it seems reasonable to follow the recommendations and practices for MTX-treated children with JRA, which do not advocate to perform a liver biopsy.496,540

4

Dosage CellCept is available in tablets, capsules or suspension for oral ingestion as well as powder for intravenous injection. For the licensed indications, the recommended dose of CellCept is 1200 mg/m2 per day or 30 mg/kg per day (maximum daily dose, 2 g) divided in two daily doses. However, in the open

546. Schmidt E, Seitz CS, Benoit S, et al. Rituximab in autoimmune bullous diseases: mixed responses and adverse effects. Br J Dermatol. 2007;156:352–356. 547. Waisbourd-Zinman O, Ben-Amitai D, Cohen AD, et al. Bullous pemphigoid in infancy: Clinical and epidemiologic characteristics. J Am Acad Dermatol. 2008;58:41–48. 548. Heller M, Shin HT, Orlow SJ, et al. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol. 2007;157:127–132. 549. Geilen CC, Arnold M, Orfanos CE. Mycophenolate mofetil as a systemic antipsoriatic agent: positive experience in 11 patients. Br J Dermatol. 2001;144:583–586. 550. Zhou Y, Rosenthal D, Dutz J, et al. Mycophenolate mofetil (CellCept) for psoriasis: a two-center, prospective, open-label clinical trial. J Cutan Med Surg. 2003;7:193–197. 551. Vento M, Perez Aytes A, Ledo A, et al. Mycophenolate mofetil during pregnancy: some words of caution. Pediatrics. 2008;122:184–185. 552. Birgerson LE, Roche Laboratories. CellCept (mycophenolate mofetil) Medication Guide. US Food & Drug Administration. 2009. Online. Available: www.fda.gov/medwatch/safety/2009/safety09.htm#CellCept

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study in children with atopic dermatitis, doses of 40–50 mg/kg per day were used, while in adults with dermatologic conditions doses as high as 3.5 g/day (corresponding to 50–90 mg/kg per day) were advocated.548 Renal insufficiency can increase the plasma concentrations of MPA up to sixfold. Patients with glomerular filtration rates 1200 mg/m2 per day or 30 mg/kg per day. Myfortic is available only as tablets for oral ingestion. The daily dose is 800 mg/m2 divided in two daily doses (maximum dose 1440 mg/day). Pediatric doses for patients with body surface area 3 months. These changes are usually reversible within several months after discontinuation of the drug.557 Nausea and vomiting from gastric irritation can be minimized by giving smaller doses more frequently, or administering with meals. Hemolytic anemia can occur in treated patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Leukopenia and thrombocytopenia have been reported to occur in a small percentage of patients receiving chloroquine. Reversible agranulocytosis has been reported with all antimalarial agents. The ophthalmologic toxicities have been well described and are most often associated with chloroquine use.567 These ocular effects are often asymptomatic but can cause blurred vision,

halos around objects, and photophobia. Therapy can be continued in patients who develop corneal deposits, as this problem is completely reversible within 2 months after drug discontinuation. Retinopathy is a rare but serious and irreversible sideeffect. Regular ophthalmologic examinations should be obtained in patients receiving antimalarial medications.568 Rare but severe cardiotoxicity may develop following prolonged use of antimalarials with both conduction disturbances and congestive heart failure.569

Monitoring Pre-treatment baseline evaluations should include a G6PD level and electrocardiogram. A baseline and monthly complete blood count should be obtained for the first 6 months to follow cell count stability. Once stable, cell counts can be followed every 3–6 months thereafter depending upon the clinical course and dosing changes. Baseline renal and liver function tests should be evaluated and repeated every 4–6 months. A direct ophthalmologic examination for signs of toxicity should be performed within 1 month of initiating therapy and repeated every 3–6 months. These tests should include visual fields, Amsler grids for the detection of macular injury (in children >2 years of age), color vision testing, fundoscopic examination, and slit lamp examination to evaluate for corneal deposits.560,568,570 Patients should also wear ultraviolet filtering sunglasses while outdoors. When treating patients with PCT, a 24-h urine for porphyrin excretion should be evaluated initially and after 1 month of therapy (Table 4.22, Box 4.6).

Table 4.22  Recommended baseline and monitoring laboratory tests for antimalarials LABORATORY TEST

BASELINE

MONITORING STUDY/LABORATORY

Complete blood count

Yes

Yes: monthly for 6 months and then every 3–6 months

Liver function tests

Yes

Yes: every 4–6 months

BUN, creatinine

Yes

Yes: every 3–6 months

Ophthalmologic tests

Yes

Yes: every 3–6 months Visual fields Amsler grids (home monitoring every 2 weeks in older children) Color vision testing Fundoscopic examination Slit lamp examination

24-h urine test for porphyrin excretion

Yes

Yes: at 1 month for porphyria cutanea tarda

Serum pregnancy test

Yes

Yes: with every prescription in females of childbearing age

Electrocardiogram

Yes

No: unless abnormal baseline ECG

G6PD level

Yes

No

BUN, blood urea nitrogen; G6PD, glucose 6-phosphate dehydrogenase.

566. Jaeger A, Sauder P, Kopferschmitt J, et al. Clinical features and management of poisoning due to antimalarial drugs. Med Toxicol Adverse Drug Exp. 1987;2:242–273. 567. Tehrani R, Ostrowski RA, Hariman R, et al. Ocular toxicity of hydroxychloroquine. Semin Ophthalmol. 2008;23:201–209. 568. Marmor MF. New American Academy of Ophthalmology recommendations on screening for hydroxychloroquine retinopathy. Arthritis Rheum. 2003;48:1764.

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569. Costedoat-Chalumeau N, Hulot JS, Amoura Z, et al. Heart conduction disorders related to antimalarials toxicity: an analysis of electrocardiograms in 85 patients treated with hydroxychloroquine for connective tissue diseases. Rheumatology (Oxford). 2007;46: 808–810. 570. Tripp JM, Maibach HI. Hydroxychloroquine-induced retinopathy: a dermatologic perspective. Am J Clin Dermatol. 2006;7:171–175.

Principles of treatment in pediatric dermatology

>> Gastrointestinal: nausea, vomiting, diarrhea, hepatotoxicity >> Skin: discoloration, pruritus, achromotrichia, exfoliative dermatitis

>> Hematologic: aplastic anemia, hemolysis, pancytopenia, thrombocytopenia, agranulocytosis

>> Central nervous system: tinnitus, seizures, irritability >> Cardiovascular: depressed cardiac activity with overdose >> Ophthalmologic: corneal deposits, diplopia, retinopathy

Contraindications to using antimalarial drugs include retinal disease, visual field changes or a known hypersensitivity to 4-aminoquinolone compounds. Relative contraindications include pregnancy (as chloroquine is known to cross the placenta), liver disease, alcoholism, administration of hepatotoxic drugs, and renal disease.438 Use of the antimalarial medications in conditions such as PCT and G6PD deficiency must be undertaken with extreme caution as reports of toxicity have been reported in PCT as well as significant hemolysis in G6PD deficiency.438 Although exacerbations of psoriasis, myasthenia gravis, and multiple sclerosis have been reported with the use of antimalarial medications, clear causal evidence is lacking.557,571,572

COLCHICINE Colchicine, extracted from the seeds and tubers of Colchicum autumnale, continues to be used for a variety of dermatologic disorders. The Colchicum species has been used to treat acute attacks of gout since the sixth century AD. Colchicine is readily absorbed after oral administration and its serum half-life is about 10–20 h. It is eliminated by several routes: biliary excretion and extrusion of the drug from cells into GI tract are the predominant ways. The extrusion of colchicine is mediated by multidrug resistance transporter molecule ABCB1 (ATP-binding cassette subfamily B member 1).573 In addition, renal excretion accounts for 10–20% of the drug elimination, while hepatic demethylation by cytochrome P450 is responsible for an additional 5–20% of the drug disposition.573

BOX 4.7 POTENTIAL OFF-LABEL USES OF COLCHICINE IN DERMATOLOGY

>> Behçet’s disease >> Recurrent aphthous stomatitis >> Dermatitis herpetiformis >> Linear IgA disease >> Leukocytoclastic vasculitis

plexes. The disruption of microtubule assembly interferes both with mitosis and with cellular migration. Colchicine appears to be especially active in neutrophils, where it has been shown to inhibit cellular adherence, motility, and chemotaxis. The mechanisms involved in immunomodulating properties of colchicine include also modulation of E-selectin and VCAM1-mediated neutrophil adhesion, inhibition of neutrophil responses to leukotriene B4, inhibition of IL-1 production, modulation of pyrin expression, inhibition of mast-cell histamine release, modulation of antigen presentation by macrophages, suppression of pro-collagen synthesis and more.573 Colchicine alters jejunal and ileal function and may cause significant diarrhea and abdominal cramping. Colchicine dosing is often limited by these commonly observed gastrointestinal sideeffects and many patients may tolerate only twice daily dosing.

Indications

Colchicine’s primary mechanism of action is the prevention of microtubule assembly by formation of tubulin–colchicine com-

Labeled indications of colchicine are acute gouty arthritis and also for prevention of attacks of familial Mediterranean fever (FMF). Off-label dermatologic uses of colchicine include various neutrophilic dermatoses such as Behçet’s disease, recurrent aphthous stomatitis, including PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis and adenitis), dermatitis herpetiformis, and linear IgA disease (Box 4.7).574–580 The effectiveness of colchicine therapy in leukocytoclastic vasculitis remains controversial. While one prospective, randomized controlled study of 41 patients showed no statistically significant therapeutic efficacy there were complete responders to colchicine in this report as well in other case series.581,582 In addition, colchicine has been used with variable efficacy in a variety of other dermatoses including psoriasis, dermatomyositis, scleroderma, and Sweet’s syndrome.

571. Herman SM, Shin MH, Holbrook A, et al. The role of antimalarials in the exacerbation of psoriasis: a systematic review. Am J Clin Dermatol. 2006;7:249–257. 572. Fischer PR, Walker E. Myasthenia and malaria medicines. J Travel Med. 2002;9:267–268. 573. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum. 2009;38: 411–419. 574. Yurdakul S, Mat C, Tüzün Y, et al. A double-blind trial of colchicine in Behçet’s syndrome. Arthritis Rheum. 2001;44:2686–2692. 575. Kallinich T, Haffner D, Niehues T, et al. Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics. 2007;119:e474–e483. 576. Altinor S, Oztürkcan S, Hah MM. The effects of colchicine on neutrophil function in subjects with recurrent aphthous stomatitis. J Eur Acad Dermatol Venereol. 2003;17:469–470.

577. Silvers DN, Jahlin EA, Berczeller PH, et al. Treatment of dermatitis herpetiformis with colchicine. Arch Dermatol. 1980;116:1373–1384. 578. Banodkar DD, al-Suwaid AR. Colchicine as a novel therapeutic agent in chronic bullous dermatosis of childhood. Int J Dermatol. 1997;36:213–216. 579. Ang P, Tay YK. Treatment of linear IgA bullous dermatosis of childhood with colchicine. Pediatr Dermatol. 1999;16:50–52. 580. Tasher D, Stein M, Dalal I, et al. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr. 2008;97:1090–1092. 581. Sais G, Vidaller A, Jucgla, et al. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. Results of a prospective, randomized controlled trial. Arch Dermatol. 1995;131:1399–1402. 582. Padeh S, Passwell JH. Successful treatment of chronic Henoch-Schonlein purpura with colchicine and aspirin. Isr Med Assoc J. 2000;2:482–483.

Mechanism of action

IMMUNOMODULATORS

BOX 4.6 SIDE-EFFECTS OF ANTIMALARIAL DRUGS

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Dosage The dosage of colchicine in children is usually extrapolated from studies on FMF. Recent consensus suggests up to 0.5 mg/day for children under the age of 5 years, 1.0 mg/day (for children 5–10 years of age), or 1.5 mg/day (for children >10 years of age). For patients with severe renal failure (glomerular filtration rate, GFR, of > Complete blood count (at the beginning of therapy, monthly, then every 3 months)

>> Electrolytes (every 3 months) >> Renal functions (every 3 months) >> Hepatic functions (every 3 months)

Drug interactions Possible interactions with drugs metabolized by cytochrome P450, including macrolide antibiotics, cyclosporine and statins, may occur. Consumption of grapefruit juice may interfere with colchicine metabolism.573,575 IMMUNOMODULATORS

Adverse effects Although in the vast majority of overdose episodes there are mild symptoms, mostly GI disturbances, overdosage of colchicine can be life-threatening.583 Manifestations of colchicine intoxification include electrolyte disorders (decreased sodium, potassium, calcium), metabolic acidosis, renal failure, respiratory distress syndrome, disseminated intravascular coagulation, bone marrow failure, central nervous system disorders and myopathy.

Monitoring Because chronic colchicine administration at recommended doses can result in leukopenia, aplastic anemia, and megalo­ blastic anemia, it is recommended to perform a complete blood count at least every 3 months on chronic therapy and it is advisable to monitor counts monthly during the first few months of therapy. Due to the low risk of electrolyte disturbances, hepatic and renal effects, it is also suggested to monitor electrolytes, hepatic and renal function at least every 3 months with longterm therapy (Box 4.8).573

DAPSONE, SULFONES AND SULFONAMIDES The sulfa drugs, sulfones and sulfonamides, are related compounds with a broad spectrum of pharmacological activity. Sulfones have a sulfoxide core with two symmetrically attached aminophenyl groups. Dapsone, 4.4′-diaminodiphenylsulfone, is the only sulfone available in the USA. Sulfonamides have a similar structure, with an aminophenylsulfone core. Of this group, sulfapyridine differs from dapsone only by the substitution of a pyridine group for one aminophenyl group. The prototype compound was first synthesized in Germany in 1908 for industrial use. A quarter of a century later, the sulfones’ antibacterial properties were realized. By the 1940s, their therapeutic spectrum was expanded to include a variety of dermatologic disorders. Currently, dapsone is the only drug in this class commonly used in dermatology. Dapsone is well absorbed from the gastrointestinal tract with bioavailability approaching 86%. Gastrointestinal absorption is reduced in severe leprosy. Peak serum concentrations are reached

583. Levsky ME, Miller MA, Masneri DA, et al. Colchicine exposures: The Texas experience. South Med J. 2008;101:480–483.

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within 2–6 h after ingestion and the elimination half-life ranges from 12 to 30 h.376 Dapsone is highly protein bound and is distributed throughout the body to all major organ systems including the skin. Dapsone also crosses the blood–brain barrier, the placenta, and is found in breast milk.584 Up to 85% of the drug is slowly excreted by kidneys, whereas the rest is excreted in the biliary tract.

Mechanisms of action Dapsone has both antimicrobial and anti-inflammatory actions. The antimicrobial effects are due to the reduction of dihydrofolate synthesis by competitive inhibition of the enzyme dihydropteroate synthase.584 The anti-inflammatory effects of the drug are not fully elucidated. However, disease processes that respond to dapsone generally are associated with neutrophil infiltrations in the affected tissues. Studies have shown that treatment of neutrophils in vitro with dapsone results in a decrease in integrin-mediated adherence of neutrophils to target cells as well as a reduction in myeloperoxidase activity. It appears that dapsone is able to reduce the ability of neutrophils to respond to chemotactic stimuli, possibly by disrupting the G-protein associated signal transduction pathway.584 It disrupts neutrophil chemotactic migration which further suppresses neutrophil recruitment and local production of toxic respiratory and secretory products. Little is known about the mechanism of dapsone in antibody-mediated diseases such as bullous dermatoses, but some research suggests a dose-dependent inhibition of neutrophilic adherence to basement zone antibody.584

Indications Dapsone is FDA approved only for treatment of leprosy and dermatitis herpetiformis in adults and children. Potential offlabel uses of dapsone in dermatology are shown in Table 4.23. Dapsone therapy is contraindicated in patients with a history of hypersensitivity reactions to dapsone, including agranulo­ cytosis.376 Dapsone has been associated with acute attacks of porphyria and is considered relatively contraindicated in porphyrias.376

Dosage The starting dose is variable depending on the disease to be treated and the co-morbidities involved. The usual starting dose

584. Zhu I, Stiller M. Dapsone and sulfones in dermatology: Overview and update. J Am Acad Dermatol. 2001;45:420–428.

Principles of treatment in pediatric dermatology

Acne fulminans Brown recluse spider bites

Actinomycetoma Lichen planus

Bullous pemphigoid Cicatricial pemphigoid

Linear IgA disease (chronic bullous disease of childhood)

Dermatitis herpetiformisa

Pemphigus vulgaris

Eosinophilic cellulitis

Pustular psoriasis

Erythema elevatum diutinum

Pyoderma gangrenosum

Granuloma annulare

Relapsing polychondritis

Granuloma faciale

Rheumatoid arthritis, Sneddon–Wilkinson disease

IgA pemphigus

Sweet’s syndrome

a

Leprosy

Table 4.24  Drug interactions with dapsone DRUG

INTERACTION

Antacids

Reduces absorption

Interferons, didanosine, zidovudine, cytotoxic chemotherapy, and clozapine

Bone marrow suppression

Probenecid

Increases dapsone levels by decreasing renal excretion

Trimethoprim, trimethoprim/ sulfamethoxazole

Increased risk of hemolysis (especially in G6PD patients), increased risk of methemoglobinemia, increases plasma concentrations

Rifampin

Induces dapsone metabolism and enhances urinary excretion of dapsone

Cimetidine

Inhibits formation of the toxic hydroxylamine metabolite of dapsone

Omeprazole

Inhibits cytochrome enzymes and decreases the rate of hydroxylamine formation

Systemic lupus (bullous SLE)

a

FDA-approved.

is 0.5–2.0 mg/kg per day, then adjusted to the lowest effective dose.

IMMUNOMODULATORS

Table 4.23  Potential uses of dapsone in dermatology

4

Drug interactions Dapsone should be used with extreme caution if an allergy exists to another drug in the sulfa family (trimethoprim-sulfamethoxazole, sulfasalazine). Dapsone should not be given with antacids as they decrease its absorption. Rifampin may lower dapsone levels 7- to 10-fold by accelerating plasma clearance. Folic acid antagonists such as pyrimethamine may increase the likelihood of hematologic reactions.376 Due to the hepatic metabolism of dapsone, any drug which is metabolized by the cytochrome P450 system may also influence dapsone metabolism (Table 4.24).

Adverse effects The most common adverse effects of dapsone therapy are hemolysis and methemoglobinemia (Table 4.25). Most patients on dapsone will have some hemolysis, but patients with hereditary G6PD deficiency are at greatest risk of clinically significant hemolytic anemia.376 An important aspect of dapsone poisoning is its ability to produce methemoglobinemia, which is long-lasting and which may recur following methylene blue therapy. Because of this, dapsone-poisoned children need to be monitored for 2–3 days.585 Methylene blue is supplied as 1% intravenous solution and given in dose of 1–2 mg/kg intravenously and repeated every 4–6 h. A recent study showed a greater decline in met­ hemoglobin levels with continuous infusion rather than bolus.585 Idiosyncratic reactions, including cholestasis, nephrotoxicity, agranulocytosis, and motor neuropathy, have been reported. The dapsone hypersensitivity syndrome (DHS) is an extremely rare idiosyncratic mononucleosis-like hypersensitivity reaction 585. Prasad R, Singh R, Mishra OP, et al. Dapsone induced methemoglobinemia: Intermittent vs continuous intravenous methylene blue therapy. Indian J Pediatr. 2008;75:245–247.

Table 4.25  Adverse reactions to dapsone PHARMACOLOGIC/ PREDICTABLE

ALLERGIC/IDIOSYNCRATIC Hepatitis: cholestatic or hepatocellular disease or both

Hemolytic anemia

Agranulocytosis

Methemoglobinemia

Cutaneous: exanthematous eruption, Stevens–Johnson syndrome, toxic epidermal necrolysis

Non-specific: nausea, vomiting, fatigue, dizziness, weakness, nervousness, shortness of breath, headache

Nephritis Pneumonitis Hypothyroidism Dapsone hypersensitivity syndrome Psychosis Peripheral neuropathy

that may result in multiorgan disease. This syndrome is similar to other hypersensitivity syndromes that can occur with anticonvulsants, allopurinol, non-steroidal anti-inflammatory medications, or sulfonamide antibiotics and presents with fever, rash, lymphadenopathy and hepatitis. It may appear 2–7 weeks after initiation of dapsone therapy. The course of DHS is variable, but it may last for 4 weeks or more, being fatal in some cases.586 The pathogenesis of DHS is not well understood and the treatment is controversial and dependent on the severity of symptoms and presence of end organ involvement. 586. Agrawal S, Agarwalla A. Dapsone hypersensitivity syndrome: a clinicoepidemiological review. J Dermatol. 2005;32:883–889.

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IMMUNOMODULATORS

Agranulocytosis, another rare life-threatening idiosyncratic reaction associated with dapsone, remains poorly understood. For unknown reasons, the risk of agranulocytosis in patients with dermatitis herpetiformis is more than 25-fold compared with other patients, and is almost unknown in patients treated for leprosy.587 Several clinical observations indicate that concomitant administration of cimetidine may improve patients’ tolerance to dapsone and reduce the risk of this complication. Patients who have tolerated dapsone for 6–12 months are unlikely to develop problems, unless the dose is changed. The use of dapsone in pregnancy is generally considered safe for the mother and fetus, but carries a pregnancy category C rating. There have been a few reports of neonatal complications linked to maternal dapsone use such as hemolytic anemia, met­ hemoglobinemia, and hyperbilirubinemia.

Monitoring Pre-treatment screening should include a G6PD level, complete blood count (CBC), renal and liver function tests, and urinalysis. Dapsone should not be used in patients with severe anemia. Also, starting dapsone in patients with signs of megaloblastic anemia should be delayed until folic acid replacement is adequate or the cause of the hemopoietic disturbance is discovered and addressed. CBC should be checked weekly for the first month, monthly for 6 months and semi-annually thereafter for signs of bone marrow suppression and hemolytic anemia. If a significant reduction in leukocytes, platelets or hemopoiesis is noted, dapsone should be discontinued and the patient followed intensively. The concomitant use of other sulfa drugs with dapsone increases the risk of hemolysis and methemoglobinemia.

GAMMAGLOBULIN All commercial intravenous immunoglobulins (IVIG) represent an IgG fraction extracted from large pools of human plasma. It was originally purified and administered to provide passive immunity for the prevention and treatment of certain viral diseases. Following intravenous infusion of IVIG, it rapidly passes out of the vasculature into lymph and extracellular space. The elimination half-life is about 23 days, although in patients with 30–50% burns it may be reduced to 2–6 days.588 In patients with extensive involvement in immunobullous skin diseases, IVIG pharmacokinetics may be similar to burn patients. The use of IVIG has undergone tremendous growth in the past several years. IVIG has been increasingly prescribed by dermatologists to treat

587. Coleman M. Dapsone-mediated agranulocytosis: risks, possible mechanisms and prevention. Toxicology. 2001;162:53–60. 588. Bonilla FA. Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes. Immunol Allergy Clin North Am. 2008;28:803–818. 589. Clynes R. IVIG therapy: interfering with interferon-gamma. Immunity. 2007;26:4–6. 590. Prins C, Gelfand EW, French LE. Intravenous immunoglobulins: properties, mode of action and practical use in dermatology. Acta Derm Venereol. 2007;87:206–218. 591. Czernik, A Beutner EH, Bystrin JC. Intravenous immunoglobulin selectively decreases circulating autoantibodies in pemphigus. J Am Acad Dermatol. 2008;58:796–801.

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diseases with an immunopathogenic basis whose therapies are either inadequate or associated with excess toxicity.

Mechanisms of action The mechanisms by which IVIG are effective in both replacement therapy and immunomodulatory therapy are different, as are the doses of IVIG required. Several different pathways of activity have been proposed to play a role in the response of disease states to IVIG therapy. IVIG can interfere with the interaction of circulating antigen–antibody complexes and Fc receptors on the surface of various immune cells, prevention of complementmediated damage, modification of cytokine actions, including blockage of IFN-γ function, inhibition of cell apoptosis, and augmentation of corticosteroid sensitivity.589,590 IVIG provides naturally occurring anti-idiotypic antibodies that may act to neutralize pathogenic autoantibodies.591 All these pathways are not mutually exclusive and the importance of each in the response to IVIG administration in different disease states remains to be elucidated.589,592

Indications Among a few FDA-approved indications for IVIG, only Kawasaki syndrome can be regarded as a dermatological indication. However, more than 50% of world sales of IVIG are for un­ licensed indications590 These off-label dermatologic uses of IVIG are summarized in Table 4.26.590,593 Beneficial therapeutic use of IVIG in autoimmune blistering diseases, including pemphigus vulgaris and foliaceus, bullous pemphigoid, cicatricial pemphigoid and epidermolysis bullosa acquisita, was documented in numerous case reports, case series, retrospective studies and two prospective open studies. Some consider IVIG as an adjuvant steroid-sparing agent in pemphigus vulgaris, while others as disease modifying that can be used as monotherapy in a severe, recalcitrant disease.593,594 A consensus of experts advocates its use in autoimmune blistering diseases when:594,595

• A disease does not respond to prednisone (≥1 mg/kg per day) for 6 weeks, with a concurrently administered immunosuppressive agent for 10–12 weeks • There is a presence of significant side-effects of conventional immunosuppressive therapy • There is an absolute or relative contraindication for the use of high-dose long-term steroids or other immunosuppressive agents • There is an uncontrolled rapid debilitating progressive disease.

592. Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345:747–753. 593. Smith DI, Swamy PM, Heffernan MP. Off-label uses of biologics in dermatology: interferon and intravenous immunoglobulin (Part 1 of 2). J Am Acad Dermatol. 2007;56:e1–e54. 594. Mydlarski PR, Ho V, Shear NH. Canadian consensus statement on the use of intravenous immunoglobulin therapy in dermatology. J Cutan Med Surg. 2006;10:205–221. 595. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol. 2003;139:1051–1059.

Principles of treatment in pediatric dermatology

Autoimmune bullous diseases Pemphigus vulgaris Pemphigus foliaceus Bullous pemphigoid Mucous membrane pemphigoid Epidermolysis bullosa acquisita Linear IgA dermatosis Pemphigoid gestationis Toxic epidermal necrolysis

Connective tissue diseases Dermatomyositis Lupus erythematosus Scleroderma Mixed connective tissue disease

Vasculitis Livedoid vasculitis ANCA-associated vasculitis Polyarteritis nodosa ANCA-negative vasculitis Leukocytoclastic vasculitis Behçet’s disease

Urticaria Delayed pressure urticaria Solar urticaria Chronic idiopathic urticaria Autoimmune urticaria Angioedema and hypereosinophilia

Atopic dermatitis Scleromyxedema Pretibial myxedema Nephrogenic fibrosing dermopathy Psoriasis and psoriatic arthritis Pyoderma gangrenosum Kaposi’s sarcoma Anticonvulsant syndrome Polymorphous light eruption

ANCA, antineutrophil cytoplasmic antibody; Ig, immunoglobulin. Adapted from Prins et al. (2007)590 and Smith et al. (2007).593

Several recent studies demonstrated that IVIG can selectively and markedly decrease serum levels of abnormal antibodies in pemphigus without decreasing the levels of normal antibodies.591,596 IVIG may also be useful as adjunct therapy in the management of severe atopic dermatitis, although results of small case series have been inconsistent.597,598 Children with atopic dermatitis may have a more favorable response to IVIG therapy than adults.594 There are also several case reports and case series, including in children, on beneficial effects of IVIG in Stevens–Johnson syndrome and toxic epidermal necrolysis, although its efficacy has not been established in controlled studies.594,599,600 IVIG therapy is contraindicated in patients with a history of anaphylaxis to IVIG, cryoglobulinemia and rapidly progressive renal disease. It is relatively contraindicated in patients with IgA

596. Arredondo J, Chernyavsky AI, Karaouni A, et al. Novel mechanisms of target cell death and survival and of therapeutic action of IVIG in pemphigus. Am J Pathol. 2005;167:1531–1544. 597. Jolles S, Hughes H, Rustin M. The treatment of atopic dermatitis with adjunctive high-dose intravenous immunoglobulin: a report of three patients and review of the literature. Br J Dermatol. 2000;142:551–554. 598. Bemanian MH, Movahedi M, Farhoudi A, et al. High dose intravenous immunoglobulin versus oral cyclosporine in the treatment of severe atopic dermatitis. Iran J Allergy Asthma Immunol. 2005;4:139–143.

deficiency, renal failure, hyperviscosity states and systemic lupus erythematosus.

Dosage IVIG dosage in immunodeficiency conditions depends on straightforward replacement of missing antibodies. The effective dosages range from 0.2 g/kg per month to 0.8 g/kg per month, depending on the extent of failure of antibody production and the increased susceptibility to infection. Anti-inflammatory or immunomodulatory doses of IVIG for autoimmune conditions are considerably larger; cumulative doses of ≥2 g/kg are given over 1–4 days. The dose is repeated every 3–4 weeks until there is an effective control of the autoimmune disease with subsequent gradual increase of intervals between each cycle.

IMMUNOMODULATORS

Table 4.26  Off-label dermatologic uses of intravenous immunoglobulin

4

Drug interactions IVIG may interfere with the immune response to live viral vaccines. It is particularly relevant in the pediatric population. It is generally recommended that such vaccines be given at least 3 weeks before the initiation of IVIG therapy or 3 months after the last dose of IVIG.376

Adverse effects IVIG is a relatively safe form of therapy. However high-dose IVIG is not without its own side-effects, including infusion reactions. As several methods of manufacturing processes are used, various IVIG preparations have varying degrees of therapeutic efficacy and tolerability.601 The immediate adverse reactions following IVIG administration are usually mild and transient flu-like symptoms and include headache, flushing, malaise, fever, chills, myalgia, fatigue, dyspnea, back pain, nausea, vomiting, diarrhea, change in blood pressure, and tachycardia. These reactions occur early and, in many cases, during the first 30 min of the infusion, and are generally rate-related and often resolve after slowing the rate of infusion.602 Chills, fever, headache, myalgia, and fatigue can persist after infusion. These side-effects can be prevented or treated with acetaminophen, diphenhydramine, or oral hydrocortisone. Anaphylaxis, although rare, is reported in the use of IVIG, particularly in those IgA-deficient patients; such patients should receive an IgA-depleted preparation of IVIG.602 As with any blood product, there are concerns about the transmission of infectious agents. Following a report of a cluster of cases of HCV transmission, the manufacturing process was modified and, in addition to careful donor screening and meticulous clinical guidelines, transmission of viral infection has been

599. Zipitis CS, Thalange N. Intravenous immunoglobulins for the management of Stevens–Johnson syndrome with minimal skin manifestations. Eur J Pediatr. 2007;166:585–588. 600. Mittmann N, Chan B, Knowles S, et al. Intravenous immunoglobulin use in patients with toxic epidermal necrolysis and Stevens–Johnson syndrome. Am J Clin Dermatol. 2006;7:359–368. 601. Lemm G. Composition and properties of IVIg preparations that affect tolerability and therapeutic efficacy. Neurology. 2002;59:S28-S32. 602. Katz U, Achiron A, Sherer Y, et al. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun Rev. 2007;6:257–259.

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virtually eliminated.376 There are no documented cases of HBV or HIV transmission with IVIG therapy. The most important late complications are acute renal failure and thromboembolic events (Table 4.26). Both complications occur usually in high-risk adult patients. Additional risk factors include pre-existing renal disease, poor hydration, diabetes mellitus, hypertension, hyperviscosity and concomitant treatment with nephrotoxic medications.602

Monitoring

IMMUNOMODULATORS

In a few patient populations, IVIG should be used with extreme caution (Box 4.9). Patients with anti-IgA antibodies or a history of anaphylaxis to IVIG should be treated with IVIG only when other alternatives have been exhausted and they should be monitored closely for any reaction. IgA-depleted IVIG and prophylactic medications should be used in these settings. Due to the possibility of renal compromise, patients with documented renal disease should be treated with extreme caution, especially when using high-dose IVIG. Measures needed to be addressed before starting treatment are summarized in Box 4.9.590,603

INTERFERONS Interferons (IFNs) are a family of over 30 distinct low-molecularweight glycoproteins produced by different cell types that inhibit viral replication and tumor growth. IFNs have been classified into three groups, based primarily on their cell of origin. Interferon-α (IFN-α) is produced mainly by leukocytes, IFN-β by fibroblasts and epithelial cells, and IFN-γ by lymphocytes. IFN-α and -β share a common receptor and have a spectrum of biologic effects that differs from those of IFN-γ.604 Purified human IFNs are increasingly available through improved production techniques, but less expensive recombinant forms are also manufactured. All IFNs are administered parenterally or intralesionally. They are catabolized and excreted by the kidneys and their plasma half-lives range 3–6 h, with a few exceptions.376

Mechanism of action Precise mechanisms of IFNs’ actions are not fully elucidated. They all act through specific cell-surface receptors. Consequently, a series of events result in inhibition of virus replication, suppression of cell proliferation, and immunomodulation, such as

603. El-Shanawany T, Jolles S. Intravenous immunoglobulin and autoimmune disease. Ann N Y Acad Sci. 2007;1110:507–515. 604. Maher SG, Romero-Weaver AL, Scarzello AJ, et al. Interferon: cellular executioner or white knight? Curr Med Chem. 2007;14:1279–1289. 605. Kilic SS, Kilicbay F. Interferon-alpha treatment of molluscum contagiosum in a patient with hyperimmunoglobulin E syndrome. Pediatrics. 2006;117:e1253–e1255. 606. Ozarmag˘an G, Didem Yazganog˘lu K, Agaçfidan A. Hyper-IgE syndrome with widespread premalign oral papillomas treated with interferon alpha2b. Acta Derm Venereol. 2005;85:433–435. 607. Torrelo A, Harto A, Sendagorta E, et al. Interferon-a therapy in atopic dermatitis. Acta Derm Venereol (Stockh). 1992;72:370. 608. Chang TT, Stevens SR. Atopic dermatitis: the role of recombinant interferon-gamma therapy. Am J Clin Dermatol. 2002;3:175–183. 609. Hanifin J, Schneider L, Leung D, et al. Recombinant interferon gamma therapy for a atopic dermatitis. J Am Acad Dermatol. 1993;28:189–197.

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BOX 4.9  PHYSICIAN’S CHECKLIST FOR HIGH-DOSE IVIG

>> Liver function, renal function, full blood count, and hepatitis screen (avoid high-dose IVIG in rapidly progressive renal disease)

>> Immunoglobulin levels to exclude IgA deficiency. If no IgA present (> Exclude high-titer rheumatoid factor and cryoglobulinemia >> Preferably ensure that a sufficient supply of a single product

and batch of IVIG is available to expose the patient to a minimum number of donors and to avoid unnecessary product changes

>> Take any baseline specimens, examination findings, or photographs required to document later any objective response

>> Follow manufacturer’s guidelines regarding reconstitution and rate of infusion (and maintain good hydration and fluid intake)

>> Provide patient information regarding high-dose IVIG therapy and consent

>> Store a sample of serum so that any future research questions or matters relating to transmission of infective agents may be addressed

Adapted from El-Shanawany and Jolles (2007).603

enhancement of phagocytic activity of macrophages and augmentation of specific cytotoxicity of lymphocytes for target cells.604

Indications There are several FDA approved indications for IFNs therapy (Table 4.27). Licensed indications for IFNs in dermatology include condyloma acuminata (IFN-α2b), melanoma (IFNα2b), and AIDS-associated Kaposi’s sarcoma (IFN-α2a and IFNα2b). There is a long list of dermatologic conditions that may respond to IFN therapy (Table 4.27).593 In addition, potential off-label uses of IFNs in pediatric dermatology are life-threatening hemangiomas in infancy, Kasabach–Merritt syndrome, atopic dermatitis (AD) and juvenile hyaline fibromatosis.605–614 Administration by injection limits the practicality of IFN therapy for anogenital condyloma in children. However, IFN-α might be useful in immunodeficient children with disseminated molluscum contagiosum or other viral warts.605,606

610. Jang IG, Yang JK, Lee HJ, et al. Clinical improvement and immunohistochemical findings in severe atopic dermatitis treated with interferon gamma. J Am Acad Dermatol. 2000;42:1033–1040. 611. Ezekowitz R, Mulliken J, Folkman J. Interferon alpha-2a therapy for life threatening hemangiomas of infancy. N Engl J Med. 1992;326:1456–1463. 612. Tamayo L, Ortiz D, Orozoco-Covarrubias L, et al. Therapeutic efficacy of interferon alfa-2b in infants with life-threatening hemangiomas. Arch Dermatol. 1997;133:1567–1571. 613. Greinwald JH Jr, Burke DK, Bonthius DJ, et al. An update on the treatment of hemangiomas in children with interferon alfa-2a. Arch Otolaryngol Head Neck Surg. 1999;125:21–27. 614. Ruiz-Maldonado R, Durán-McKinster C, Sáez-de-Ocariz M, et al. Interferon alpha-2B in juvenile hyaline fibromatosis. Clin Exp Dermato. 2006;31:478–479.

Principles of treatment in pediatric dermatology

Table 4.27  FDA-approved uses of interferon therapy INTERFERON-β

Kaposi’s sarcoma (2α) Condyloma acuminata

INTERFERON-γ Chronic granulomatous disease of childhood

Multiple sclerosis

Kaposi’s sarcoma

Hairy cell leukemia

Dosage

Hepatitis C Melanoma

Melanoma

Potential uses of interferon therapy Atopic dermatitis Squamous cell carcinoma Cutaneous T cell lymphoma Herpes simplex Verruca vulgaris/bowenoid papulosis Life-threatening hemangiomas Behçet’s disease Fibrotic disease (systemic sclerosis, keloids, morphea) Kasabach–Merritt phenomena

medical condition, including diabetes mellitus predisposed to ketoacidosis, coagulation disorders, cardiovascular disease, thyroid dysfunction, autoimmune diseases, transplant patients, depression (particularly with suicidal ideation), or hepatic disorders. IFN is relatively contraindicated in pregnant or nursing women and carries a class C pharmacologic rating. IFNs should only be given in those circumstances when the benefits of therapy clearly outweigh the risks of treatment.

Basal cell carcinoma Melanoma Keratoacanthoma Varicella zoster Discoid lupus erythematosus Follicular mucinosis Psoriatic arthritis Mycosis fungoides

The antiangiogenic effects of IFN-α therapy in the treatment of Kaposi’s sarcoma suggested that it may be beneficial in the treatment of other forms of proliferative vascular disease. Several prospective and retrospective studies have documented the efficacy of daily subcutaneous injections of recombinant IFN-α2a for alarming hemangiomas, Kasabach–Merritt syndrome, and diffuse hemangiomatosis in infants.611–613 A recent study evaluated treatment with IFN-α2b in 20 patients with alarming hemangiomas refractory to other therapies. An excellent response (50% or more reduction in the original size) was observed in 17 patients (85%) who received IFN-α2b from 6 to 24 months (median, 14 months).615 Both IFN-α and -γ have been used in the treatment of refractory AD.607,608 Since circulating and tissue lymphocytes of patients with AD produce excessive amounts of IL-4 and reduced levels of IFN-γ, IFN-γ may be the more useful form of therapy. Indeed, various studies with IFN-γ showed marked improvement in patients with AD.593 Two prospective randomized placebocontrolled studies in 134 patients with AD, including children, documented beneficial effect of thrice weekly subcutaneous IFN-γ for 12 weeks.609,610 All IFNs are contraindicated when patients have a history of hypersensitivity to any constituent in the preparation. Caution should be used when the patient has any underlying debilitating

615. Jiménez-Hernández E, Dueñas-González MT, Quintero-Curiel JL, et al. Treatment with interferon-alpha-2b in children with life-threatening hemangiomas. Dermatol Surg. 2008;34:640–647. 616. Kaselas C, Tsikopoulos G, Papouis G, et al. Intralesional administration of interferon A for the management of severe haemangiomas. Pediatr Surg Int. 2007;23:215–218. 617. Michaud AP, Bauman NM, Burke DK, et al. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope. 2004;114:1231–1236.

IFNs are inactivated in the stomach. Therefore, they must be locally or systemically injected. The treatment regimens vary considerably in different licensed and unlicensed indications. Therefore, treating physicians should refer to relevant medical literature when considering IFN therapy for a specific indication. IFN-α2a in treatment of hemangiomas is given subcutaneously or intralesionally in doses 1–3 million units/m2 per day once daily. For licensed indications, such as AIDS-related Kaposi sarcoma, larger doses of up to 5 million units/m2 per day are given.616 IFN-α2b may be administered IM or subcutaneously 30 million units/m2 per dose thrice weekly until disease progression has been controlled or maximal response has been achieved. For patients with malignant melanoma IFN-α2b is given intravenously in doses of 20 million units/m2 per dose during the induction phase followed by 10 million units/m2 per dose during the maintenance phase of the treatment.617 IFN-γ may be administered subcutaneously thrice weekly in doses ranging from 25–75 µg/m2 per dose (0.5 × 106 IU/m2, 1.5 × 106 IU/m2).

IMMUNOMODULATORS

INTERFERON-α

4

Drug interactions IFNs may inhibit hepatic metabolism of xanthines, potentially leading to increased serum concentrations of these medications.

Adverse effects Much like insulin administration, IFN injections are minimally painful and are generally well tolerated by children. Side-effects from IFN therapy most often resemble a flu-like illness but can affect many organ systems. Symptoms include fever, myalgias, generalized gastrointestinal complaints, depression, anorexia, chills. Other common adverse effects include alopecia, drug eruptions, pruritus, hypertension, neutropenia, anemia, thrombocytopenia and abnormal liver enzymes Rarely, IFNs may induce or aggravate neuropsychiatric and autoimmune disorders.618,619 An uncommon complication from use of IFN-α therapy is spastic diplegia. This complication is exclusively reported in about 2.5% of infants younger than 1 year of age

618. Navid F, Furman WL, Fleming M, et al. The feasibility of adjuvant interferon alpha-2b in children with high-risk melanoma. Cancer. 2005;103:780–787. 619. Hauschild A, Gogas H, Tarhini A, et al. Practical guidelines for the management of interferon-alpha-2b side-effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer. 2008;112:982–994.

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who were treated for vascular lesions.617 The causal relationship between spastic diplegia and IFNs is supported by finding of elevated endogenous IFNs (α,β and γ) in premature-born infants who developed spastic diplegia.617

Monitoring

IMMUNOMODULATORS

Evaluation prior to the treatment includes: complete clinical history and physical examination and the following laboratory tests are recommended prior to treatment and periodically thereafter: complete blood count, blood chemistries (including electrolytes, liver function) and thyroid-stimulating hormone (TSH) and baseline chest X-ray. Patients with pre-existing cardiac abnormalities or who are in the advanced stages of cancer should have ECG taken prior to and during treatment. All monitoring should be carried out weekly during the first month and monthly thereafter. Furthermore, periodic neurologic examination is recommended throughout the course of treatment with IFN so as to detect neurotoxicity in the early stages.604

IODINE (POTASSIUM IODIDE) Potassium iodide (KI) has been used in medicine for over 150 years, and it remains an effective therapy for several dermatologic conditions such as sporotrichosis and several hypersensitivity reactions. Following oral ingestion, it is rapidly absorbed, widely distributed into the thyroid and salivary glands, choroid plexus and placenta. About 90% of ingested iodides are excreted in the urine, with smaller amounts appearing in the faeces, saliva, and sweat.620 Iodides cross the placenta and are distributed into breast milk.

Mechanism of action It had been shown that KI inhibits neutrophil chemotaxis in peripheral blood, suppresses the generation of inflammatory oxygen intermediates from activated neutrophils, but specific mechanisms by which it exerts its antifungal and antiinflammatory effects remain poorly understood.620

Indications While KI is not FDA approved specifically for any dermatologic conditions, it has been used in the management of many cutaneous disorders including various fungal infections (excluding the mucormycoses), granulomatous dermatoses, panniculitides, and neutrophilic dermatoses.620,621 KI should not be used in individuals with known hypersensitivity to iodides. Special caution should be taken in patients with underlying thyroid disease, renal insufficiency, Addison’s disease, and cardiac disease. Because KI crosses the placenta and is distributed in breast milk, it should not be used in pregnant or breast-feeding females.

620. Sterling JB, Heymann WR. Potassium iodide in dermatology: a 19th century drug for the 21st century – uses, pharmacology, adverse effects, and contraindications. J Am Acad Dermatol. 2000;43:691–697. 621. da Rosa AC, Scroferneker ML, Vettorato R, et al. Epidemiology of sporotrichosis: a study of 304 cases in Brazil. J Am Acad Dermatol. 2005;52:451–459.

184

Dosage KI is usually provided as saturated solution (SSKI). The dosage of SSKI depends upon the condition being treated. For treatment of inflammatory dermatoses, an oral dose of 300 mg administered three times daily would be an appropriate starting dose for adults. This dose can then be gradually increased as tolerated to achieve the desired anti-inflammatory response.620 In contrast, in the treatment of fungal infections, including sporotrichosis, the initial dose is 1 g/day and is gradually increased as tolerated to 3 g/day. Most inflammatory conditions respond promptly within 2–4 weeks of the therapy, while treatment for sporotrichosis may require 12–16 weeks.622 The treatment should be continued for at least 1 month after the disappearance or stabilization of the lesions.

Drug interactions Special caution should be taken to avoid concomitant administration of other potassium-containing medications, potassiumsparing diuretics and angiotensin-converting enzyme (ACE) inhibitors because of the risk of hyperkalemia.620 Lithium and amiodarone may potentiate thyroid toxicity while used concomitantly with KI.

Adverse effects While KI is generally considered quite safe, there are myriad potential systemic and cutaneous adverse effects.620 Many of these side-effects are dose-related and observed more often with chronic therapy. Common systemic side-effects include diarrhea, nausea, vomiting, and abdominal pain. Because this solution can cause gastrointestinal irritation, it is best administered in combination with water, juice or milk. Signs of iodine toxicity include a metallic taste and/or burning sensation of the mouth, soreness of the gingiva and teeth, headache, and enlargement or tenderness of the parotid and submaxillary glands. Hyperkalemia may cause cardiac arrhythmias, confusion, paresthesias, and weakness. As with any iodide, chronic use of SSKI can often lead to a variety of skin problems, including acneiform eruptions, vasculitis, dermatitic eruptions and iododerma (a distinct vegetating eruption). Potential effects on the thyroid gland should also be considered with chronic KI therapy. Depending upon the underlying functional integrity of the thyroid gland, excess iodine administration can result in either hypothyroidism and goiter or hyperthyroidism. KI-induced thyroid abnormalities are usually reversible upon discontinuation of therapy.

Monitoring Patients should be questioned prior to initiating therapy regarding any previous history of thyroid disease and baseline thyroid

622. Bonifaz A, Saúl A, Paredes-Solis V, et al. Sporotrichosis in childhood: clinical and therapeutic experience in 25 patients. Pediatr Dermatol. 2007;24:369–372.

Principles of treatment in pediatric dermatology

BIOLOGICS The label ‘biologics’ has become a common term for therapeutic drugs synthesized from products of living organisms that are engineered to target specific humoral or cell-surface targets. Recent advances in molecular biology and biotechnology have led to the development of specifically targeted molecules aimed at interrupting the inflammatory cascade in a more specific way than traditional drugs.

differences in efficacy. In this section, only those drugs approved for dermatological indications will be addressed.

Infliximab Infliximab (Remicade) is a humanized, chimeric anti-TNF-α monoclonal IgG1κ antibody. It is composed of human constant and murine variable regions. Infliximab binds specifically to human TNF-α. Following intravenous administration of infliximab it is distributed primarily in the vascular compartment with half-life of 7–12 days and can be still detected in the serum after 8 weeks. Elimination of infliximab is most probably accomplished through degradation by unspecific proteases. The pharmacokinetics of the drug in patients with renal or hepatic dysfunction is unknown. There is no known difference in the pharmacokinetics of infliximab in men, women, or children.624

ANTI-TUMOR NECROSIS FACTOR-α THERAPY

Mechanism of action

Tumor necrosis factor alpha (TNF-α) is produced primarily by monocyte/macrophages but is also made by keratinocytes, melanocytes, mast cells and Langerhans cells. TNF-α is initially synthesized as a transmembrane protein that is subsequently cleaved to produce the soluble plasma protein. Both the membrane-bound and soluble factors can interact with one of two TNF-α receptors. One of the receptors, TNFRp55, is ubiquitous, while TNFRp75 is found primarily on hematopoietic and endothelial cells. In addition, the extracellular domain of each receptor can be cleaved to generate a soluble factor that can act to modulate TNF-α activity. Binding of TNF-α to its receptors leads to the activation of a number of transcription factors that control expression of inflammatory cascade genes. In turn, produced chemokines stimulate the activation or recruitment of various cells, ultimately leading to activation of the inflammatory pathway.623 TNF-α plays an important role in the host defense to infections, but inappropriate and excessive production may lead to a variety of inflammatory skin diseases. TNF-α has been implicated in many inflammatory disease processes including psoriasis, Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, respiratory disease (chronic bronchitis, chronic obstructive pulmonary disease, acute respiratory distress syndrome and asthma), sepsis, cardiac disease (atherosclerosis, myocardial infarction, myocarditis and cardiac allograft rejection), renal disease (ischemic renal injury, renal transplant rejection and glomerulonephritis).623 Currently, four hybrid antibody molecules – infliximab, etanercept, adalimumab and certolizumab – that block the activity of TNF-α are being used to treat a variety of inflammatory diseases. These molecules inhibit TNF-α-stimulated production of proinflammatory cytokines, such as IL-1, IL-6, IL-8 and monocyte chemoattractant protein (MCP)-1, and subsequent cell cycle arrest and apoptosis. An additional TNF-antagonist, golimumab, is under clinical investigations. Different anti-TNF therapies have different binding and pharmacokinetic profiles resulting in

Infliximab binds to both soluble TNF-α in the serum and TNF-α receptors on target cells. In addition, infliximab binds complement and induces antibody-mediated cytotoxicity resulting in lysis of cells expressing membrane-bound TNF-α.625

623. Bradley JR. TNF-mediated inflammatory disease. J Pathol. 2008;214:149–160. 624. Klotz U, Teml A, Schwab M. Clinical pharmacokinetics and use of infliximab. Clin Pharmacokinet. 2007;46:645–660.

BIOLOGICS

function tests including TSH, T4, antithyroglobulin and antimicrosomal antibodies should be obtained in patients if there is a suspicion of underlying thyroid abnormalities. All patients should have a follow-up TSH obtained after the first month of therapy.

4

Indications Infliximab is approved for refractory Crohn’s disease and ulcerative colitis in adults and children (>6 years of age), ankylosing spondylitis, psoriatic arthritis, as well as for adult patients with moderate to severe plaque psoriasis who failed to respond to or have a contraindication to other systemic therapies. Although infliximab is not licensed for use in children in the UK, the British National Formulary for Children (BNFC) recommends this therapy for children aged over 2 years with severe, active or fistulizing Crohn’s disease.376 Recently, a panel of European experts employed a structured survey (called the Delphi methodology) aimed to reach a consensus on ‘the best clinical practice’ of using infliximab for psoriasis.626 This group of experts concluded that patients considered suitable or highly suitable for infliximab therapy are those who have one or more of the following criteria: moderate to severe psoriasis and two or more failed systemic therapies; psoriatic arthritis in association with skin symptoms; associated psoriasis of the nails, face or genitals; moderate to severe psoriasis in conjunction with Crohn’s disease or concomitant metabolic syndrome; a Psoriasis Area and Severity Index (PASI) > 20; improvement of 2 on the Physicians’ Global Assessment (PGA) or a reduction of 2 h) intravenous infusion. The recommended dose for adult patients with psoriasis is 5 mg/kg followed with additional similar doses at 2 and 6 weeks after the first infusion and then every 8 weeks thereafter. Infliximab can be used with or without methotrexate.376

Purified protein derivative (PPD) tuberculin skin test and a chest X-ray should be done before beginning treatment to detect latent tuberculosis. Treatment of latent tuberculosis in patients with a reactive tuberculin test reduces the risk of tuberculosis reactivation in patients receiving infliximab. Blood chemistry, including liver function tests (LFT), hepatitis B panel, β-hCG (in women of childbearing potential), complete blood count (CBC), erythrocyte sedimentation rate (ESR), and clinical follow-up every 3 months is also recommended.636,637 Patients should be monitored for signs of infection during the therapy and for 6 months after cessation of the treatment. All patients with heart failure should be closely monitored and infliximab stopped in those who develop new or worsening symptoms of heart failure. After the occurrence of an infusion reaction, continuation of the treatment is often questioned. This depends on the severity of the reaction, the efficacy of treatment and possible treatment alternatives. Although premedication with prednisone, anti­ histamines and acetaminophen had been frequently used in patients with mild reactions to infliximab infusion, there is no evidence for prophylactic effect of such premedication.636 A panel of American experts in psoriasis recommends concurrent administration of methotrexate for reduction of infusion reactions.637 In subsequent infusions following a preceding reaction, the rate of administration should start with slow infusion (> Keep bulky dressings in place for a minimum of 48 h. >> Do not remove Steri-Strips from the wound. If strips are lifting off, secure these with additional tape or Band-Aids.

>> Keep the wound dry until suture removal. >> Blood staining on the Steri-Strips is expected when the

pressure dressing is removed. You may cover these, but do not remove them.

>> Tylenol for pain; avoid ibuprofen (Motrin or Advil). Most pain

results from excessive activity. If pain occurs, restrict activities.

>> Physical activity, including but not limited to the following, should be restricted for 4 weeks following surgery:



No sports activities, including: swimming, bicycle, scooter, skateboard or roller blade riding, dance, karate, horseback riding, frisbee, golf, tennis bowling, lasertage.

– – –

No gym at school for 4 weeks.



No tumbling, pillow fights or wrestling.

No sleepovers. Avoid excessive walking (including shopping and ‘walking the mall’ with friends).

>> For bleeding or drainage from the wound, tenderness or pain (especially after 48°) contact:________

>> Follow-up suture removal:________

ognized.261 In addition, dietary supplements, especially in the form of herbal medicines, can act as anticoagulants.262,263 A careful history of these should be taken before the procedure. Bleeding in the postoperative period in pediatric patients is most commonly associated with trauma to the wound. Careful listing of restrictions is critical to minimize trauma in young children. Toddlers present a particular challenge for surgeons and parents alike. The elective use of a knee immobilizer to prevent climbing and running in the immediate postoperative period can markedly reduce the risk of trauma to the surgical site in addition to easing postoperative stress for the parents. Hematomas that are smaller than a ping-pong ball should be left to reabsorb. Larger hematomas should be drained with replacement of a pressure dressing to prevent reformation. Contact dermatitis to tissue adhesives is another common postoperative complication. Application of topical antibiotic ointment to the skin is also associated with a significant

cefuroxime 250 mg BID or cefadroxil 500 mg BID for the treatment of uncomplicated skin and skin structure infections. Clin Ther. 2002;24:1134–1147. 260. Hurst EA, Yu SS, Grekin RC, et al. Bleeding complications in dermatologic surgery. Semin Cutan Med Surg. 2007;26:189–195. 261. Federici AB. Management of von Willebrand disease with factor VIII/von Willebrand factor concentrates: results from current studies and surveys. Blood Coagul Fibrinolysis. 2005;1:S17–S21. 262. Javed F, Golagani A, Sharp H. Potential effects of herbal medicines and nutritional supplements on coagulation in ENT practice. J Laryngol Otol. 2008;122:116–119. 263. Dinehart SM, Henry L. Dietary supplements: altered coagulation and effects on bruising. Dermatol Surg. 2005;31:819–826.

Surgical techniques

B

C

D

SURGICAL TECHNIQUES

A

5

Figure 5.19  Postoperative pressure dressing for the scalp. (A) Bulky dressing

E

is used to cover the excision site. (B) Roll of gauze is wrapped around the head to keep dressing in place. (C) Silk tape is applied to surface of rolled gauze and along the forehead skin and posterior neck skin to secure dressing in place. (D) Tube bandage is pulled over the dressing. (E) Patient’s face and ears are cut out of the tube bandage.

incidence of contact dermatitis.264,265,266 Avoidance of these topicals is recommended. When performing surgery of any type, it is important for the surgeon to remember that there are certain danger areas where there is a risk of inadvertent injury to underlying sensory or motor nerves.267 Knowing anatomy is an important prerequisite

to operating in the pediatric patient. One commonly overlooked danger area is lateral to the eyebrow, which is the location of the temporal branch of the facial nerve. Dermoid cysts can occur in this location and require deep dissection and particular caution. This nerve gives motor innervation to the forehead and lies at a relatively superficial level in the skin. Most surgeons are

264. Gehrig KA, Warshaw EM. Allergic contact dermatitis antibiotics: epidemiology, responsible allergens and management. J Am Acad Dermatol. 2008;58:1–21. 265. Sheth VM, Weitzul S. Postoperative topical antimicrobial use. Dermatitis. 2008;19:181–189.

266. Gorgievska Sukarovska B, Turcić P, Marasović D, et al. Allergic contact dermatitis to antibacterial agents. Acta Dermaovenereol Croat. 2009;17:70–76. 267. Ketschmer T, Heinen CW, Antoniadis G, et al. Iatrogenic nerve injuries. Neurosurg Clin North Am. 2009;20:73–90.

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DRESSINGS

acquainted with the location of the facial nerve found in the preauricular area, so this is not a common problem. Also, the facial nerve lies relatively deep within the mass of the parotid gland in most individuals so the risk of injury is relatively small. The marginal mandibular branch of the facial nerve crosses the angle of the mandible near the mental foramen where it is superficial and easily injured. This nerve innervates orbicularis oris and depressor muscles of the lip. The 11th cranial (spinal accessory) nerve is also not deeply located. It lies superficially within the posterior triangle of the neck, bordered by the sternocleidomastoid and trapezius muscles and clavicle. Injury to this nerve will result in shoulder drop. The final nerve which may be inadvertently injured because of its superficial location is the common peroneal nerve. This nerve is found on the lateral aspect of the proximal lower leg. If damaged, foot drop will likely result. When the dermatologic surgeon is working in one of these high-risk areas, it may be prudent to perform a more superficial biopsy than normal. To add an additional measure of safety, local infiltration of sterile saline into the biopsy area following injection of local anesthetic will bulge the skin and subcutaneous tissue up away from the deeper nerves. This effectively increases the amount of tissue that must be transected before reaching the level of the motor nerves. The only arterial structure likely to be damaged by surgical biopsies is the temporal artery. This vessel takes a variably circuitous route within or slightly anterior to the temporal hairline. Before performing biopsies in this location, especially punch biopsies, care should be taken to palpate for the location of this vascular structure. If this vessel is accidentally severed, the wound should be explored, and the proximal end of the vessel should be suture-ligated with polyglycolic acid suture to prevent postoperative bleeding. The diagnostic or therapeutic biopsy techniques and excisional surgeries performed by dermatologists are relatively simple to learn and safe to perform. By following some simple guidelines and taking some precautions, uncomplicated surgical skin procedures can be performed even in infants and small children.

Impregnates

Adaptic, Vaseline gauze, Biobrane gauze, Xeroflo, Jelonet, Aquaphor gauze

Polyurethane films

Op-Site, Bioclusive, Tegaderm, Ensure-It, ACU-derm, Polyskin, Uniflex, Omniderm, Mefilm

Hydrocolloids

Duoderm, Comfeel, Ulcus, J&J Ulcer Dressing, Actiderm, Restore, Ultec, Duoderm-CGF, Hydrapad, IntraSite, Tegasorb, Granuflex, Coloplast

Hydrogels

Vigilon, Spenco Second Skin, Geliperm, Elasto-Gel, Cutinova Gelfolie, Cutinova-Thin

Alginates

AlgiDerm, Kaltostat, SeaSorb, Tegagen, Sorbsan, Melgisorb

Foams

Synthaderm, Lyofoam, Allevyn, Epigard

Miscellaneous

N-terface, Biobrane, Mepitel

With little doubt, no aspect of dermatologic surgery has undergone more recent change than wound care and surgical dressings (Table 5.1). This is largely the result of the recognition that, of all the local factors that can favorably influence wound healing, maintaining the surface humidity of the wound is the most important consideration.268–270 A demonstrable reduction in the rate and quality of healing has been proved in association with wound desiccation.271,272 Wound desiccation, occurring with an air exposure time of only 2–3 hours, can result in the creation of additional necrosis at the base of the wound,

which can delay healing by up to 50%.273 Despite our increased knowledge of the pathophysiology of the healing wound, a number of wound care practices that have been shown to be ineffective or harmful are still widely used. This includes the repeat application of toxic wound cleansing agents, inappro­ priate use of antibiotics, and the practice of wet-to-dry dressings.274 The traditional technique that has been used for years to prevent wound desiccation consisted of the application of a thin layer of occlusive antibacterial ointment, followed by the application of a non-adherent sterile gauze dressing. An absorptive cotton gauze layer, placed on the surface for protection against external trauma, was held in place with slight compression using paper tape. Dressings were typically changed once or twice a day following interval cleansing of the wound surface with a 3% solution of hydrogen peroxide. Although effective, dressings of this type were particularly unsuitable for pediatric patients. They were bulky and difficult to maintain with the high activity level of a child. In addition, frequent dressing changes were traumatic and painful for both parent and child. Fortunately, many new synthetic surgical dressings have been introduced over the past several years. These dressings were developed in an attempt to reduce the amount of wound care required by the patient, while simultaneously maximizing the opportunity for rapid wound healing through the creation of the moist ideal environment for the wound healing processes to occur. While the precise indications for many of these dressings have not been unequivocally established, they usually are interchangeable to reduce postoperative wound care, minimize pain and swelling,271 speed healing,272 and prevent desiccation.275 The

268. Founder MA, Lazarus GS, Cowan DA, et al. Treating the chronic wound: a practical approach to the care of nonhealing wounds and wound care dressings. J Am Acad Dermatol. 2008;58:185–206. 269. Aubock J. Synthetic dressings. Curr Probl Dermatol. 1999;27:26. 270. Bello YM, Phillips TJ. Therapeutic dressings. Adv Dermatol. 2000;16: 253. 271. Eaglstein WH. Experiences with biosynthetic dressings. J Am Acad Dermatol. 1985;12:434.

272. Thomas S. Hydrocolloid dressings in the management of acute wounds: a review of the literature. Int Wound J. 2008;5:602–613. 273. Hinman CD, Maibach H. Effect of air exposure and occlusion on experimental human skin wounds. Nature. 1963;200:377. 274. Nwomeh BC, Yager DR, Cohen LK. Physiology of the chronic wound. Clin Plast Surg. 1998;25:341. 275. Winter GD, Scales JT. Effect of air drying and dressings on the surface of a wound. Nature. 1963;197:191.

DRESSINGS

238

Table 5.1  Common types of surgical dressings

first two types of surgical dressings to be developed were made from polyurethane and hydrocolloid materials. These dressings have been shown to be very useful in treating children with small sutured wounds because of their shared features of relative water impermeability and self-adherence. When treating small sutured wounds, either type of dressing can be applied directly to the surface of the wound immediately after completion of the procedure and left in place until suture removal.276 A small pressure dressing can be placed over the hydrocolloid dressing for the first 48 h if the suspected activity level of the child will increase the risk for postoperative bleeding. This can be removed in 48 h if the dressing is too bulky, maintaining the wound sterility and avoiding exposure to the air. These techniques reduce the amount of wound care required by the patient or by parents while protecting the wound from dust, dirt and bacterial invasion.277–279 The dressings also speed the rate of wound healing by maintaining the surface humidity of the wound.280–282 The disadvantage of these dressings lies in the misconception by parents that children can continue normal bathing habits and physical activities. Synthetic polyurethane and hydrocolloid dressings have also revolutionized the care of ulcerated hemangiomas.283 The use of these dressings can markedly reduce the pain, risk of infection, and rate of time to healing in these open wounds. Dressings can be kept in place for several days at a time and the dressing adhesives are less irritating to infant skin than standard tape adhesive. The hydrocolloid dressings are particularly effective when there is significant exudate from the wounds, since they are able to absorb many times their weight in exudative fluid. Hydrogel dressings are more effective in painful wounds with minimal exudate. They promote autolytic debridement of necrotic tissue with minimal discomfort.284,285 Dressings can be applied immediately post-laser treatment for these ulcerated wounds and the infrequent need for the dressing changes minimizes the pain and trauma, both for the infant and parents. Synthetic polyurethane and hydrocolloid surgical dressings have also been used with great success in the management of split-thickness skin graft donor sites where they simultaneously reduce pain and speed the rate of re-epithelialization.286,287 The

hydrocolloid dressings are also effective in debriding ulcers288 and for treating superficial burns.289 For patients who are susceptible to friction blisters, the hydrocolloid dressings may be used prophylactically at predisposed sites on the heels or toes before engaging in physical activity. Several unique synthetic surgical dressings have also been introduced with very specific indications.290 One of these, N-Terface, is constructed as a porous monofilament fabric from high-density plastic. It is used as an interpositional membrane on the surface of skin graft recipient sites, as it allows the passage of surface exudate from the wound without becoming adherent to it. This permits dressings to be changed in an atraumatic fashion without disturbing the graft. Another unique dressing, Biobrane, has been used successfully in managing dermabrasion wounds and skin graft donor sites. This dressing is composed of a nylon mesh that is bound to dimethylsiloxane and purified type 1 porcine skin collagen polypeptides. The dressing adheres to the surface of the wound to provide a flexible covering that maintains the humidity by reducing the amount of water lost from the skin. In this fashion, Biobrane has been used successfully in managing dermabrasion wounds,291 skin graft donor sites,292 burns, Stevens–Johnson syndrome and toxic epidermal necrolysis.293 Mepitel is a nonadherent soft silicon mesh dressing that is widely used to reduce the pain of open wounds during dressing changes. It has been used over surgical sites, open wounds of patients with epidermolysis bullosa, ulcerated hemangiomas and over laser surgery sites and leg ulcers, with improvement in pain and increased rates of healing.294 For more exudative wounds, the hydrogel dressings are most effective. These are non-adherent, gas-permeable, and largely composed of water and polyethylene oxide or polyvinyl alcohol.295 This group of synthetic surgical dressings has the remarkable ability to absorb one to two times their weight in exudative fluid, while maintaining the surface humidity of the wound. Because of these properties, dressings in this group have been used to manage dermabrasion wounds296 and superficial open wounds following carbon dioxide laser surgery279 or pulsed dye laser surgery for ulcerated hemangiomas.283

276. Hunt TK, Hopf H, Hussain Z. Physiology of wound healing. Adv Skin Wound Care. 2000;135:6. 277. Mertz PM, Marshall DA, Eaglstein WH. Occlusive wound dressings to prevent bacterial invasion and wound infection. J Am Acad Dermatol. 1985;12:662. 278. Baker PD. Creating the optimal environment: an overview of dressings for chronic wounds. Adv Nurse Pract. 2005;13:37–38. 279. Worley CA. So, what do I put on this wound? The wound dressing puzzle: part III. Dermatol Nurs. 2005;17:299–300. 280. Lee CK, Hansen SL. Management of acute wounds. Surg Clin North Am. 2009;89:659–676. 281. Hien NT, Prawer SE, Katz HI. Facilitated wound healing using transparent film dressing following Mohs micrographic surgery. Arch Dermatol. 1988;124:903. 282. Viclano V, Castera JE, Medrano J, et al. Effect of hydrocolloid dressings on healing by second intention. Eur J Surg. 2000;166:229. 283. Freiden IJ. Special symposium: management of hemangiomas. Pediatr Dermatol. 1997;14:57. 284. Lay-Flurrie K. The properties of hydrogel dressings and their impact on wound healing. Prof Nurse. 2004;19:269–273. 285. Hampton S. A small study in healing rates and symptom control using a new sheet hydrogel dressing. J Wound Care. 2004;13:297–300. 286. Barnett A, Berkowity RL, Mills R, et al. Comparison of synthetic adhesive moisture vapor permeable and fine mesh gauze dressings for splitthickness skin graft donor sites. Am J Surg. 1983;145:379.

287. Persson K, Salemark L. How to dress split thickness skin grafts: a prospective randomized study of four dressings. Scand J Plast Reconstr Surg Hand Surg. 2000;34:55. 288. Handfield-Jones SE, Grattan CE, Simpson RA, et al. Comparison of a hydrocolloid dressing and paraffin gauze in the treatment of venous ulcers. Br J Dermatol. 1988;118:425. 289. Hermans MH. Hydrocolloid dressing (Duoderm) for the treatment of superficial and deep partial thickness burns. Scand J Plast Reconstr Surg Hand Surg. 1987;21:283. 290. Salasche SJ, Winton GB. Clinical evaluation of a nonadhering wound dressing. J Dermatol Surg Oncol. 1986;12:1220. 291. Whitaker IS, Prowse S, Potokar TS. A critical evaluation of the use of Biobrane as a biologic skin substitute: a versatile tool for the plastic and reconstructive surgeon. Ann Plast Surg. 2008;60:333–337. 292. Prasad JK, Feller I, Thomson PD. A prospective controlled trial of Biobrane versus scarlet red on skin graft donor areas. J Burn Care Rehabil. 1987;8:384. 293. Bradley T, Brown RE, Kucan JO, et al. Toxic epidermal necrolysis: a review and report of the successful use of Biobrane for early wound coverage. Ann Plastic Surgery. 1995;35:124. 294. White R, Morris C. Mepitel: a non-adherent wound dressing with Safetac technology. Br J Nurs. 2009;18:58–64. 295. Mandy SH. A new primary wound dressing made of polyethylene oxide gel. J Dermatol Surg Oncol. 1983;9:153. 296. Geronemus RG, Robins P. The effect of two new dressings on epidermal wound healing. J Dermatol Surg Oncol. 1982;8:850.

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Table 5.2  Pediatric applications of skin substitutes SUBSTITUTE

TISSUE TYPE

PEDIATRIC USE

Epidermal grafts

Living keratinocyte sheets

Congenital nevi, EB, vitiligo, burns

Extracellular matrix allogeneic, acellular chondroitin-6-sulfate with silicone backing generated by allogeneic human dermal fibroblasts

Surgical wounds, EB

Living allogeneic bilayered construct keratinocytes, fibroblasts and bovine type 1 collagen

EB, chronic wounds, excisional wounds

Cultured epidermal autographs, allografts (Epicel)

Dermal substitutes Nonliving dermal replacements Alloderm Integra TransCyte

Composite grafts Human skin equivalent Apligraf

Burns

DRESSINGS

In the past decade, tremendous progress has been made in the development of biologic dressings.270,297 Many of these skin substitutes have been approved by the United States Food and Drug Administration (FDA) in the treatment of chronic wounds such as burns and venous leg ulcers (Table 5.2). Although these are rare problems in the pediatric dermatology population, the benefit of these systems is apparent for wound healing problems such as epidermolysis bullosa or surgical wounds. Three types of grafts have been developed since Rheinwald and Green first developed a method that made cultivation of human keratinocytes in vitro possible in 1975.298 The original grafts were epidermal in nature and derived from either the patient’s own skin (autografts) or from allogenic donors (allografts).299 Success in the pediatric population in treatment of giant congenital nevi300 and epidermolysis bullosa301 has been seen with autografts. Although they provided the benefit of coverage of large areas, they required skin biopsy, considerable time for graft cultivation and were quite fragile as well as very costly. Cultured epidermal allografts that derive from neonatal foreskin are now commercially available. They have

been successfully used in treating epidermolysis bullosa302 and dermabrasion wounds.303 Allografts have the advantage of being readily available with no skin biopsy or donor wound site. The second group of skin substitute products that have been developed is dermal replacement products: AlloDerm, Integra, TransCyte, Dermagraft, E-Z Derm, Oasis and Mediskin. AlloDerm is a chemically treated human cadaveric cryopreserved de-epidermalized allograft that forms an acellular dermal matrix with an intact basement membrane complex. Integra is a bilaminar structure comprised of bovine collagen and a shark derived chondroitin-6-sulfate dermal matrix backed by a removable silicon rubber membrane that functions like epidermis. Trans­ Cyte is an extracellular matrix generated by human newborn fibroblasts cultured on a nylon mesh with a silicon epidermal layer. Dermagraft is a bioabsorbable mesh of human neonatal dermal fibroblasts cultured on polygalactic acid suture (Vicryl). E-Z Derm is an acellular porcine dermis comprised of collagen network chemically cross-linked with aldehyde. Oasis is porcine small-intestinal submucosa and Mediskin is porcine epidermis and dermis. All of these have been used to accelerate the healing of diabetic ulcers,304,305 in the treatment of burn injuries,306 in

297. Chern PL, Baum CL, Arpey CJ. Biologic dressings: current applications and limitations in dermatologic surgery. Dermatol Surg. 2009;35:891–906. 298. Rheinwald J, Green H. Serial cultivation of strains of human epidermal keratinocytes: Formation of keratinizing colonies from single cells. Cell. 1975;6:331–344. 299. Philips TJ. New skin for old: Developments in biological skin substitutes (editorial; comment). Arch Dermatol. 1998;134:344–349. 300. Gallico GI, O’Connor N, Compton C, et al. Cultured epithelial autografts for giant congenital nevi. J Plast Reconstr Surg. 1989;84:1–9. 301. Carter D, Lin A, Varghese M, et al. Treatment of junctional epidermolysis bullosa with epidermal autografts. J Am Acad Dermatol. 1987;17:246–250.

302. Witt PD, Cohen DT, Mallory S. Use of a permanent acellular dermal allograft in recessive dystrophic epidermolysis bullosa involving the hands. Arch Dermatol. 1999;135:503–506. 303. Arambula H, Sierra-Martinez E, Gonzalez-Aguirre N, et al. Frozen human epidermal allogeneic cultures promote rapid healing of facial dermabrasion wounds. Dermatol Surg. 1999;25:708–712. 304. Campitiellow F, Della Corte A, Fattopace A, et al. The use of artificial dermis in the treatment of chronic and acute wounds: regeneration of dermis and wound healing. Acta Biomed. 2005;76:69–71. 305. Omar AA, Mavor AID, Jones AM, et al. Treatment of venous leg ulcers with Dermagraft. Eur J Vas Endovasc Surg. 2004;27:666–672. 306. Ehrenreich M, Ruszczk Z. Update on dermal substitutes. Acta Dermatoven Croat. 2006;14:172–187.

BIOLOGICAL DRESSINGS

240

Surgical techniques

5

PEDIATRIC SURGICAL DRESSINGS: POSTOPERATIVE WOUND CARE

chronic wound.

DRESSINGS

Figure 5.20  Placement of Apligraf on epidermolysis bullosa patient with

Success in pediatric surgery requires the use of patient-friendly dressings and postoperative wound care instructions that address the level of activity and special needs of the pediatric patient. Wound care instructions and postoperative restrictions must be reviewed with the pediatric patient prior to scheduling the surgery and again at the time of surgery. Written postoperative instructions are essential (see Box 5.5). There are two important premises to caring for the postoperative wounds in the pediatric patient. The first is to minimize manipulation of the wound and thereby maintain wound integrity and sterility, and the second is to minimize postoperative activity thereby decreasing the postoperative complication rate.

Punch biopsy sites 307

308

resurfacing of scars, in reconstruction of donor sites and in some patients with epidermolysis bullosa.309 The most widely used of the biologic dressings in the pediatric population is composite grafts, also known as human skin equivalent or Apligraf (Fig. 5.20). This dressing is a bilayered living construct that is composed of cultured human neonatal foreskin keratinocytes, fibroblasts and bovine type 1 collagen.306 Apligraf is approved by the FDA for use in venous ulcers and has been used in the treatment of patients with epidermolysis bullosa with successful wound healing.309–312 Studies have shown that the use of Apligraf for chronic venous ulcers is superior to compression alone and results in much more rapid healing.313 A multicenter study looking at the efficacy of Apligraf for the treatment of partial- and full-thickness surgical wounds has also been undertaken, demonstrating safe and satisfactory cosmetic results that were the same or better than what would be expected with split-thickness autografts in half of the patients.314,315 The use of Apligraf to treat large burn wounds and as a skin replacement to cover the wounds from removal of giant congenital nevi has also been reported.316 Composite grafts offer an advantage in that the construct acts as a barrier against infection and mechanical damage by providing structural support, while secreting cytokines that can interact with the underlying tissue to promote wound repair.309 Further studies will be needed to define the place of this composite graft in the treatment of pediatric surgical wounds and chronic wound patients with epidermolysis bullosa.

Punch biopsy sites should be kept dry for 48 h following the biopsy. Topical antibiotic ointment and adhesive tape should be changed on a daily basis subsequent until suture removal is recommended. Scalp biopsy sites should be covered with ointment only. Facial biopsy sites can be covered with hydrocolloid or polyurethane dressings and left untouched until suture removal at 5–7 days.

307. Ismail A, Jarvi K, Canal AC. Successful resurfacing of scars from previous deliberate self-harm using Integra dermal matrix substitute. J Plast Renconstr Aesthet Surg. 2008;61:839–841. 308. Rowe NM, Morris L, Delacure MD. Acellular dermal composite allografts for reconstruction of the radial forearm donor site. Ann Plast Surg. 2006;57:305–311. 309. Fivenson DP, Schershun L, Cohen LV. Apligraf in the treatment of severe mitten deformity associated with recessive dystrophic epidermolysis bullosa. Plast Reconstr Surg. 2003;112:584–588. 310. Fivenson DP, Scherschun L, Cohen LV. Graftskin therapy in epidermolysis bullosa. J Am Acad Dermatol. 2003;48:886–892. 311. Falabella AF, Valencia IC, Eaglstein WH, et al. Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds. Arch Dermatol. 2000;136:1225.

312. Fine JD. Skin bioequivalents and their role in the treatment of inherited epidermolysis bullosa. Arch Dermatol. 2000;136:1259. 313. Martin LK, Kirsner RS. Use of a meshed bilayered cellular matrix to treat a venous ulcer. Adv Skin Wound Care. 2002;15:260–262, 264. 314. Eaglstein WH, Alvarez OM, Auletta M, et al. Acute excisional wounds treated with a tissue-engineered skin (Apligraf). Dermatol Surg. 1999;25:195–201. 315. Phillips T. Tissue engineered skin. Arch Dermatol. 1999;135:977–978. 316. Sood R, Balledux J, Koumanis DJ, et al. Coverage of large pediatric wounds with cultured epithelial autografts in congenital nevi and burns: results and technique. J Burn Care Res. 2009;30(4):576–586.

Shave biopsy sites Wounds left to heal by second intention require specialized care in the pediatric patient to monitor for signs of infection. The most important aspect of postoperative care is preventing wound desiccation. This can be accomplished with the liberal application of topical antibiotic ointment and fresh adhesive tape on a daily basis or with the use of polyurethane or hydrocolloid surgical dressings. The latter is preferable and can be changed every 2–3 days to speed healing. Dressings kept on longer will increase the risk of infection. Bathing daily will require daily dressing changes since even polyurethane dressings become dislodged with exposure to water. It is typical for a rim of erythema to develop surrounding the second intention wound. Healing typically takes 2–3 weeks, depending on the size of the wound. Exudate from the wound and pain are signs of infection and should be brought to the attention of the surgeon immediately.

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Table 5.3  Recommended timing of suture removal DAYS Face Trunk or extremities   interrupted sutures   running subcuticular sutures

5–7

Scalp

10 14–21 12–14

Palms and soles

10–12

Sutured wounds DRESSINGS

In general, wound dressings that minimize the necessity of wound care by parents will be most successful in the pediatric population. It is impossible to keep wound dressings intact with daily bathing, even when extraordinary attempts are made to use polyurethane dressings and to cover the affected area during the shower. I usually recommend that bathing be limited to hairwashing and sponging the child until suture removal. This routine works best for pre-adolescents. For adolescent-age patients, the routine can be modified to allow for more ageappropriate personal hygiene. The appropriate timing for suture removal depends on the type of suture placed and the location of the wound (Table 5.3). In general, suture puncture sites will re-epithelialize in approximately 10 days. For areas on the body that heal rapidly, such as the face and genital skin, removal of interrupted sutures at 7 days is unlikely to leave noticeable suture marks. Unfortunately, the trunk, extremities, and scalp require longer for complete healing, especially in an active child. Interrupted sutures removed at 10 days may even result in suture marks on the trunk and extremities. Here, a running subcuticular suture offers a great advantage, in that it can be safely left in place for much longer without running the risk of producing suture marks (see above.)

Scalp dressings The pediatric dermatologic surgeon is frequently called upon to remove lesions from the scalp, including nevus sebaceus, congenital nevi, and aplasia cutis. Wound dressings are particularly challenging here. For any dressing to be adherent to the scalp, the scalp must be shaved. Unfortunately, a shaved scalp is more traumatic for a child than the procedure itself and is not recommended. Since scalps are highly vascular and therefore at the greatest risk of bleeding of all body sites, a modified scalp dressing is recommended that will avoid the need for removing scalp hair in larger wounds. Wounds of ≤1 cm in the scalp can usually be managed with antibiotic ointment only, without the need for any dressing. Wounds should be absolutely dry before suture closure. The ointment should be applied regularly several times per day to minimize crusting of the scalp wound and facilitate

317. Wagner AM, Listina K. The ultimate dressing: No mess, no fuss, no phone calls. Pediatr Dermatol. 1999;16:62. 318. Carrington PR. Tacky but refined: A ‘slick’ technique for dressings that hold better. Dermatol Surg. 2000;26:929. 319. Sakagami H, Kishino K, Kobayashi M, et al. Selective antibacterial and apoptosis-modulating activities of mastic. In Vivo. 2009;23:215–223.

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removal of the sutures with minimal discomfort. For prepubertal children, I recommend no hair-washing until suture removal. For adolescents, bathing is restricted for 48 h and then permitted daily with liberal application of antibiotic ointment to the wound after the shower. For larger scalp wounds, a pressure dressing can be used on the scalp for 48 h (Fig. 5.19). Liberal antibiotic ointment is applied to the sutures on the scalp surface and non-adherent dressing is applied over the antibiotic ointment. Fenestrated gauze is placed over the non-adherent dressing and a roll of gauze is used in a turban fashion to hold the fenestrated gauze in place. Silk tape is used along the forehead and the posterior neck, avoiding contact with the hair, to keep the turban in place and an elastic tube bandage is placed on top of the dressing.317 At 48 h, the dressing can be snipped under the chin and the tape removed from the forehead and posterior scalp. The entire dressing will come off without trauma and ointment can be applied on a daily basis to the exposed sutures to prevent crusting.

Facial wounds Polyurethane and hydrocolloid wound dressings are most useful on the face. These can be applied directly to the sutured wound and left in place until suture removal. If necessary, a small pressure dressing can be made out of gauze and a polyurethane dressing or tape placed over the wound for the first 48 h. Most facial wounds do not require pressure dressing. The new synthetic dressings hasten healing and reduce the risk of infection by maintaining the integrity of the wound until suture removal.5 It is recommended that wounds closed with skin adhesive should be steri-stripped before covering with a polyurethane dressing to increase the security of the closure in children.

Extremity and trunk wounds Although the simplest to perform, extremity and trunk surgery can be most frustrating for the dermatologic surgeon, because these scars spread significantly in the pediatric age group, due to the elasticity of tissue and the activity level in this patient population. The use of running subcuticular sutures, which can be kept in place for longer, and non-absorbable suture material in the deep dermis, can minimize spreading of the wound. However, restriction of activity in the postoperative period is essential to maximize the appearance of postoperative scarring in these locations. Wounds closed with a running subcuticular suture should be steri-stripped before covering with a polyurethane dressing to improve wound edge apposition (Fig. 5.21). Steri-Strips stay on better if extra adhesive is applied to the skin surface.318 In addition, Mastisol, the most widely used bandage adhesive, which is a resinous exudate from the Pistacia lentiso plant, has antibacterial properties.319 Allergic contact dermatitis has been reported with mastisol.320,321 This should be kept dry and intact until suture removal. The use of bulky pressure dressings on extremities can be helpful in reminding the pediatric patient that a

320. Widman TJ, Oostman H, Storrs FJ. Allergic contact dermatitis from medical adhesive bandages in patients who report having reaction to medical bandages. Dermatitis. 2008;19:32–37. 321. Worsnop F, Affleck A, Varma S, et al. Allergic contact dermatitis from Mastisol mistaken for cellulitis. Contact Dermatitis. 2007;56:357–358.

Surgical techniques

5

risk of infection, these wounds should be covered only with antibiotic ointment. Hydrocolloid and polyurethane dressings are of limited use on the palms and soles since they do not adhere well. Postoperative complications on the foot in the pediatric population are proportionate to the activity level of the child. Restricting ambulation is essential for good wound healing in this location. The thickness of the statum corneum on the palms and soles results in hydration and maceration of the skin that can be mistaken for partial dehiscence. It is worthwhile to review with the parent the expected appearance of the wound to avoid unnecessary concern in the postoperative period.

POSTOPERATIVE FOLLOW-UP DRESSINGS

A

B

Figure 5.22  (A,B) Extremity wounds over joints should be immobilized to decrease movement of the wound in the immediate postoperative period in children.

procedure was done and that activities should be restricted. Since there is minimal postoperative pain, most children are ready to resume normal activity within 24 h of a procedure. The bulkier dressing is visible and can restrict activity over joints, reminding the child of the need to modify activity level. In general, for preadolescents, the bulkier and more colorful the dressing, the happier the patient. Wraps across joints are especially helpful on extremities with excision lines (Fig. 5.22). The use of soft splints (Velcro closure joint immobilizers) or casting material molded to the ankle and wrapped to limit movement can also be helpful. These do not fully restrict movement around the joints, but they do restrict movement significantly to prevent climbing and running. This is especially important in toddlers who are too young to understand the need for restriction of activity. For lesions around the knee or on the ankle and foot, crutches can be helpful for patients 8 years of age and older. Younger patients are not coordinated well enough to use these and they should be avoided.

Palms and soles Excisions on the palms and soles or between the toes and fingers are particularly prone to infection, especially in the pediatric population. A running suture technique should be avoided in these locations. The wound in this location should be cleansed on a daily basis after 48 h and examined by the parent for evidence of drainage, erythema, or wound dehiscence. Any evidence of erythema, pain or exudate should be treated with oral antibiotics such as cephalexin for a 10-day period. Since maceration of the skin in the web spaces contributes to an increased

It is important to maintain close contact with families in the postoperative period. Most parents are extraordinarily concerned about pain and postoperative care. A quick phone call the day after a procedure is very reassuring for families and helps minimize complications. Be sure to provide families with phone numbers to call with any problems. Wound infection is rare in the first five postoperative days. Yet parents, and even healthcare providers, will immediately assume that a fever after surgery is most likely related to wound infection. Recommending that families contact you or your staff before removing the dressing is very helpful to avoid unnecessary dressing removal. Clinical signs of wound infection are the development of pain after 5–7 days, odor and drainage. Fever resulting from infection in a wound is highly unlikely. Any wound infection that is severe enough to cause systemic symptoms should demonstrate saturation of the dressing with surrounding cellulitis. All other sources of fever should be addressed before attributing the fever to a wound infection. Many parents are concerned about their inability to ‘see’ the wound to properly evaluate it. Reassurance that wound dehiscence and infection are preceded by pain is very helpful. A painless wound is highly unlikely to be a problem. In sites where infection is more likely, such as the feet, hands and groin, the liberal use of antibiotic ointment as the only dressing allows for ready access to the wound for evaluation and cleansing. Parents are frequently concerned that the dressing will fall off. Careful application of the Steri-Strips, hydrocolloid, or polyurethane dressing with skin adhesive is usually sufficient to prevent this complication.318 Despite parental concerns, most infants leave their dressings alone. If the pressure dressing falls off inadvertently in the first 48 h, there is no need to replace it. It functions only to prevent bleeding and trauma. If the dressing immediately covering the wound becomes loose, it should be reinforced, but not replaced. Blood-stained dressings can be covered with adhesive tapes or gauze if the parents prefer not to see the soiled areas. Some blood-staining on the dressing is normal and parents should be alerted to this likelihood. Unless blood is seeping through or around the dressing, there is no cause for concern. The risk of infection is reduced if the initial wound dressing remains intact.

DRESSINGS

Figure 5.21  Running subcuticular suture.

HYPERTROPHIC SCARS AND KELOIDS Hypertrophic scarring occurs frequently in the pediatric population. This is probably due to the markedly increased activity level of young children. It is therefore essential that all patients are followed closely in the postoperative period. Facial wounds 243

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BOX 5.6 TREATMENTS* FOR HYPERTROPHIC SCARS AND KELOIDS

>> Occlusion (polyurethane dressings) >> Silicon gel sheeting (gel and ointment also available) >> Pressure dressings >> Intralesional triamcinolone >> Other intralesionals (5-fluorouracil, bleomycin, interferon alpha, verapamil)

DRESSINGS

Figure 5.23  Hypertrophic scar following 1st stage excision of large congenital nevus.

should be examined early to allow early intervention if this is occurring and are typically seen 1–2 months after suture removal. Wounds in all other locations should be examined 3 months postoperatively. Parents should be alerted to the appearance of a hypertrophic scar (Fig. 5.23). Although spreading of the scar on a trunk or extremity is quite likely in the first three postoperative months, the tissue should not become firm or raised above the skin. In the likelihood that this occurs, it is important to begin treatment early. Keloids are benign fibrous tumors that constitute an abnormal healing response and grow beyond the boundaries of a normal scar. These are more common in the setting of a family history and in Asians, Hispanics and Blacks.322,323 It is important to ask families about a family history of keloids before the surgery in order to approach and prepare the family if there is a significant risk. There are few randomized trials evaluating the efficacy of treatment for hypertrophic scars and keloids. No single treatment is usually adequate and a polytherapeutic strategy is often necessary and associated with the greatest improvement (Box 5.6).324 There are many myths about scar treatment. Families should be informed about scientific data relating to treatment outcomes to avoid wasted effort and expense. Foremost in this category is the application of Vitamin E,325,326 and onion extracts (Mederma),327,328 which have not demonstrated any medical efficacy in clinical trials. Topical application of these products

322. Juckett G, Hartman-Adams H. Management of keloids and hypertrophic scars. Am Fam Physician. 2009;80:253–260. 323. Robles DT, Moore E, Draznin M, et al. Keloids: pathophysiology and management. Dermatol Online J. 2007;13:9. 324. Reish RG, Eriksson E. Scars: a review of emerging and currently available therapies. Plast Reconstr Surg. 2008;122:1068–1078. 325. Zuranda JM, Kriegel D, Davis IC. Topical treatments for hypertrophic scars. J Am Acad Dermatol. 2006;55:1024–1031. 326. Baumann L, Spencer J. The effects of topical vitamin E on the cosmetic appearance of scars. Dermatol Surg. 1999;25:311–315. 327. Chung V, Kelley L, Marra D, et al. Onion extract gel versus petrolatum emollient on new surgical scars: prospective double-blinded study. Dermatol Surg. 2006;32:193–198. 328. Saulis A, Mogford JH, Mustoe TA. Effect of Mederma on hypertrophic scarring in the rabbit ear model. Plast Reconstr Surg. 2002;110:177– 183.

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>> Topical creams: – imiquimod 5% cream – retinoids – vitamin A – vitamin E – onion extract (Mederma) >> Cryotherapy >> Laser >> Radiotherapy >> Re-excision * No effect, negative effect, or side-effects outweigh benefits.

may offer benefit if accompanied by firm massage, however, and recommendation of this approach is recommended for families who are unconvinced or attached to these treatments based on personal anecdotal experience. Pressure on scars has long been known to improve outcome and remains a mainstay of treatment for burn patients to prevent scar hypertropy.329,330 Similarly, there may be benefit to scar occlusion. The most widely used postoperative intervention for scars and keloids is the use of a silicon scar sheeting,331 which takes advantage of both of these benefits.

Silicone gel for scars and keloids Numerous silicone scar patch systems have been developed for the treatment of hypertrophic scars and keloids.332 Since these systems are painless, they are the mainstay of treatment of these problems in the pediatric population. The mechanism of action of silicon sheeting is not completely understood but studies indicate that cytokine-mediated signaling from the keratinocytes to the dermal fibroblasts results in a suppression of fibroblast metabolism and reduced collagen deposition.333,334

329. Macintyre L, Baird M. Pressure garments for use in the treatment of hypertrophic scars – an evaluation of current construction techniques in NHS hospitals. Burns. 2005;31:11–14. 330. Puzey G. The use of pressure garments on hypertrophic scars. J Tissue Viability. 2002;12:11–15. 331. O’Brien L, Pandit A. Silicon gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev. 2006;25:CD003826. 332. O’Brien L, Pandit A. Silicon gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev. 2006;25:CD003826. 333. Tandara AA, Mustoe TA. The role of epidermis in the control of scarring: evidence for mechanism of action of silicone gel. J Plast Reconstr Aesthet Surg. 2008;61:1219–1225. 334. Mustoe TA. Evolution of silicone therapy and mechanism of action in scar management. Aesthetic Plast Surg. 2008;32:82–92.

The occlusion and hydration of the scar or keloid by these dressings also contribute to their efficacy.335 The remodeling phase of scars is very prolonged and these dressings should be worn for a prolonged period of at least 6 months for maximum improvement with close follow-up when they are discontinued.336 The longer the patch is in place, the greater the effect of minimizing scar hypertrophy. For adolescents, night-time use of these patches may be reasonable. For younger children, wearing these patches 24  h each day is recommended. The most effective patch systems come with cleansers to allow cleaning of the patch on a daily basis. Each patch lasts approximately 3 weeks using this method. For patients who are unable to afford the costly scar patch systems, stretch foam tape can be helpful. Once hypertrophy has been identified in a healing wound, follow-up should be every 2–3 months until the physician and parents are content with the appearance of the scar or the hypertrophy has resolved.

Laser treatment for keloids was first attempted, unsuccessfully, with the CO2 laser.341 This is not recommended. The pulsed dye laser is currently considered the laser of choice in the management of hypertrophic scars and keloids.342 Although most

effective in reducing erythema and pruritus, it has also been shown to reduce scar volume and improve the texture of the scar surface in hypertrophic scars and keloids.343–345 Treatment with the pulsed dye laser should be accomplished at low energy (3–5 J/cm2 with 7 mm spot) to avoid breakdown of the skin and hyperpigmentation, which are common problems with recurrent treatments, especially in pigmented races where keloids are more prevalent. The pain of this procedure, like cryotherapy, limits its usefulness in children to those over 8 years. Topical anesthetic creams can be helpful to reduce treatment discomfort which is less than would be expected when treating vascular lesions, since lower energies are used. In general, 3–6 treatments are done at 8-week intervals for maximum effectiveness.345 Many other treatments have been recommended for the management of keloids and hypertrophic scars. Topical imiquimod 5% cream has demonstrated some improvement but most patients experience side-effects of erythema and discomfort that limit application.325,346,347 Similarly, topical vitamin A and topical retinoids have been used with variable outcomes and a sideeffect profile of local irritation and risk of systemic absorption in pediatric patients that limits their usefulness.325,348,349 Intralesional injection of 5-fluorouracil alone and in combination with triamcinolone has shown efficacy in some studies.350,351 Use in pediatrics is limited by the risk of systemic absorption of the F-fluorouracil. Similarly, intralesional bleomycin has been effective in some studies, but systemic toxicity and pain with injection make this an inappropriate treatment in children.352,353 Intralesional interferon-alpha-2b has not been shown to be effective.354 For severe and symptomatic keloids, radiotherapy has been employed, primarily as an adjunct to repeat surgical resection.355–357 Various forms of irradiation have been used, including superficial X-rays (Grenz rays), electron beam and low and high dose beta radiation.323 Side-effects include hyper- and hypopigmentation, erythema, telangiectasia and atropy of the overlying skin. Risk of malignancy in a scar following radiation is rare.342 There is no agreement in the literature regarding the

335. Sawada Y, Sone K. Hydration and occlusion treatment for hypertrophic scars and keloids. Br J Plast Surg. 1992;45:599–603. 336. Harte D, Gordon J, Shaw M, et al. The use of pressure and silicone in hypertrophic scar management in burn patients: a pilot randomized controlled trial. J Burn Care Res. 2009;30:632–642. 337. Leventhal D, Furr M, Reiter D. Treatment of keloids and hypertrophic scars: a meta-analysis and review of the literature. Arch Facial Plast Surg. 2006;8:362–368. 338. Ketchum LD, Robinson DW, Master FW. Follow-up on treatment of hypertrophic scars and keloids with triamcinolone. Plast Reconstr Surg. 1971;48:256–259. 339. Manuskiatti W, Fitzpatrick R. Treatment response of keloidal and hypertrophic sternotomy scars. Arch Dermatol. 2002;138:1149–1155. 340. Wu WS, Wang FS, Yang KD, et al. Dexamethasone induction of keloid regression through effective suppression of VEGF expression and keloid fibroblast proliferation. J Invest Dermatol. 2006;126:1264–1271. 341. Poochareon VN, Berman B. New therapies for the management of keloids. J Crainofac Surg. 2003;14:654–657. 342. Reish RG, Eriksson E. Scar treatments: preclinical and clinical studies. J Am Coll Surg. 2008;206:719–730. 343. Kuo YR, Wu WS, Jeng SF, et al. Suppressed TGF-B1 expression is correlated with up-regulation of matrix metalloproteinase-13 in keloid regression after flashlamp pulsed-dye laser treatment. Lasers Surg Med. 2005;36:38–42. 344. Lupton JR, Alster TS. Laser scar revision. Dermatol Clin. 2002;20:55–65. 345. Chan HH, Wong DS, Ho WS, et al. The use of pulsed dye laser for the prevention and treatment of hypertrophic scars in Chinese persons. Dermatol Surg. 2004;30:987–994. 346. Stashower ME. Successful treatment of earlobe keloids with imiquimod after tangential shave excision. Dermatol Surg. 2006;32:380–386.

347. Prado A, Andrades P, Benitez S, et al. Scar management after breast surgery: preliminary results of a prospective, randomized, and doubleblind clinical study with Aldara cream 5% (imiquimod). Plast Reconstr Surg. 2005;115:966–972. 348. Daly T, Golitz LE, Weston WL. A double-blind placebo-controlled efficacy study of tretinoin cream 0.05% in the treatment of keloids and hypertrophic scars. J Invest Dermatol. 1986;86:470. 349. Mizutani H, Yoshida T, Nouchi N, et al. Topical tocoretinate improved hypertrophic scar, skin sclerosis in systemic sclerosis and morphea. J Dermatol. 1999;26:11–17. 350. Fitzpatrick RE. Treatment of inflamed hypertrophic scars using intralesional 5-FU. Dermatol Surg. 1999;25:224–232. 351. Kontochristopoulos G, Stefanaki C, Panagiotopoulos A, et al. Intralesional 5-fluorouracil in the treatment of keloids: an open clinical and histopathologic study. J Am Acad Dermatol. 2005;52:474–479. 352. Yamamoto T. Bleomycin and the skin. Br J Dermatol. 2006;155:869–875. 353. Naeini FF, Najafian J, Ahmadpour K. Bleomycin tattooing as a promising therapeutic modality in large keloids and hypertrophic scars. Dermatol Surg. 2006;32:1023–1030. 354. Davison SP, Duncan MR. Ineffective treatment of keloids with interferon alpha-2b. Plast Reconstr Surg. 1989;117:247–252. 355. Botwood N, Lewanski C, Lowdell C. The risks of treating keloids with radiotherapy. Br J Radiol. 1999;72:1222–1224. 356. Ogawa R, Mitsuhashi K, Hyakusoku H, et al. Postoperative electron-beam irradiation therapy for keloids and hypertrophic scars: retrospective study of 147 cases followed for more than 18 months. Plast Reconstr Surg. 2003;111:547–555. 357. Al-Attar A, Mess S, Thomassen JM, et al. Keloid pathogenesis and treatment. Plast Reconstr Surg. 2006;117:286–300.

Intralesional triamcinolone In addition to scar patching systems, injection of triamcinolone acetate 20–40 µg/cc into the hypertrophic areas of the scar at monthly intervals can be very effective.323,337–340 This can be readily accomplished in most children over the age of 8 with the use of a topical anesthetic cream prior to the procedure. For keloid management it is critical to repeat these injections regularly at 4–6 week intervals for sustained effect. Most patients are treated for a minimum of 6–12 months to prevent regrowth with cessation of treatment.

Pulsed dye laser

5

DRESSINGS

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SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

optimal dosage, fractionation or timing of treatment. A single dose given 24  h after resection of keloids has a high cure rate.358 For many patients with severe scar hypertrophy of keloid formation, it is best to begin treatment with scar revision.323,342 Tissue expansion or redesigning the closure along skin surface tension lines using a Z-plasty, W-plasty or a well-designed flap may be an option depending on the scar location and size. An important aspect to the management of hypertrophic scars and keloids in pediatric patients is counseling against further body piercings and the risk of future development of hypertrophic scarring and keloids with any subsequent surgical procedure. Elective or cosmetic surgery should be discouraged in this setting. Medically necessary procedures should be approached with special attention to minimizing wound tension and early postoperative intervention with adjunctive measures to prevent formation of hypertrophic scar and keloid.

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

>> Verruca vulgaris >> Verruca plana >> Verruca plantaris >> Condyloma acuminatum >> Keloids >> Hypertrophic scars >> Molluscum contagiosum >> Acrochordon >> Dermatofibroma >> Hemangioma (controversial) >> Granuloma annulare

Cryosurgery is one of the most common procedures performed in pediatric dermatology. Liquid nitrogen (boiling point of −195.8°C) is the cryogenic agent that is used most commonly. The ready availability of this inexpensive agent makes this form of therapy very popular even among primary care physicians. It is important to understand the mechanism of action of cryogenic agents, the types of lesions that are amenable to treatment, the appropriate method of application, and the potential complications with this therapy in the pediatric population. Cryosurgery is the production of localized areas of frostbite on the skin. With the application of liquid nitrogen to the skin surface, intracellular and extracellular ice crystals form within the tissue. This may cause direct injury to the cell membranes or cause cell death indirectly through changes in electrolytes and osmotic pressure. The cold injury to cutaneous blood vessels also accounts for part of the clinical effectiveness of the cryosurgical procedure. Cutaneous injury and cell death occur during the rewarming phase after application of the cryogen as the tissue returns to room temperature.359 The depth of injury with cryosurgery is severe with prolonged application or repeat freeze/ thaw cycles. It is this property that allows for effective treatment of cutaneous malignancy. Unfortunately, it is also this property that leads to inadvertent complications with incorrect use in pediatric patients. Other agents have been used to apply cryotherapy to the skin surface, including dimethyl ether (Histofreezer) or chlorodi­ fluoromethane (Verruca-Freeze).360 When applied to the skin surface, these achieve temperatures that are considerably lower (−40 to −80°C ) and are not as effective as treatment with liquid

nitogen.361 In addition, there is now an over-the-counter cryotherapy wart remover that has gained great popularity in the USA with parents. This product (Wartner) combines dimethyl ether with propane in a foam pad that can be applied directly to the surface of the wart for a recommended 10–20 s. The skin temperature achieved with this system is approximately −57°C. Efficacy of this system is limited by the user’s ability to apply the painful treatment long enough to adequately cause tissue injury. Cryotherapy in the pediatric population is used to remove benign cutaneous lesions.362 The goal of the therapy is to minimize the discomfort and side-effects while maximizing treatment efficacy. Many cutaneous lesions are amenable to cryotherapy. The lesions most commonly treated in children are listed in Box 5.7. Acne is no longer treated with cryotherapy. All atypical or unusual lesions should be biopsied prior to treatment with cryotherapy. Cutaneous viral skin infections account for the vast majority of cryotherapy treatments in pediatric patients. Superficial application of cryotherapy is used to treat these lesions. The method used and duration of application of liquid nitrogen will depend on the size, type and location of the lesion being treated. Cryotherapy is a first-line treatment by most dermatologists for single or small numbers of verruca vulgaris in the pediatric population. It is a practical treatment with a reasonable cure rate. Most patients will require more than one treatment, optimally at 2–3 week intervals. A Cochrane review reported that cryotherapy was no more effective than simple topical treatment for non-genital warts, indicating that this treatment should never be presented as a cure.363 Patients under the age of 8 years with multiple lesions should be treated with other modalities. The pain of cryotherapy applied repeatedly to multiple warts is too severe for young children. Children should not be restrained for wart treatment. There are multiple, effective medical therapies available that are better alternatives in this population, including

358. Ragoowansi R, Cornes PG, Moss AL, et al. Treatment of keloids by surgical excision and immediate postoperative single-fraction radiotherapy. Plast Reconstr Surg. 2003;111:1853–1859. 359. Torre D. Dermatological cryotherapy: a progress report. Cutis. 1973; 11:782. 360. Herman BE, Corneli HM. A practical approach to warts in the emergency department. Pediatr Emerg Care. 2008;24:246–254.

361. Erkens AM, Kiujprs RJ, Knottnerus JA. An end to office hours of warts? A randomized study of the effectiveness of liquid nitrogen and of the Histofreezer. Ned Tijdschr Geneeskd. 1991;135:171–174. 362. Babich D, Crollick JS. Pediatric dermatologic surgery for the primary care pediatrician. Pediatr Clin North Am. 1998;45:1437–1453. 363. Gibbs S, Harvey I, Sterling JC, et al. Local treatments for cutaneous warts. Cochrane Database Syst Rev. 2004;4:CD001781.

CRYOSURGERY

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BOX 5.7 LESIONS TREATED WITH CRYOTHERAPY IN PEDIATRIC PATIENTS

Surgical techniques

cimetidine,364,365 topical imiquimod,366 topical retinoids, salicylic acid plasters, occlusion therapy with duct tape367–370 or immunotherapy.371 Liquid nitrogen is commonly applied to the surface of the verruca using a cotton-tipped applicator. To maximize efficacy, it is recommended that extra cotton be rolled onto the end of the applicator. The lesion is touched gently allowing the ice ball to spread through the verruca by convection rather than pressure. When the entire lesion is white and a 1–2 mm rim of white appears on the normal skin, the lesion has been adequately treated. This typically takes 30–45 s. The depth of the freeze is equal to the size of the white rim on the normal skin. Cryotherapy applied in this manner is unlikely to cause scarring. Application of the cryogen with pressure or repeat freeze/thaw cycles is not routinely recommended. For smaller lesions, treatment will take seconds. For larger plantar warts, treatment of each wart will take 45–60 s. Mosaic plantar warts may require two freeze/thaw cycles and repeat application at 2-week intervals for several treatments. Most flat and filiform warts require a single treatment only. Half of common warts will require two treatments for complete resolution. Liquid nitrogen can also be applied to the skin with a spraying device or a solid brass probe. Most children are frightened by the appearance and noise of these systems. For older children, the cryogen spray unit is a rapid means of applying liquid nitrogen to larger palm and sole lesions. The more rapidly the infected tissue is frozen and the slower the thawing, the better the degree of necrosis, and the more effective the therapy. Cryotherapy is the most painful procedure performed by a pediatric dermatologist. It is inappropriate to use this therapy on children who are unwilling or unable to tolerate the discomfort. All lesions treated with cryotherapy are benign. Often the parental concern is much greater than that of the patient, especially in younger children. The severity of the treatment should fit the severity of the problem. It is important to keep this in mind when treating patients for benign lesions. Some 65% of all verrucae spontaneously involute in 2 years. The insistence of a parent that a child be treated does not justify psychological damage to the patient. The pain of cryotherapy can be minimized with some simple techniques.372 Topical anesthetic agents are not very effective in this procedure, but they are excellent at hydrating the skin overlying the verruca and facilitating paring without discomfort (Fig. 5.24).373 The smaller the wart, the shorter the duration of cryotherapy and pain for the child. Children returning for a second

treatment should be premedicated with acetaminophen or ibuprofen 30 min before the next appointment. The least painful areas should be treated first. For multiple periungual warts, digital blocks are an excellent solution in patients over 10 years of age (Fig. 5.25).374 Topical anesthetic can be applied to the web spaces prior to the visit. The pain of the injection is preferable to the discomfort during and after cryotherapy. Injection of local anesthetic under the verruca to minimize pain is not recommended. Saturation of the tissue with fluid before freezing can result in the production of an ice ball deeper within the normal tissue than desired and extension of the field of necrosis, increasing the risk of scarring. All patients should be offered acetaminophen after therapy, if it has not been previously administered. Throbbing occurs in the area for an average of 20 min after treatment. Patients should be instructed to keep the treated limbs elevated and avoid ‘flicking’ the hands. Finally, distraction is a powerful tool in the pediatric population. Pouring the remaining liquid nitrogen onto the floor or in the basin with the water for soaking is both fun and therapeutic for the patient. Covering the lesions with adhesive dressing is also recommended. Molluscum contagiosum is another lesion commonly treated with cryotherapy in the pediatric population. Larger lesions on the trunk and extremities that do not respond to topical cantharidin375,376 can be effectively removed with light freezing. It is usually sufficient to hold the cryotherapy on the lesion for 3–5 s only. Even minimal inflammation, regardless of the nature of the injury, can cause these lesions to involute.377 Cryotherapy can also be used to treat molluscum on the orbital rim or upper eyelid where cantharidin is contraindicated. For extensive lesions, alternate medical therapies are preferred such as

364. Chern E, Cheng YW. Treatment of recalcitrant periungual warts with cimetidine in pediatrics. J Dermatol Treat. 2009; Epub ahead of print. 365. Fit KE, Williams PC. Use of histamine2-antagoinists for the treatment of verruca vulgaris. Ann Pharmacother. 2007;41:1222–1226. 366. Oster-Schmidt C. Imiquimod: a new possibility for treatment-resistant verrucae plana. Arch Dermatol. 2001;1375:666–667. 367. Bacelieri R, Johnson SM. Cutaneous warts: an evidence-based approach to therapy. Am Fam Physician. 2005;15:647–652. 368. Focht DR III, Spicer C, Fairchok MP. The efficacy of duct tape vs cryotherapy in the treatment of verruca vulgaris (the common wart). Arch Pediatr Adolesc Med. 2002;156:971–974. 369. de Haen M, Spigt MG, van Uden CJ, et al. Efficacy of duct tape vs placebo in the treatment of verruca vulgaris (warts) in primary school children. Arch Pediatr Adolesc Med. 2006;160:1121–1125. 370. Ringold S, Mendoza JA, Tarini BA, et al. Is duct tape occlusion therapy as effective as cryotherapy for the treatment of the common wart? Arch Pediatr Adolesc Med. 2002;156:975–977.

371. Dasher DA, Burkhart CN, Morrell DS. Immunotherapy for childhood warts. Pediatr Ann. 2009;38:373–379. 372. Wagner AM. Pain control in the pediatric patient. Dermatol Clin. 1998;16:609–617. 373. Gupta AK, Koren G, Shear NH. A double-blind, randomized, placebocontrolled trial of eutectic lidocaine/prilocaine cream 5% (EMLA) for analgesia prior to cryotherapy of warts in children and adults. Pediatr Dermatol. 1998;15:129–133. 374. Wagner AM, Suresh S. Peripheral nerve blocks for warts, taking the cry out of cryotherapy and laser. Pediatr Dermatol. 1998;15:238–241. 375. Silverberg NG, Sidbury R, Mancini AJ. Childhood molluscum contagiosum: experience with cantharidin therapy in 300 patients. J Am Acad Dermatol. 2000;43:503–507. 376. Coloe J, Morrell DS. Cantharidin use among pediatric dermatologists in the treatment of molluscum contagiosum. Pediatr Dermatol. 2009;26:405–408. 377. Smolinski KN, Yan AC. How and when to treat molluscum contagiosum and warts in children. Pediatr Ann. 2005;34:211–221.

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Figure 5.24  (A,B) Topical anesthetic cream is applied under occlusion prior

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to paring of warts.

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cimetidine,378,379 topical retinoids,380 10% potassium hydroxide solution,381 or topical 5% imiquimod.382,383 Condyloma acuminatum is an increasing problem in the pediatric population due to the high rate of adult infection and ascending viral infection at the time of birth. Condyloma on moist skin responds well to chemodestruction with podophyllin and trichloroacetic acid, but lesions on glabrous skin require alternate therapy. Liquid nitrogen can be used effectively to treat these patients.384 As with molluscum contagiosum, short 3–5 s applications of cryotherapy are usually effective. Alternately, forceps can be used to pick up the pedunculated lesion and the applicator applied to the forceps rather than the tissue directly. This method is also helpful in treating filiform warts on the face and eyelids. Antibiotic ointment and daily bathing are recommended to minimize the risk of infection in the blistered skin after treatment.

Cryotherapy has also been used to treat early capillary hemangiomas, predominantly in Europe and the Far East.385–387 Contact cryosurgery using an applicator tip that is a constant 232°C is an effective method to induce remission and regression of superficial lesions with minimal side-effects.388 The pulsed dye laser is largely used for this purpose in North America. Treatment of superficial hemangiomas is controversial using any method. Other benign cutaneous lesions can be effectively treated with cryotherapy, including acrochordons, granuloma annulare,388 hypertrophic scars,323,389 keloids,341,390 verrucous epidermal nevus,391 pyogenic granuloma,392 and dermatofibromas. With the exception of acrochordons, it is unusual to treat these lesions in the pediatric population. The use of cryotherapy in children is associated with numerous complications, especially when inappropriately applied. The most common complications of liquid nitrogen cryotherapy are postoperative pain, hypo- or hyperpigmentation, atrophic scarring, permanent nail dystrophy and inadvertent nerve injury. Transient hypopigmentation is common in pigmented races. Melanocytes exhibit extreme sensitivity to cold resulting in significant injury with treatment. Extreme caution should be used in the treatment of any facial lesions in dark-skinned patients. Cryotherapy is not recommended to treat flat warts on the face of a pigmented child. The high risk of pigment loss will make the areas treated more visible than the lesions themselves. Permanent hypopigmentation can result in all patients from aggressive therapy. Atrophic scarring and hypopigmentation are most common when treating lesions overlying joints, especially the knees (Fig. 5.26) and elbows.393 Hypertrophic, painful scarring can result from aggressive cryotherapy for plantar warts. A painful scar on the sole of the foot is disabling. Nail dystrophy frequently results from repeat application of liquid nitrogen to periungual warts. It is not uncommon to see recurrence of the verruca at the proximal nail fold of a dystrophic nail treated repeatedly with cryotherapy. Cryotherapy to the cuticle area is especially likely to produce permanent nail changes and alternative therapies may be preferable for persistent periungual warts. The lateral digits are also a common site for inadvertent nerve injury.393 It is important to be aware of the location of superficial nerves when applying cryotherapy to the skin surface. The lateral aspects of the fingers and toes, the volar aspect of the wrist and the olecranon fossa of the elbow are areas particularly suscepti-

378. Yashar SS, Shamiri B. Oral cimetidine treatment of molluscum contagiosum [Letter]. Pediatr Dermatol. 1999;16:493. 379. Smolinski KN, Yan AC. How and when to treat molluscum contagiosum and warts in children. Pediatr Ann. 2005;34:211–221. 380. Scheinfeld N. Treatment of molluscum contagiosum: a brief review and discussion of a case successfully treated with adapalene. Dermatol Online J. 2007;13:15. 381. Metkar A, Pande S, Khopkar U. An open, nonrandomized, comparative study of imiquimod 5% cream versus 10% potassium hydroxide solution in the treatment of molluscum contagiosum. Ind J Dermatol Venereol Leprol. 2008;74:614–618. 382. Myhre PE, Levy ML, Eichenfield LF, et al. Pharmacokinetics and safety of imiquimod 5% cream in the treatment of molluscum contagiosum in children. Pediatr Dermatol. 2008;25:88–95. 383. Hanna D, Hatami A, Powell J, et al. A prospective randomized trial comparing the efficacy and adverse effects of four recognized treatments of molluscum contagiosum in children. Pediatr Dermatol. 2006;24:334. 384. Culton DA, Morrell DS, Burkhart CN. The management of condyloma acuminata in the pediatric population. Pediatr Ann. 2009;38:368–372. 385. Cremer H. Cryosurgery for hemangiomas [letter; comment]. Pediatr Dermatol. 1998;15:410–411.

386. Cremer JH, Djawari D. Fruhtherapie der kutanen hamangiome mit der kontaktkryochirurgie. Chir Praxis. 1995;49:295–312. 387. Chen WL, Zhang B, Li JS, et al. Liquid nitrogen cryotherapy of lip mucosa hemangiomas under inhalation general anesthesia with sevoflurane in early infancy. Ann Plast Surg. 2009;62:154–157. 388. Reischle S, Schuller-Petrovic S. Treatment of capillary hemangiomas of early childhood with a new method of cryosurgery. J Am Acad Dermatol. 2000;42:809–813. 389. Juckett G, Hartman-Adams H. Management of keloids and hypertrophic scars. Am Fam Physician. 2009;80:253–260. 390. Rusciani L, Paradisi A, Alfano C, et al. Cryotherapy in the treatment of keloids. J Drugs Dermatol. 2006;5:591–595. 391. Panagiotopoulos A, Chasapi V, Nikolaou V, et al. Assessment of cryotherapy for the treatment of verrucous epidermal naevi. Acta Derm Venereol. 2009;89:292–294. 392. Ghodsi SZ, Raziei M, Taheri A, et al. Comparison of cryotherapy and curettage for the treatment of pyogenic granuloma: a randomized trial. Br J Dermatol. 2006;154:671–675. 393. Yaffe B, Shafir R, Tsur H, et al. Complications of liquid nitrogen cryosurgery for verrucae over bony prominences. Ann Plastic Surg. 1986;16:146–149.

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60 50 40 30 10

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Figure 5.25  (A,B) Digital blocks are helpful to control the pain of cryotherapy or laser in the treatment of warts.

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Figure 5.26  Scarring of knee from repeat cryotherapy for warts.

ble to nerve injury with cryotherapy. Lighter applications of liquid nitrogen should be used in all of these areas. Successful use of cryotherapy in the pediatric population requires knowledge of the risk and benefits of this therapy. It is also important to inform parents of the risks and the limitations of treatment. It is a common misconception that one treatment with liquid nitrogen will be sufficient to cause resolution of a wart and that the procedure is painless. Education of parents and patients is crucial to minimize morbidity and increase patient satisfaction.

CURETTAGE Curettage or superficial scraping of cutaneous lesions is a dermatologic practice used much more commonly in adult patients. Despite this, there are several benign cutaneous lesions that are encountered in the pediatric population that respond well to curettage. Molluscum contagiosum, a benign viral skin infection, is commonly treated with topical cantharidin. This produces a superficial blister with resolution of the lesions. Cantharidin is not very effective for larger molluscum contagiosum lesions and should not be used on the face due to the increased risk of scarring. Persistent and troublesome lesions can be effectively treated with cryotherapy (see above) or with gentle curettage.377,394 A recent prospective randomized trial of treatments for molluscum contagiosum demonstrated curettage to be the most efficacious treatment with the lowest rate of side-effects compared with cantharidin, salicylic acid and glycolic acid in combination and topical imiquimod. It is important to pre-treat the lesions to be curetted with topical anesthetic cream 30–60 min prior to the procedure to minimize the discomfort. A disposable curette is preferable to the reusable instruments commonly used by adult dermatologists to curette small skin cancers. The former are sharper, requiring less pressure for effective removal. Lesions are easily and painlessly removed by gentle scraping with a low risk of scarring. Antibiotic ointment can be used to cover the abraded areas after curettage to minimize the risk of infection. Curetting

394. Nix TE Jr. Liquid nitrogen neuropathy. Arch Dermatol. 1965;92:185. 395. Brown J, Janniger CK, Schwartz RA, et al. Childhood molluscum contagiosum. Int J Dermatol. 2007;45:93–99.

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Surgical techniques

Figure 5.27  Pyogenic granuloma on the neck of an infant.

molluscum has the added advantage of removing the lesion while the patient is in the clinic. Parent satisfaction is increased when they can see that the lesions are gone. Pyogenic granulomas are also treated with curettage.395 This method is superior to cryotherapy, which is simpler for the physician but often requires more than one treatment.392 These are benign eruptive vascular tumors that occur commonly in children (Fig. 5.27). The cause is unknown, although trauma may play a role in the production of these tumors which have occurred at sites of minor skin injury or in response to superficial laser treatment of vascular lesions on the skin. Typical lesions are 6–12 mm and pedunculated with a prominent collarette. Bleeding is a usual complication and patients often present to the emergency room for evaluation and treatment of these bleeding lesions. Often, a large portion of the tumor will fall off during these episodes only to grow back over the next several days. Pyogenic granulomas are usually treated by shave or snip excision at the base where the tumor attaches to the skin surface. Any remaining vascular tissue is then curetted and light electrodesiccation of the base is accomplished using a hyfrecator. The resulting wound is covered with antibiotic ointment and a dressing to prevent desiccation and crust formation. Pyogenic granulomas treated in this manner rarely recur and the scar that is produced is small and round corresponding to the stalk of the pedunculated lesion. Lesions can also be removed by excision but curettage is the preferred method to minimize the size of the resultant scar. One exception to this is pyogenic granuloma of the eyelid or of mucous membranes. A higher rate of recurrence with curettage alone is noted in these locations.396 Pulsed dye laser has also been used and will be discussed later in this chapter. Small verruca plana can also be effectively treated with curettage. This is a simple method to remove troublesome facial lesions in adolescents. Lesions should be treated with topical retinoids for several weeks prior to curettage. Spontaneous invo-

396. Wagner AM. An 8-year girl with enlarging papule on the eyelid. Pediatr Ann. 2006;35:429–430.

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lution of lesions is common in this period. Remaining lesions can be covered with topical anesthetic cream 30–60 min before the procedure and lightly curetted. Lesions readily peel from the skin when treated in this manner. This procedure is only recommended for type I–III Caucasians since curettage will remove pigmentation in the upper layer of the skin, which can make the areas more visible in darker skinned patients.

ELECTROSURGICAL PROCEDURES

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

Electrosurgery has long been used in the treatment of dilated cutaneous blood vessels, removal of unwanted hair, and superficial destruction of benign cutaneous tumors.397,398 Visible light lasers have largely supplanted the use of electrosurgery for these purposes. This is especially true in the pediatric population where the pain associated with electrosurgery is poorly tolerated and inappropriate for such cosmetic concerns. Removal of dilated cutaneous blood vessels and spider angiomas can be readily accomplished with minimal discomfort using the pulsed dye laser and topical anesthetic creams.399,400 Unwanted hair removal in adolescents or in congenital nevi or Becker’s nevus is more successfully and less painfully approached with hair removal lasers and intense light systems.401 The risk of unacceptable scarring is markedly reduced with these new approaches.402 Electrosurgery is no longer the treatment of choice for removal of flat or filiform warts. These can be approached less painfully and more effectively with lasers or cryotherapy. Electrosurgery is still used in the treatment of pyogenic granulomas and in the control of minor bleeding during surgical excisions.403 Superficial vessels can be treated with electrocautery, electrodesiccation or electrocoagulation. In electrocautery, an exposed hot wire tip is held in direct contact with the blood vessel producing hemostasis. This method works poorly in a wet field and is difficult to do with precision. Electrodesiccation is the most common form of electrosurgery used in the pediatric population. Here, a monopolar surgical electrode is used to desiccate the tissue at the site of contact using heat generated from a monoterminal electrosurgical device. For larger procedures, bi-terminal electrosurgical devices are needed to produce electrocoagulation. Patients must be grounded to use this system where current flows out of the surgical electrode, through the patient, into the indifferent electrode (grounding pad) and directly back to the unit’s power generator. The advantage of the bi-terminal electrosurgery unit is that tissue can be both coagulated and cut. In addition, the energy can be delivered with bipolar electrodes using a small forceps allowing for precise destruction of blood vessels and hemostasis.404 It is important that special attention be paid to electrosurgery during excisional surgery in the pediatric population. The activity of patients in the immediate postoperative period is significant, despite efforts by the parents and surgeon at enforcing restric397. Blankenship ML. Electrosurgery, electrocautery and electrolysis. Int J Dermatol. 1979;18:443. 398. Buzina DS, Lipozencić J. Electrosurgery – have we forgotten it? Acta Dermatovenereol Croat. 2007;15:96–102. 399. Richards KA, Garden JM. The pulsed dye laser for cutaneous vascular and nonvascular lesions. Semin Cutan Med Surg. 2000;19:276. 400. Bernstein EF. The pulsed-dye laser for treatment of cutaneous conditions. G Ital Dermatol Venereol. 2009;144:557–572. 401. Rajpar SF, Hague JS, Abdullah A, et al. Hair removal with the long-pulse alexandrite and long-pulse Nd: YAG lasers is safe and well tolerated in children. Clin Exp Dermatol. 2009;34:684–687.

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tions. The wise surgeon will ensure that the wound is completely dry before closing to minimize the likelihood of a postoperative hematoma or bleeding from the excision site. One uncommon situation in the pediatric population where electrodesiccation can be useful is in the cosmetic management of milia. Although milia typically resolve spontaneously over time, electrodesiccation of milia using low energy under topical anesthetic cream is an effective way to minimize and eliminate these lesions rapidly with few side-effects.405 Multiple milia are often a result of occlusive creams, including sunscreens in the adolescent population. Care should be taken to advise adolescents bothered by these, in appropriate topical products for daily facial use.

PROCEDURES FOR ACNE AND ACNE SCAR REVISION Acne surgery is not performed commonly in a pediatric dermatology practice. The mainstay of acne treatment is medical and adolescents are not eager to undergo procedures that may require the use of needles or sharp objects. There are two basic procedures that are commonly offered to pediatric acne patients: comedone extraction and injection of intralesional steroids into cysts or deep inflammatory papules. Superficial peeling with glycolic acid or salicylic acid, blue and blue/red light therapies, microdermabrasion, laser treatment with 1450-nm diode, ICGdiode PDT, and MAL- or ALA-assisted PDT are all new treatment modalities that may also be offered to select patients as an adjunct to conventional medical therapy.406 Light and laser treatments for acne will be addressed later in this chapter. The management of acne scars is beyond the scope of most pediatric dermatologists. However, simple surgical procedures to correct small hypertrophic and atrophic scars are easily performed in adolescents. The use of fillers for atrophic scars, skin resurfacing lasers and dermabrasion will be discussed briefly.

Comedone extraction When sebaceous material and keratin debris fill the follicular orifice, it may become desiccated and result in the formation of an open comedone. To improve the cosmetic appearance, as well as attempt to re-establish the normal transfollicular elimination of sebum, this blockage must be removed with only minimal trauma to the adjacent tissue. This can usually be accomplished with use of a comedone extractor.407 Many different types of comedone extractors are available, but all share the common feature of having a slot or hole in one end of a relatively flat blade-like instrument. To use this instrument, the hole is placed directly over the comedone and pressed downward. This creates peripheral pressure around the comedone, causing it to be extruded upwards without rupturing or damaging the follicle. If 402. Cantatore JL, Kriegel DA. Laser surgery: an approach to the pediatric patient. J Am Acad Dermatol. 2004;50:165–188. 403. Lane JE, O’brien EM, Kent DE. Optimization of thermocautery in excisional dermatologic surgery. Dermatol Surg. 2006;32:669–675. 404. Pollack SV, Grekin RC Electrosurgery and electroepilation. In: Roenigk & Roenigk’s dermatologic surgery. 2nd ed. New York: Marcel Dekker; 1996:219. 405. Al-Mutairi N, Joshi A. Bilateral extensive periorbital milia en plaque treated with electrodesiccation. J Cutan Med Surg. 2006;10:193–196. 406. Spencer JM. Microdermabrasion. Am J Clin Dermatol. 2005;6:89–92. 407. Shalita AR. Surgical procedures for the treatment of acne vulgaris. J Dermatol Surg. 1975;1:46.

Surgical techniques

Intralesional triamcinolone for acne Occasionally, large inflammatory papules and cysts develop despite compliant oral antibiotic therapy. Deep inflammatory acne lesions have a high risk of scarring. For more mature adolescents, relief can be obtained with intralesional injections of the fluorinated corticosteroid, triamcinolone. A concentration of 2.5–5 mg/mL and a dosage of 0.1–0.2 mL per cyst is usually all that is required. Application of topical anesthetic cream can decrease the pain of the needle stick, although burning is still present when the triamcinolone is injected. The injection of more concentrated or larger volumes of steroid solution should be done with caution, since hypopigmentation and atrophy can result.

Microdermabrasion for acne Recently, a tool was developed that exfoliates the statum corneum mechanically to improve acne and skin texture. Unlike classic dermabrasion, this is not a resurfacing technique. In microdermabrasion, polyester or nylon bristles, or more commonly, aluminum oxide crystals are propelled onto the skin surface at variable speeds and then suctioned off using a vacuuming wand or handpiece. Both the speed of the microdermabrasion tool and the suction at the skin surface are controlled by the operator.406,408 Although initial results with this technique were encouraging, the benefit of microdermabrasion in treating active acne lesions is questionable. The best reported results demonstrated only a 50% decrease in lesional count in 75% of patients that were treated eight times at 1-week intervals. During this time, all patients in the study were on oral antibiotics and all but one on topical retinoids. Moreover, the protocol allowed for adjustment

408. Kempiak SJ, Uebelhoer N. Superficial chemical peels and microdermabrasion for acne vulgaris. Semin Cutan Med Surg. 2008;27:212–220. 409. Lloyd JR. The use of microdermabrasion for acne: a pilot study. Dermatol Surg. 2001;27:329–331. 410. Alam M, Omura NE, Dove JS, et al. Glycolic acid peels compared to microdermabrasion: a right-left controlled trial of efficacy and patient satisfaction. Dermatol Surg. 2002;28:475–479. 411. Riveria AE. Acne scarring: a review and current treatment modalities. J Am Acad Dermatol. 2008;59:659–676. 412. Grimes PE. Microdermabrasion. Dermatol Surg. 2005;31:1160–1165. 413. Katz BE, Truong S, Maiwald DC, et al. Efficacy of microdermabrasion preceding ALA application in reducing the incubation time of ALA in laser PDT. J Drugs Dermatol. 2007;6:140–142.

of the patient’s acne medication during the treatment.409 In a right-sided, left-sided comparison of six treatments with nylon brush dermabrasion or 20% glycolic acid peels, the majority of patients preferred the peels.410 Side-effects of microdermabrasion include bruising, a burning or stinging sensation, temporary stripping of the treated skin, photosensitivity and occasional pain.411 The skin is intact after the procedure and no special dressings are required. A common complication is eye irritation from the aluminum oxide crystals. Eye protection should be provided during treatment to reduce the risk of chemosis or punctate keratitis from the crystals.412 Microdermabrasion should be considered an adjunct therapy for acne, at best. It may have a role in combination with other acne procedures, such as chemical peels or ALA-PDT therapy by removing the statum corneum prior to treatment to improve the efficacy of these therapies.413

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

material is not readily expressed, a small beveled needle or no. 11 blade scalpel can be used to dislodge the keratin plug in the top of the pore. Comedone extraction will be more successful if the patient uses a topical retinoid on a regular basis. The effects of the retinoid on comedone formation facilitate extraction of the keratin plug minimizing trauma. Closed comedones appear as small 1–3 mm, white milial lesions. To prevent inadvertent injury during the extraction process, a very superficial stab wound is made into the comedone using a no. 11 scalpel blade or a small-caliber beveled needle. This acts to guide the direction of the sebum and keratin upwards through the incision and without rupturing laterally through the wall of the follicle or down into the skin, as the extractor exerts lateral pressure and minimizes injury to the normal surrounding tissue.

5

Chemical peels in acne treatment Superficial chemical peels have been used as another adjunct to the medical treatment of acne. Superficial peels can be accomplished with alpha hydroxy acids (glycolic acid, lactic acid or citric acid), beta hydroxy acid (salicylic acid), Jessner’s solution (salicylic acid, resorcinol, lactic acid and ethanol in combination), resorcinol and even lowstrength (4 mm, areas that shadow and give the skin surface an undulated appearance. Abnormal fibrous scar bands cause the dermis to adhere to the subcutis, producing these lesions. The depth of the tethering process makes it poorly responsive to superficial dermabrasion or laser resurfacing. Correction requires release of the anchoring fibrous bands using a technique called subscision. This technique was first described by Orentreich and Orentreich in 1995.447 An 18-gauge 1.5-inch tribeveled needle is most effective for this technique. The needle is inserted with the blade facing upward at the periphery of the scarred area towards the base of the scar at the level of the dermal subcutaneous junction. It is turned horizontally while in the skin and gently swept from side to side so that the cutting edge is parallel to the skin surface and can cut and release the adherent fibrous bands that produce traction on the overlying skin. A gentle piston-like motion allows the needle to be advanced through the scar tissue. Three separate insertion sites that form a triangle around the area allow for the most effective treatment. Bruising persists for about 1 week. Boxcar scars are round to oval depressions with sharply demarcated vertical edges that appear punched out like varicella scars. These do not taper to a point like icepick scars, and are wider on the surface. Shallow boxcar scars respond well to punch excision with or without laser resurfacing but deeper boxcar scars (1.5– 4 mm) are best corrected with punch elevation. Here, the punch biopsy size is chosen to match the inner diameter of the scar. The tissue is elevated above the normal skin and affixed to the surrounding tissue with 6–0 polypropylene suture, or 2-octylcyanoacrylate glue. Care must be taken not to crush the tissue with a forceps during punch elevation. A bent 30-gauge needle can be used to spear the tissue and hold it for suturing or surface gluing. Retraction of the elevated skin occurs during healing to produce a level surface. Dermabrasion or laser resurfacing is often used in conjunction with the techniques described above to improve the overall texture of the skin (see below).448–469 It is recommended that

445. Jacob CJ, Dover JS, Kramerer MS. Acne scarring: a classification system and review of treatment options. J Am Acad Dermatol. 2001;45:109–110. 446. Jemec JB, Jemec B. Acne: treatment of scars. Clin Dermatol. 2004;22:434–438. 447. Orentreich DS, Orentreich N. Subcutaneous incisionless (subcision) surgery for the correction of depressed scars and wrinkles. Dermatol Surg. 1995;21:543–549. 448. Roenig K, Roenigk HH Jr. Dermabrasion: state of the art. J Dermatol Surg Oncol. 1985;11:306. 449. Baker TM. Dermabrasion. As a complement to aesthetic surgery. Clin Plast Surg. 1998;25:81–88. 450. Orentriegh N, Orentriech DS. Dermabrasion. Dermatol Clin. 1995;13: 313–327. 451. Sawcer D, Lee HR, Lowe NJ. Lasers and adjunctive treatment for facial scars: a review. J Cutan Laser Ther. 1999;1:77–85. 452. Jordan R, Cummins C, Burls A. Laser resurfacing of the skin for the improvement of facial acne scarring: a systemic review of the evidence. Br J Dermatol. 2000;142:413–423. 453. Woo SH, Park JH, Kye YC. Resurfacing of different types of facial acne scar with short-pulsed, variable-pulsed, and dual-mode Er:YAG laser. Dermatol Surg. 2004;30:488–493. 454. Alster TS, Tanzi EL, Lazarus M. The use of fractional laser phothermolysis for the treatment of atrophic scars. Dermatol Surg. 2007;33:295–299. 455. Arndt KA, Noe JM. Lasers in dermatology. Arch Dermatol. 1982;118:293. 456. Wheeland RG, Walker NPJ. Lasers – twenty-five years later. Int J Dermatol. 1986;25:209. 457. Alora MB, Anderson RR. Recent developments in cutaneous laser. Lasers Surg Med. 2000;26:108.

458. Ross EV, McKinlay JR, Anderson RR. Why does carbon dioxide resurfacing work? Arch Dermatol. 1999;135:444–454. 459. Ratner D, Tse Y, Marchell N, et al. Cutaneous laser resurfacing. J Am Acad Dermatol. 1999;41:367–389. 460. Jeong JT, Kye YC. Resurfacing of pitted facial acne scars with a long-pulsed Er:YAG laser. Dermatol Surg. 2001;27:107–110. 461. Manstein D, Herron GS, Sink RK, et al. Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med. 2004;34:426–438. 462. Chiu RJ, Kridel RW. Fractionated photothermolysis: the Fraxel 1550-nm glass fiber laser treatment. Facial Plast Surg Clin North Am. 2007;15:229–237. 463. Walgrave SE, Ortiz AE, MacFalls HT, et al. Evaluation of a novel fractional resurfacing device for treatment of acne scarring. Lasers Surg Med. 2009;41:122–127. 464. Tierney EP, Kouba DJ, Hanke CW. Review of fractional photothermolysis: treatment indications and efficacy. Dermatol Surg. 2009;35:1445–1461. 465. Hantash BM, Gladstone HB. Current role of resurfacing lasers. G Ital Dermatol Venereol. 2009;144:229–241. 466. Kim S, Cho KH. Clinical trial of dual treatment with an ablative fractional laser and a nonablative laser for the treatment of acne scars in Asian patients. Dermatol Surg. 2009;35:1089–1098. 467. Chapas AM, Brightman L, Sukal S, et al. Successful treatment of acneiform scarring with CO2 ablative fraction resurfacing. Lasers Surg Med. 2008;40:381–386. 468. Tannous Z. Fractional resurfacing. Clin Dermatol. 2007;25:480–486. 469. Whang KK, Lee M. The principle of a three-staged operation in the surgery of acne scars. J Am Acad Dermatol. 1999;40:95.

Icepick

Rolling

Boxcar Skin surface

Laser

SMAS

Figure 5.29  A novel classification system for acne scarring. (From: Jacob et al.445)

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

254

Surgical techniques

Skin resurfacing for acne scars The mainstay of treatment for acne scarring prior to the development of specialized surgical techniques was dermabrasion.448–450 This remains one of the most effective therapies for acne scarring but success is operator dependent and sideeffects can be severe because of the aggressive nature of the procedure. The dermabrasion procedure employs a compact, high-speed electric motor that drives a rotating wire brush or cylindrical drum coated with various grits of industrial diamonds. After light freezing of the surface of the skin with a refrigerant, the instrument is applied to the surface to rapidly remove the epidermis and the papillary and superficial reticular dermis in a segmental fashion. The depth of removal is dependent on the type of scarring present and the anatomic location. This is, in turn, controlled by the amount of pressure applied to the skin surface while the abrader is turning, the speed of the motor, how long the instrument is held in one place, and the number of times the instrument is passed over the same site. Postoperative complications including alteration in pigment, hypertrophic or keloidal scarring and milia formation are not uncommon with the procedure.450 The development of hypertrophic scarring following dermabrasion is increased in acne patients who have been treated with oral retinoids. In these patients, dermabrasion is contraindicated for a period of at least 18–24 months following completion of retinoid therapy. Dermabrasion has largely been replaced with ablative laser resurfacing techniques using the carbon-dioxide laser, the gentler erbium:yttrium-aluminum-garnet (Er:YAG) laser, and most recently, the fractionated lasers.451–454 Both approaches improve overall texture, thereby producing a more homogeneous appearance to the skin. Carbon dioxide laser has been used in dermatology for 25 years. This laser emits an invisible beam of mid-infrared light with a wavelength of 10 600 nm.455,456 It has no specificity as to tissue color but is precisely absorbed by intracellular and extracellular water, generally limiting penetration to 0.03–0.1 mm of skin. Conventional CO2 lasers have been replaced by resurfacing CO2 laser systems that use high-energy, short pulses or use a focused continuous wave CO2 beam with a rapid beam scanner system that moves the laser spot at constant velocity but dwells for 5 years

Inject in papillary derm. Inject in deep derm.

Human collagen   AlloDerm   CosmoDerm   CosmoPlast

N N N

1 year 3–7 month >7 months

Bovine collagen   Evolence 1 year

N

Silicon   AdatoSil   Silikon 1000   Siloskin

N N N

Hyaluronic acid   Hylaform   Hylaform Plus   Restylane   Perlane   Captique   Juvederm   Dermalive   Reorderm

N N N N N N N N

Calcumhypdroxyopath   Radiese

N

12–16 months

Epsilon-aminocaproic acid   Fibrel

N

12 months

Polylactic acids   Sculptra

N

>1 year

}

}

Inject at dermal fat junction

Restylane > Restylane Fine Lines) the deeper the product is meant to be injected.482 These products are all cross-linked with divinyl sulfone, whereas Juviderm is cross-linked with 1,4-butanedioldiglycidyl ether, and Dermalive with a 40% acrylate suspension in microparticles. Injection of hyaluronic acid products does not require overcorrection. Erythema, edema, bruising, inflammation, delayed reactions, papules, pustules, flushing and swelling have been reported rarely but skin testing is not required. Longevity is about 1 year with the exception of Dermalive. Here injections are repeated every 3 months until the desired effect is achieved with about 40% retention with each injection.411 Another filler substance, Fibrel, used to correct contour scars is material made from a mixture of lyophilized gelatin powder, aminocaproic acid, and the patient’s plasma. This material attempts to stimulate the production of collagen at the site of a depressed scar by using the adsorbable gelatin to provide a structural framework for a clot to form and the aminocaproic acid to inhibit fibrinolysis and stabilize collagen. Fibrel is a physical filler so it is more effective for large scars with deep fat atrophy. In this technique, an intradermal skin test is also required, since a positive reaction can be expected in 1.9% of patients. Although

473. Maloney BP, Murphy BA, Cole HP III. Cymetra. Facial Plast Surg. 2004;20:129–134. 474. Bauman L. CosmoDerm/CosmoPlast (human bioengineered collagen) for the aging face. Facial Plast Surg. 2004;20:125–128. 475. Beer K. Evolence: the thing of shapes to come. Skin Aging. 2007;15:22–23. 476. Cohen SR, Berner CF, Busso M, et al. ArteFill: a long-lasting injectable wrinkle filler material – summary of the US Food and Drug Administration trials and a progress report on 4- to 5-year outcomes. Plast Reconstr Surg. 2006;118:64S–76S. 477. Langdon RC. Regarding dermabrasion for acne scars [letter; comment]. Dermatol Surg. 1999;25:919–920.

478. Pinski KS, Roenigk HH. Autologous fat transplantation. J Dermatol Surg Oncol. 1992;18:179–184. 479. Moseley TA, Zhu M, Hedrick MH. Adipose-derived stem and progenitor cells as fillers in plastic and reconstructive surgery. Plast Reconstr Surg. 2006;118:121S–128S. 480. Barnett JG, Barnett CR. Treatment of acne scars with liquid silicone injections: 30-year perspective. Dermatol Surg. 2005;31:1542–1549. 481. Monheit GD. Hyaluronic acid fillers: Hylaform and Captique. Facial Plast Surg Clin North Am. 2007;15:77–84. 482. Brandt FS, Cazzaniga A. Hyaluronic acid fillers: Restylane and Perlane. Facial Plast Surg Clin North Am. 2007;15:63–76.

5

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Surgical techniques

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inconclusive, this appears to provide a longer period of correction compared with bovine collagen. Injection of this filler is particularly painful and may lead to a local inflammatory response. Since it also requires a patient blood draw it is probably not the best choice in pediatric patients. Poly-L-lactic acid, Sculptra, is a newer product that is mainly used in filling larger areas of lipoatrophy, but can also be used to treat scars. Like Fibrel, it is thought to stimulate neocollagenesis over 3–6 months accounting for the longevity of the treatment. Radiesse is a calcium hypoxyapatite microsphere in a polysaccharide gel that lasts about 12–16 months. Few sideeffects are noted with this filler. Skin tests are not required with these synthetic fillers. Outcomes are user-dependent and require skill for optimal recontouring, especially when larger areas of atropy are treated. Effective treatment of acne scars requires knowledge and experience of a combination of excisional surgery skills, and the use

of chemical peels, laser therapy, filler injection and resurfacing. All of these techniques are within the realm of a pediatric dermatologic surgeon.

LASERS It is almost 50 years since the development of the first functional laser system in 1960. Lasers have allowed the successful treatment of numerous skin conditions for which previous therapy had either not existed or offered such poor results that it was not considered useful.483,484 Table 5.5 lists the lasers currently in use in dermatology. Since lasers offer significant opportunities to manage a variety of vascular and pigmented conditions found in infants, children, adolescents, and teenagers, it is certainly appropriate for dermatologists to become familiar with their indications, to permit thoughtful consideration of all possible forms of treatment for managing their patients’ conditions.

Table 5.5  Currently available lasers LASER

WAVELENGTH (NM)

MODE OF EMISSION

TARGET

USE

Excimer (XeCl) (xenon chloride)

308

Pulse

Hemoglobin

Psoriasis, vitiligo

Argon

488, 514

Continuous wave

Hemoglobin, melanin

Vascular lesions

Copper vapor

511, 578

Quasi-continuous wave

Hemoglobin, melanin

Vascular lesions, skin lesions

KTP (potassium titanyl phosphate)

532

Quasi-continuous wave

Hemoglobin, melanin

Vascular and other skin lesions

Q-switched frequency doubled Nd: YAG (neodymium: yttrium aluminum garnet)

532

Nanosecond pulsed

Melanin, other pigment, hemoglobin

Red tattoo, epidermal pigment

Pulsed dye

585–600

Pulsed

Hemoglobin

Vascular lesions

Argon dye

630

Continuous wave

Amino levulinic acid and other photosensitizes

Photodynamic therapy

Ruby/Q-switched ruby

694

Pulsed/nanosecond pulsed

Pigment, melanin

Tattoos, hair removal, pigmented lesions (nevus of Ota/Ito)

Alexandrite/Qswitched Alexandrite

755

Pulsed

Pigment, melanin

Tattoos, hair removal, pigmented lesions (nevus of Ota/Ito)

Diode (aluminum gallium arsenide)

800

Continuous wave/ pulsed

Melanin, hemoglobin

Leg veins, hair removal

Q-switched Nd: YAG (neodymium: yttrium aluminum garnet)

1064

Nanosecond pulsed

Pigment

Tattoo-black

Long pulsed Nd: YAG

1064

Pulsed

Pigment, hemoglobin

Hair removal, leg veins

Long pulsed Nd: YAG

1320

Pulsed

Water

Skin rejuvenation

Diode

1450

Pulsed

Water

Skin rejuvenation

Erbium: glass

1540

Pulsed

Water

Skin rejuvenation

Erbium: YAG

2940

Pulsed

Water

Resurfacing

Carbon dioxide

10 600

Continuous wave/ pulsed

Water

Warts, rosacea, skin resurfacing

483. Cordisco MR. An update on lasers in children. Curr Opin Pediatr. 2009;21:499–504.

258

484. Acland KM, Barlow RJ. Lasers for the dermatologist. Br J Dermatol. 2000;143:244.

Surgical techniques

The word laser is an acronym, which stands for light amplification through the stimulated emission of radiation. These instruments are capable of producing extremely intense and precisely controlled light that has three unique characteristics. First, laser light is of single wavelength or is monochromatic. Second, it is temporally and spatially in phase or coherent. Finally, it is highly collimated, so that it can be propagated over long distances with little divergence of the beam.456 All laser systems are composed of the same four components. The first is the laser medium, which determines the wavelength of the emitted laser light and also generally gives each laser its name. The laser medium may be composed of a solid (e.g., ruby, Nd:YAG, or Alexandrite lasers), a liquid (e.g., dye lasers), or a gas (e.g., argon, krypton, and carbon dioxide lasers). The laser medium is contained within an optical cavity that serves as a resonator in which the laser process occurs. This usually has the configuration of a tube with mirrors at either end, one of which is only partially reflective to allow the beam of light to emerge. The third component is the pump or power source, which is used to energize the system. The power source may be electrical or radiofrequency energy, but photo-optical energy, as in the argon dye laser or flashlamp dye laser, or even mechanical or chemical energy, may also be employed. The fourth component of all laser systems is the delivery system, which may be an articulated arm having mirrored joints or fiberoptics. Laser energy is produced when the pump energizes the atoms or molecules of the laser medium and creates a condition known as population inversion. This condition occurs when there are more atoms or molecules existing in a higher unstable energy state than in the normal resting energy state. Once this critical energy level is created, stimulated emission of energy occurs. As an energized atom or molecule returns or decays to its stable resting energy state, it releases a photon of energy. If this photon strikes another energized molecule or atom, it results in the release of two photons of energy of precisely the same wavelength and traveling in exactly the same direction in phase with one another. As this cascade process continues, energy amplification occurs, with more and more photons traveling together within the optical cavity or resonator. As the photons travel back and forth between the two parallel mirrored ends, the amplification process continues to build. Only a small portion of the photons are permitted to exit as a laser beam through the partially reflective mirrored end of the optical cavity. This beam of light may be released as a single pulse, as with the ruby laser, as a chain of pulses, as in the copper vapor laser, or in continuous fashion, as with the carbon dioxide, krypton, and argon lasers. Laser systems that have continuous discharge patterns can be gated with a mechanical or electronic shuttering mechanism to produce individual pulses of energy of variable duration or broken into a predetermined computerized geometric pattern, using a robotic scanning device. These scanners act to separate adjacent pulses from one another temporally and spatially, reducing the potential for thermal damage and the unwanted scarring that may result from it.485,486

More than 20 different laser systems are currently FDA approved and available for the treatment of a host of different skin conditions in the USA (Table 5.5). The different applications of the laser systems are generally determined as functions of their wavelengths, the amount of energy delivered to the tissue, the length of time the light has contact with the skin, and the optical characteristics of the tissue. The power density or irradiance (IR) is a measure of the brightness or intensity of the laser beam:

485. Mordon S, Rotteleur G, Buys B, et al. Comparative study of the ‘point by point’ technique and the ‘scanning’ technique for laser treatment of port-wine stains. Lasers Surg Med. 1989;9:398. 486. McDaniel DH, Modron S. Hexascan: a new robotized scanning laser handpiece. Cutis. 1990;45:300.

487. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science. 1983;220:524–527.

IR =

5

laser output ( W ) πr 2

EF =

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

where r = the radius of the laser beam. This factor can be precisely determined based on the size of the laser beam and the power setting of the laser. In general, the higher the irradiance, the greater the effect will be on the tissue.487 The energy fluence (EF) is a measure of the quantity of energy delivered by a single pulse to a target tissue: laser output ( W ) × exposure time ( s ) = J cm 2 πr 2

The shorter the exposure, the less the tissue will be heated. The longer the exposure to laser energy, the greater the tissue heating and the greater will be the possibility of non-specific thermal injury to the surrounding tissues. Poor precision or reduced specificity of the laser–tissue interaction will increase the chance of unwanted additional tissue damage, prolonging the time required for healing, and reducing the quality of the cosmetic result. Improved understanding of these principles has changed the manner in which many cutaneous disorders are now treated with lasers, improving the results and allowing the treatment of many conditions earlier in life, with fewer complications than before. In addition to IR and EF, the optical characteristics of the target tissue can also play a major role in determining the effect produced by laser energy, a concept generally known as laser–tissue interaction. If light is reflected from the surface of the target or transmitted completely through it, the energy does not interact with the tissue, so no effect will result. In order for light to have any effect on tissue, it must be absorbed by some cellular component, tissue chromophore, or protein. The two main chromophores of skin are melanin and hemoglobin; both have absorption peaks that are within the visible portion of the electromagnetic spectrum. This knowledge allows the laser surgeon to select a laser system with the appropriate emission to treat both melanocytic and vascular lesions of the skin with relative selectivity because of the precise absorption. Conversely, the mid-infrared energy from the carbon dioxide laser is absorbed by intracellular and extracellular water and not by a specific chromophore. As a consequence, this laser lacks color specificity and produces the same effects in all soft tissues, regardless of their color, since they are composed of 70–90% water. In order to control the laser–tissue interaction, a specific laser must emit sufficient energy to injure the target and the energy that is emitted must be selectively absorbed in the skin by the

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desired target without injuring the surrounding tissue. Newer laser systems accomplish this in three ways. First, the wavelength emitted by the laser must be absorbed primarily by the skin component that is being targeted. Second, the duration of the laser impulse must be adjusted to match the thermal relaxation time of the tissue chromophore, a theory known as selective photothermolysis. This theory, introduced by Anderson and Parrish in 1983, is the basis for many advancements in dermatological lasers.487 When light is absorbed by a target tissue in the skin, it heats up the tissue and immediately diffuses away. The thermal relaxation time of any tissue is the time it takes for that tissue to cool and is roughly proportional to the square of the diameter of the target in millimeters.488 By limiting the exposure duration to the thermal relaxation time, the spread of thermal damage to the surrounding tissue and therefore the risk of scarring can be reduced. Finally, since most laser targets are components of the dermis, chromophores that are present within the epidermis must be minimized to reduce thermal injury to the upper layers of the skin during treatment of deeper layers. Pigmented and vascular lesions in the dermis are therefore optimally treated when the epidermis is unpigmented (tanning is minimal) to avoid inadvertent injury to the epidermis and resultant post-inflammatory hyper- or hypopigmentation or scarring. In addition, the use of cryogen spray units to cool the epidermis during laser treatment minimizes the thermal injury to the epidermis.488,489 With the evolution of new laser technology, there has been an explosion of new laser systems and companies interested in expanding their utility. Many of the new laser systems have been developed for rejuvenation of the aging face and have little use in the pediatric population. Resurfacing lasers (see above) have been beneficial for the management of acne and other scars. The mainstay of laser in the pediatric population remains the use of vascular lasers for the management of congenital port-wine stains, vascular malformations and ulcerated hemangiomas. Other acquired lesions, such as spider angiomas and pyogenic granulomas, can also be treated with these same laser systems.490

LASER TREATMENT OF VASCULAR LESIONS IN CHILDREN The treatment of vascular birthmarks and acquired vascular lesions in children is by far the widest use of laser surgery in the pediatric population. Port-wine stains were the lesions originally targeted for treatment by these lasers, but as the technology has improved the spectrum of vascular lesions amenable to treatment with laser has expanded (Table 5.6).

488. Alova MBT, Anderson RR. Recent developments in cutaneous lasers. Lasers Surg Med. 2000;26:108. 489. Nelson JS, Milner TE, Anvari B, et al. Dynamic epidermal cooling during pulsed laser treatment of port-wine stain, a new methodology with preliminary clinical evaluation. Arch Dermatol. 1995;131:695–700. 490. Astner S, Anderson RR. Treating vascular lesions. Dermatol Ther. 2005;18:267–281. 491. Goldman L. The argon laser and the port wine stain. Plast Reconstr Surg. 1980;65:137. 492. Arndt KA. Argon laser therapy of small cutaneous vascular lesions. Arch Dermatol. 1982;118:220. 493. Brauner GJ, Schliftman A. Laser surgery for children. J Dermatol Surg Oncol. 1987;13:178. 494. Dorer JS, Arndt KA. New approaches to the treatment of vascular lesions. Lasers Surg Med. 2000;26:158.

260

In the 1970s and 1980s, the argon laser was the first laser system to become available for the treatment of port-wine stains. Because the two primary emission energy peaks from this laser occurred at wavelengths that overlapped the absorption spectrum for oxyhemoglobin, it was assumed that very precise and selective damage to blood vessels with a minimal amount of injury to non-vascular tissues would be possible.491 However, the existence of a number of side-effects and complications, such as textural changes, hypertrophic scarring,492 and permanent hypopigmentation, proved that there were a significant number of limitations, including the inability to treat children effectively.493 Thermal injury from this laser is not restricted to the blood vessel resulting in injury and scarring in the surrounding dermis. In addition, there is inadvertent absorption by melanin in the overlying epidermis, which not only causes damage to the epidermis but also reduces the amount of energy available to reach the blood vessels.494 In an attempt to minimize the side-effects of these laser systems, the argon-pumped tunable dye laser which delivered light with a wavelength of 577 or 585 nm was chosen to treat port-wine stains.495 This laser released energy in a continuous fashion but the light was mechanically or electronically shuttered to deliver pulses using a robotic scanner.496 The pulse duration with this system was still substantially longer than the thermal relaxation time of the small vascular channels that make up port-wine stains, however, and there was still a significant risk of complications with this system. The first laser system developed for the treatment of port-wine stains in children that utilized the principle of selective photothermolysis497 was the flashlamp-pumped pulsed dye laser. Although modifications of this laser system have occurred in the past 23 years to optimize treatment outcome, the pulsed dye laser remains the laser of choice in the treatment of vascular lesions in children. Like the argon dye laser, the pulsed dye laser also uses an organic dye, energized by short pulses of white light from a flashlamp, to produce yellow light with a wavelength of 585–600 nm. It differs from the argon dye laser in that the energy is released in short pulses.494,498 For the ideal treatment of port-wine stains, pulse durations are in the 1–10 ms range and vary depending on the size of the vessels.499 The original pulsed dye laser had a pulse duration of 450 µs. Pulsed dye laser systems have now been developed that allow for adjustment of the pulse duration and wavelength. The spot size has increased from 3–10 mm and the power emitted by the lasers has increased significantly.500 Dynamic cooling units are attached to the laser systems to allow protection of the epidermis during laser treatment at these higher energies and to reduce the discomfort

495. Scheibner A, Wheeland RG. Use of the argon-pumped tunable dye laser for port-wine stains in children. J Dermatol Surg Oncol. 1991;17:735. 496. McDaniel DH, Mordon S. Hexascan: a new robotized scanning laser handpiece. Cutis. 1990;45:300. 497. Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science. 1983;220:524. 498. Garden JM, Tan OT, Kerschmann R, et al. Effect of dye laser pulse duration on selective cutaneous vascular injury. J Invest Dermatol. 1986;87:653. 499. Dierickx CC, Casparian JM, Venugopaban V, et al. Thermal relaxation of port-wine stain vessels probed in vivo: the need for 1–10 ms laser pulse treatment. J Invest Dermatol. 1995;105:709–714. 500. Stier MF, Glick SA, Hirsch FJ. Laser treatment of pediatric vascular lesions: port wine stains and hemangiomas. J Am Acad Dermatol. 2008;58:261–285.

Surgical techniques

5

LESION

LASER OF CHOICE

WAVELENGTH (NM)

PULSE DURATION (MS)

FLUENCE (J/CM2)

COMMENT

Port-wine stain (PWS)

Pulsed dye

585–600

0.45–40

Up to 40

Average 8–12 treatments. Recurrence > on sunexposed areas

Hypertrophic or resistant PWS

KTP Nd:YAG IPLS (intense pulsed light system)

532 1064 515–1200

1–200 0.25–500 2–200

Up to 240 5–900 10–80

Use for PDL failure Increased risk of scarring Requires operator skill

Ulcerated and superficial hemangiomas

Pulsed dye

585–600

0.45–40

Up to 40

High risk of scarring in proliferative phase

Spider angioma

Pulsed dye

585–600

0.45–40

Up to 40

Diascopy with glass-slide when elevated

Facial telangiectasia

Pulsed dye KTP IPLS Nd:YAG

585–600 532 515–1200 1064

0.45–40 1–200 2–200 0.25–500

Up to 40 Up to 240 10–80 5–900

Most purpura 1st like For larger, resistant vessels

Telangiectative rosacea

Pulsed dye laser IPLS (intense pulsed light system)

585–600 515–1200

0.45–40 2–200

Up to 40 10–80

Vascular malformation

KTP Nd:YAG

532 1064

1–200 0.25–800

Up to 240 5–900

Pyogenic granuloma

Pulsed dye

585–600

0.45–40

Up to 40

Best if 75% lightening, and >75% of patients will have >50% lightening after four treatments (Fig. 5.30).503 Patients who continued beyond nine treatments who had not obtained >75% clearance had more significant clearing after 10–25 treatments.504 In children, studies demonstrate >50% lightening in 87% of patients,505 with many studies predicting almost 100% clear-

ance.506,507 Treatment in early infancy may also offer some advantages,508–510 although this remains controversial.511,512 Some authors suggest that the advantage attributed to early laser treatment may be secondary to the physiologic decrease in hemoglobin that is noted in the first 6 months of life, coupled by the maturation of vasomotor response.513 The more superficial,

503. Garden JM, Polla LL, Tan OT. The treatment of portwine stains by the pulsed dye laser: analysis of pulse duration and long-term therapy. Arch Dermatol. 1988;124:889–896. 504. Kauvar ANB, Geronemus RG. Repetitive pulsed dye laser treatments improve persistent port wine stains. Dermatol Surg. 1995;21:515–521. 505. Reyes BA, Geronemus R. Treatment of portwine stains during childhood with the flashlamp-pumped pulsed dye laser. J Am Acad Dermatol. 1990;23:1142–1148. 506. Tan OT, Sherwood K, Gilchrest BA. Treatment of children with portwine stains using the flashlamp-pumped tunable dye laser. N Engl J Med. 1989;320:416–421. 507. Garden JM, Burton CS, Geronemus R. Dye laser treatment of children with portwine stains. N Engl J Med. 1989;321:901–902. 508. Nguyen CM, Yohn JJ, Huff C. Facial port wine stains in childhood: prediction of the rate of improvement as a function of the age of the patient, size and location of the port wine stain and the number of

treatments with the pulsed dye (585 nm) laser. Br J Dermatol. 1998;38:821–825. 509. Ashinoff R, Geronemus RG. Flashlamp-pumped pulsed dye laser for port-wine stains in infancy: earlier versus later treatment. J Am Acad Dermatol. 1991;24:467–472. 510. Chapas AM, Eickhorst K, Geronemus RG. Efficacy of early treatment of facial port wine stains in newborns: a review of 49 cases. Lasers Surg Med. 2007;39:563–568. 511. Alster TS, Wilson F. Treatment of port wine stains with the flashlamp pumped pulsed dye laser: extended clinical experience in children and adults. Ann Plast Surg. 1994;32:478–484. 512. Van der Horst C, Koster PHL, DeBorgre CAJM, et al. Effect of the timing of treatment of port wine stains with the flash-lamp-pumped pulsed dye laser. N Engl J Med. 1998;338:1028–1033. 513. Cordoro KM, Speetzen LS, Koerper MA, et al. Physiologic changes in vascular birthmarks during early infancy: mechanism and clinical implications. J Am Acad Dermatol. 2009;60:669–675.

smaller caliber, tortuous vessels with slow blood flow respond the best to laser therapy.514 Redder stains predict a better response than pink stains since vessels are more superficial.501 Different anatomical areas also respond differently to laser treatment. PWS of the central cheeks, the upper lip or those with a V2 distribution are less responsive.515 Lower extremities and more distal extremities, especially on the palmar or plantar surfaces, respond poorly. The best results are seen in periorbital, lateral face, post-auricular and neck areas, and on the upper chest and arms.515,516 Larger stains do less well than smaller stains.517 Recurrence of PWS in children, especially those in highly sun-exposed areas, is expected. An estimated rate of recurrence of 50% between 3 and 4 years is typical.483,490,518–522 After a primary treatment series that averages 8–10 treatments, most children return annually or every several years for a ‘tune up’ treatment to restore the clearance of the stain to its best appearance. Side-effects of pulsed dye laser treatment are minimal. In a large series of 701 patients, 9.1% developed hyperpigmentation, which resolved over 6–12 months; 1.4% developed hypopigmentation; blistering and crusting, which did not usually result in an undesirable outcome, occurred in 5.9% and 0.7%, respectively; and atrophic scarring occurred in 4.3%.523 These results have been confirmed in other studies.524,525 A low incidence of atrophic and hypertrophic scarring has been reported by many authors.526–528 Textural changes appear to occur more frequently in the pediatric population and it is recommended that lower energies be used initially with cryogen spray or other epidermal cooling systems to minimize these side-effects. Patients with more melanin pigmentation in their skin are more susceptible to post-inflammatory changes following laser. Effective treatment in this population requires greater care due to the absorption of laser energy by melanin. Longer intervals between treatments are required to allow for resolution of the postinflammatory changes. The results with dark-skinned patients are less impressive and patients have an increased risk of permanent pigmentary abnormalities and atrophic scarring.529 Despite this, patients with type V skin can be treated with pulsed dye

laser with proper caution, provided that treatment expectations and risks are fully discussed. Protective goggles should be worn by the patient and operator to avoid eye injury. These goggles should allow light transmission, with reflection of light of the specific wavelength generated by the laser to be utilized. For pulsed dye laser (spanning 585– 600 nm) either green or blue protective lenses are available. Green glasses create a problem in the operating room, since red light is transmitted as black, which makes the pulse oximeter monitor display impossible to read. Blue glasses are preferred in this setting.530 For treatment around the eye, non-plastic eye shields are required. Ethyl chloride cryogen spray, supplemental oxygen, and green vinyl tubing should be avoided to reduce the risk of flash fires.531,532 One of the greatest challenges in pulsed dye lasers in the pediatric population is providing an adequate level of comfort for the patient during treatment. The laser light impact on the skin is analogous to the snap of a small rubber band. With the use of a dynamic cooling system and the topical application of anesthetic creams such as EMLA (lidocaine/prilocaine in a eutectic mixture) or LMX (4% lidocaine gel), most pediatric patients will tolerate up to 50 pulses.533,534 Treatment of facial stains is more painful than stains on the chest or extremities. Hands, feet, the upper lip, and periorbital areas are the most painful. Chloral hydrate or other mild sedatives are not recommended, since they do not provide analgesia and the degree of sedation and cooperation that is attainable after administration of these agents is unpredictable and often detrimental to the procedure. Most pediatric patients will require a form of general anesthetic to safely and adequately control pain during extensive pulsed dye laser treatment. Intravascular propofol, ketamine or combinations of versed and fentanyl can be used effectively, but should only be administered by well-trained pediatric anesthetists. All of these agents can induce serious complications including respiratory arrest. Ketamine does not cause respiratory depression but is associated with hallucinations in many patients. The most effective anesthetic for infants and young children are inhalant agents such as nitrous oxide

514. Fiskarstrand EJ, Svaasand LO, Kopstad G, et al. Photothermally induced vessel-wall necrosis after pulsed dye laser treatment: lack of response if in PWS with small sized or deeply located vessels. J Invest Dermatol. 1996;107:671–674. 515. Renfro L, Geronemus R. Anatomical differences of portwine stains in response to treatment with the pulsed dye laser. Arch Dermatol. 1993;128:182–188/. 516. Holy A, Geronemus RG. Treatment of periorbital portwine stains with the flashlamp-pumped pulsed dye laser. Arch Opththalmos. 1992;110:793–797. 517. Morelli JG, Weston WL, Huff JC. Initial lesion size as a predictive factor in determining the response of port-wine stains in children treated with the pulsed dye laser. Arch Pediatr Adolesc Med. 1995;149:1142–1144. 518. Osten SS, Warner M, Flock S. Port wine stains: an assessment of 5 years of treatment. Arch Otolaryngol Head Neck Surg. 1996;122:1174–1179. 519. Mork NJ, Austad J, Helsing P. Do port wine stains recur after successful treatment with pulsed dye laser? J Eur Acad Dermatol Venereol. 1998;11:S142-S143. 520. Michel S, Landthaler M, Hohenleutner U. Recurrence of port-wine stains after treatment with the flash lamp pumped pulsed dye laser. Br J Dermatol. 2000;143:1230–1234. 521. Cordisco MR, Greco MF, Komar B, et al. Poster presentation at the 33rd Annual Meeting of the Society for Pediatric Dermatology. 522. Huikeshoven M, Koster PH, de Borgie CA, et al. Redarkening of port-wine stains 10 years after pulsed-dye-laser treatment. N Engl J Med. 2007;356: 1235–1240. 523. Seukeran DC, Collins P, Sheehan-Dar RA. Adverse reactions following pulsed tunable dye laser treatment of port wine stains in 701 patients. Br J Dermatol. 1997;136:725–729.

524. Levine VJ, Geronemus RG. Adverse effects associated with the 577 and 585-nanometer pulsed dye laser in the treatment of cutaneous vascular lesions: a study of 500 patients. J Am Acad Dermatol. 1995;32:613–617. 525. Boixda P, Nunez M, Perez B, et al. Complications of 585 nm pulsed dye laser therapy. Int J Dermatol. 1997;36:393–397. 526. Sommer S, Sheehan-Dare RA. Atrophie blanche-like scarring after pulsed dye laser treatment. J Am Acad Dermatol. 1999;41:100–102. 527. Gaston DA, Clark DP. Facial hypertrophic scarring from pulsed dye laser. Dermatol Surg. 1998;24:523–525. 528. Buscaglia DA. Hypertrophic scarring from pulsed dye laser treatment. Dermatol Surg. 1999;25:75. 529. Sommer S, Sheehand-Dare RA. Pulsed dye laser treatment of port-wine stains in pigmented skin. J Am Acad Dermatol. 2000;42:667–671. 530. Eichenfield LF. Vascular lesion laser: practical techniques or some ‘light’ suggestions. Pediatr Dermatol. 1999;16:332–334. 531. White J-M, Siegfried E, Boulder M, et al. Possible hazards of cryogen use with pulsed dye laser. Dermatol Surg. 1999;25:250–253. 532. Waldorf HA, Kauvar ANB, Geronemus RG, et al. Remote fire with the pulsed dye laser – risk and prevention. J Am Acad Dermatol. 1996;34:503–506. 533. Tan OT, Stafford TJ. EMLA for laser treatment of portwine stains in children. Lasers Surg Med. 1992;12:543–548. 534. Mallory SB, Lehman PA, Vanderpcol DR, et al. Topical lidocaine for anesthesia in patients undergoing pulsed dye laser treatment for vascular malformations. Pediatr Dermatol. 1993;10:370–375.

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with sevoflurane.535,536 These agents can be rapidly administered by mask without the need for intubation in most patients. Recovery is quick and side-effects are minimal. An experienced pediatric anesthesiologist should be on hand to administer these agents. PWS undergo a natural history of thickening and darkening with time. It is not uncommon to see hypertrophy of stain with the development of vascular blebs in older adolescents and adults. The frequency of these changes is reduced by early treatment of the PWS in the pediatric population.

LASER PEARLS IN THE TREATMENT OF PORT-WINE STAINS SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

As with any surgical procedure in children, the use of PDL often requires some specialized pediatric skills. When lasering young children who are awake for the procedure, it is important to demystify the laser. Refer to the laser as a special light, analogous to a small flashlight that flashes like a camera. Demonstrating the function of the laser can help to reassure young patients. Since parents are in the room for the procedure and may be equally traumatized and frightened, offering to demonstrate the laser by pulsing a parent once on the volar surface of the wrist can reassure both the patient and the family. Most parents are instantly relieved to realize that the laser is minimally uncomfortable. Use of LMX is a must to minimize the sting that occurs after the cool burst from the dynamic cooling agent disappears. Having the child hold a cold gauze or ice to place over the area immediately after treatment occupies them and permits instant relief from the discomfort of the laser. If larger areas are being treated, always treat the least painful areas first. Pulse a specified number of times and then pause before continuing. When many pulses are required, children are better able to get through the laser in smaller sessions. Most children can hold still for 10 pulses comfortably. Never pulse more times than you have promised and be concrete in estimating the number of pulses that will be required. If you promise 30, do not do 38. Distracting the child with a reward when the laser if over can be extremely helpful in providing the ground-work to get them back for the next laser treatment. The use of general anesthetic can introduce new challenges for the laser surgeon. Although most anesthetic agents cause peripheral vasodilatation, it is common to see the stain fade as the depth of anesthetic is increased. This may be secondary to dilation of the normal skin vessels surrounding the port-wine stain and a ‘steal’ effect. Several tricks can be employed to increase blood in the target tissue. On an extremity, application of a tourniquet is recommended. Covering the area to be treated with warm water soaked gauze or blankets from the OR warmer can also help. For facial stains, placing the patient in slight Trendelenburg can increase blood flow to the head. It is always a good idea to outline the stain before lasering. For faint stains, this can be accomplished with a washable marker in

535. Grevelink JM, White VR, Bonodr R, et al. Pulsed laser treatment in children and the use of anesthesia. J Am Acad Dermatol. 1997;37:75–81. 536. Chen BK, Eichenfield LF. Pediatric anesthesia in dermatologic surgery: when hand-holding is not enough. Dermatol Surg. 2001;27:1010–1018. 537. Ahcan U, Zorman P, Recek D, et al. Port wine stain treatment with a dual-wavelength Nd:Yag laser and cryogen spray cooling: a pilot study. Lasers Surg Med. 2004;34:164–167.

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the clinic. Skin markers are difficult to wash off and cause an undesirable plume that spatters the laser window if the laser itself is used to remove the ink. The laser itself can be used to outline most stains without the need for a marker. Always begin by outlining the edge of the stain so the erythema and edema from histamine release produced by laser treatment do not obscure the edge of the stain. Use of the dynamic cooling units dramatically reduces injury to the epidermis but also cools the skin surface causing vasoconstriction and pallor. With decreased blood in the tissue, purpura is markedly reduced and the central portion of the stain can look untreated compared with the purpura on the outlined rim. One way to minimize this is to cover the laser area in a circular pattern rather than in a back and forth block. This allows more time for the skin to recover from the cooling effect of the dynamic cooling system before it is lasered. Using a warm gauze to cover the previously treated areas can also be helpful. Since most PWS are irregular in shape, it can be difficult to place the laser spots perfectly to avoid skipped areas and ‘patterning’ while avoiding too much overlap that increases the risk of tissue injury and scarring. A smaller spot size can be used to ‘fill-in’ missed areas but this requires changing of the laser fiber and recalibration. A faster way to ‘fill-in’ missed areas is to take a 2 × 2 gauze and fold it in half so the laser light cannot penetrate it. Cover the previously treated area with the gauze leaving the irregular untreated area exposed and laser half on the patient and half on the gauze. By manipulating the amount of laser that is administered to the gauze, very irregular and small areas can be treated without risking overlap.537

Treatment of resistant PWS Many factors determine the efficacy of treatment of PWS with PDL including: the age of the patient, the size of the lesion, the anatomic location of the lesion, the depth of the vessels, and the lesion color.501,508–517 The vast majority of PWS treated with PDL do not resolve completely.483,505 Moreover, recurrence is expected with time.483,490,518–521 Recent advances in laser technology and in the development of adjunct angiogenesis inhibitors may offer promise for improvement of resistant PWS.483 A new combined modality laser system (Cynergy Multiplex) can deliver pulsed sequential light at 595 nm followed by 1064 nm some 50–2000 ms later. This system has shown early promise as a tool to gain deeper penetration of light energy to cause vascular coagulation.538,539 Use of the long pulsed Nd:YAG to treat PWS is not new. Use of this laser has been limited by the high risk of scarring, even when a cooling unit is used. For this reason, it is recommended that use of this laser should be limited to the most skilled laser surgeons. Only the minimal purpuric fluence should be used to avoid the production of methemoglobin in the tissue. Methemoglobin has a much higher absorption than hemoglobin and leads to increased

538. Chapas A, Fazeli A, Goldberg D, et al. Sequential, dual wavelength treatment of port wine birthmarks: pilot study. Laser Surg Med. 2006;18:21. 539. Tanghetti EA. Multiplex 595 nm, 1064 nm laser treatment for blebbed port wine birthmarks and telangiectasia. Lasers Surg Med. 2006;18:21.

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scattering and risk of scarring.540 Test spots can be done to determine this dose, or the laser can be used at reduced fluences when the PDL is used first. Significant improvement in resistant lesions has been noted using lower fluences than those used for either laser alone when the light is delivered in rapid succession.538,539 Continued treatments with pulsed dye laser despite the lack of rapid and obvious improvement can be helpful in persistent PWS. Hypertrophic, nodular, extremely large stains and stains in challenging locations such as the distal limbs, and central face including the upper lip, cheek and nose that were treated for 9–20 treatments, despite the fact that they failed to lighten >75% in the original treatment series, demonstrated significant improvement in lightening with repetitive treatments and no increase in side-effects.504 Combination laser therapy with a hybrid laser, the Nd:YAG/ KTP emitting two wavelengths simultaneously (1064 and 532), has also been shown to be effective for resistant stains. The high risk of scarring noted with the KTP laser when used alone is reduced, since the longer pulsed laser allows for effective treatment of 30% lower fluences which reduces the risk of scarring.537 Purple or blue tinged PWS, like vascular malformations, often require more aggressive therapy. This use of the Nd:YAG alone has been shown to benefit these lesions, and to a lesser degree, the 810 nm diode laser and the 755 nm alexandrite laser.540,541 Pulse stacking has also been recommended as a means of improving the response to pulsed dye laser in thicker vascular malformations.542 Two studies compared the conventional 585 nm pulsed dye laser treatment of port-wine stains to the newer 595 nm laser treated stains. Interestingly, despite the deeper penetration of the longer wavelength laser, the conventional system seemed preferable.543,544 This author has used both of these laser systems and has observed impressive improvement in lightening in patients treated with both lasers when a switch was made to the alternative system. This probably reflects the presence of vessels of varying sizes and depths that respond preferentially to each of these lasers. Photodynamic therapy may also hold promise in the treatment of PWS. Here, either transcutaneous chromophore (ALA) or intravenous chromophores including hepatoporphyrin or

The natural history of hemangiomas is one of rapid growth followed by spontaneous involution. Since involution occurs without any intervention, the efficacy of pulsed dye laser on impacting the natural history of this common lesion has been difficult to evaluate. Much controversy surrounds the use of this laser, especially in early proliferative lesions, where both the risk of ulceration and the benefit of treatment are probably the highest.549,550 The only double-blind placebo-controlled trial evaluating the efficacy of laser therapy in the treatment of hemangiomas was published in 2006 by Batta et al.551 These authors concluded that a wait and see policy was best, rather than lasering, since improved outcome was only demonstrated for the most superficial hemangiomas, many of which healed with atrophy or hypopigmentation that was felt to possibly result from the laser treatment itself. This study has been criticized because the lasers used on patients in this study lacked the dynamic cooling units that are felt to reduce the risk of epidermal changes. Haywood and co-workers speculated that resolution of hemangiomas treated with PDL was more rapid than untreated lesions552 and other authors suggest a positive effect in countering rapid proliferation if PDL is undertaken very early and at regular intervals.553 The same author (Geronemus) published an earlier study demonstrating no improvement in deeper hemangiomas or in the deep component of mixed hemangiomas using laser therapy.554 A 3-month follow-up of 550 patients treated during the first year of life demonstrated 67% complete

540. Yang MU, Yaroslavsky AN, Farinelli WA, et al. Long-pulsed neodymium:yttrium aluminum-garnet laser treatment for port-wine stains. J Am Acad Dermatol. 2005;52:480–490. 541. Groot D, Rao J, Johnston P, et al. Algorithm for using a long-pulsed Nd:Yag laser in the treatment of deep cutaneous vascular lesions. Dermatol Surg. 2003;29:35–42. 542. Jasim ZF, Handley JM. Treatment of pulsed dye laser-resistant port wine stain birthmarks. J Am Acad Dermatol. 2007;57:677–682. 543. Greve B, Raulin C. Prospective study of port wine stain treatment with dye laser: comparison of two wavelengths (585 nm vs 595 nm) and two pulsed durations (0.5 milliseconds vs 20 milliseconds). Lasers Surg Med. 2004;34:168–173. 544. Chang CJ, Kelly KM, Van Gemert MJ, et al. Comparing the effectiveness of 585-nm vs 595-nm wavelength pulsed dye laser treatment of port wine stains in conjunction with cryogen spray cooling. Lasers Surg Med. 2002;31:352–358. 545. Channual JC, Choi B, Pattanachinda D, et al. Long-term vascular effects of photodynamic and pulsed dye laser protocols. Lasers Surg Med. 2007;19:36. 546. Channual JC, Choi B, Osann K, et al. Vascular effects of photodynamic and pulsed dye laser therapy protocols, Lasers Surg Med. 2008;40:644–650. 547. Phung TL, Oble DA, Jia W, et al. Can the wound healing response of human skin be modulated after laser treatment and the effects of exposure

extended? Implications on the combined use of the pulsed dye laser and a topical angiogenesis inhibitor for treatment of port wine stain birthmarks. Lasers Surg Med. 2008;40:1–5. 548. Chang CJ, Hsiao YC, Mihm MC Jr, et al. Pilot study examining the combined use of pulsed dye laser and topical imiquimod versus laser alone for treatment of port wine stain birthmarks. Lasers Surg Med. 2008;40:605–610. 549. Witman PM, Wagner AM, Scherer K, et al. Complications following pulsed dye laser treatment of superficial hemangiomas. Lasers Surg Med. 2006;38:116–123. 550. Lesesky EB, Cunningham BB, Makkar HS. Pediatric surgical pearls: minimizing complications. Semin Cutan Med Surg. 2007;26:54–64. 551. Batta K, Goodyear HM, Moss C, et al. Randomised controlled study of early pulsed dye laser treatment of uncomplicated childhood hemangiomas: results of a 1-year analysis. Lancet. 2006;360:521–527. 552. Haywood RM, Moon BE, Mahaffey PJ. The treatment of early cutaneous capillary hemangiomas (strawberry naevi) with the turnable dye laser. J Plast Surg. 2000;53:302–307. 553. Chapas AM, Geronemus RG. Our approach to pediatric dermatologic laser surgery. Lasers Surg Med. 2005;37:255–263. 554. Ashinoff R, Geronemus RG. Failure of the flashlamp-pumped pulsed dye laser to prevent progression to deep hemangioma. Pediatr Dermatol. 1993;10:77–80.

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benzoporphyrin when irradiated with 576 nm light or 585 nm PDL demonstrated combined therapy that was better than either therapy alone in an optimized in-vivo rodent model.545,546 Using the same in-vivo rodent, window chamber model application of the antiangiogenic agent rapamycin to skin exposed to laser showed no reformation and reperfusion of blood vessels. This may have great implications in the treatment of PWS to prevent recurrence.547 A recent pilot study of imiquimod, another antiangiogenic agent, applied along with PDL and alone resulted in the best blanching response at test spots.548 Further investigation of the role of topical antiangiogenic agents on resistant and recurrent PWS is needed.

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BOX 5.8 CLINICAL CRITERIA FOR CONSIDERING PULSED DYE LASER IN THE TREATMENT OF SUPERFICIAL HEMANGIOMAS

>> Functional impairment or potential functional impairment >> Ulceration or area at high risk for ulceration (groin, lip) >> Rapid enlargement or large surface area >> Cosmetic disfigurement* >> Recurrent bleeding or trauma * With parental knowledge of risk of scarring.

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Figure 5.31  Ulcerated hemangioma on the buttock.

or marked regression in flat and superficial hemangiomas with 87% patient satisfaction.555 Response of hemangiomas to PDL is largely a function of vessel diameter and depth. Vessels most amenable to treatment are between 50–150 µm in size and 9 treatments) and by lowering the power from 15–20  W down to 2–5  W, the rate of ulceration was reduced from 20% to 2%.572 Reduction in the size of these large, often inoperable hemangiomas is 50–90% over 3–9 months. One area that has been greatly impacted by the use of bare fiber KTP laser is subglottic hemangioma.573 For 10–20% of patients with airway hemangiomas, severe compromise can occur during the proliferative phase that has traditionally been approached with tracheostomy placement. The use of bare fiber KTP laser to treat these lesions using fiber optic cables can reduce the need for tracheostomy.574,575 Laser therapy is associated with a risk of secondary subglottic stenosis from scarring and should be used with caution in this patient population. Although this laser system offered an alternative approach for rapidly enlarging, disfiguring or deeply ulcerated or airway threatening hemangiomas, the discovery of propranolol as an effective medical treatment for hemangioma of infancy is likely to markedly reduce the need for such aggressive laser therapy in the management of these lesions.576–580

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574. Madgy D, Ahsan SF, Kest D, et al. The application of the potassium-titanylphosphate (KTP) laser in the management of subglottic hemangioma. Arch Otolaryngol Head Neck Surg. 2001;127:47–50. 575. Kacker A, April M, Ward RF. Use of potassium titanyl phosphate (KTP) laser in management of subglottic hemangiomas. Int J Pediatr Otorhinolaryngol. 2001;59:15–21. 576. Léauté-Labrèze C, Dumas de la RE, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–2651. 577. Siegfried EC, Keenan WJ, Al-Jureidini S. More on propranolol for hemangiomas of infancy. N Engl J Med. 2008;359:2846–2847. 578. Fraser K. 67th Annual Meeting of the American Academy of Dermatology, San Francisco, California, 6–10 March 2009. Am J Clin Dermatol. 2009;10:205–210. 579. Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: risks and recommendations. Pediatr Dermatol. 2009;26:610–614. 580. Michel JL, Patural H. Response to oral propranolol therapy for ulcerated hemangiomas in infancy. Arch Pediatr. 2009;16:1565–1568. 581. Tan E, Vinciulo C. Pulsed dye laser treatment of spider telangiectasia. Australas J Dermatol. 1997;38:22–25. 582. Swinehart JM. Textural change following treatment of facial telangiectasis with the turnable pulsed-dye laser. Arch Dermatol. 1999;135:472–473.

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Telangiectatic rosacea can also be treated with PDL. Many older adolescents and young adults with benign familial telangiectasia or rosacea prefer not to have laser treatment that results in significant purpura. Although PDL remains the gold standard in these conditions, KTP or intense pulsed light systems can be used that lead to mild erythema only post-treatment. Intense pulse light uses fluences between 32 and 40 J/cm2 and 20-ms pulse width and is optimal for facial ruddiness or matted telangiectasias with no down-time for the patient. Multiple treatments are necessary for optimal results.490,583 Pyogenic granulomas have also been successfully treated with pulsed dye laser584–586 but multiple treatments are required and lesions raised >3–4 mm above the skin are best treated by conventional methods. Laser does offer the advantage of a very low risk of scarring and is an appropriate option for early pyogenic granulomas on the face. When treated, multiple pulses are required and partial diascopy, as described for the elevated central arteriole in some spider angiomas, can be helpful to increase the depth of penetration. Some pyogenic granulomas leave behind non-vascular, skin tag-like remnants as a result of pedunculated growth. CO2 laser can be used to treat these remnants with good cosmetic results.490 Multiple pyogenic granulomas often appear within extensive port-wine stains and are treated to prevent symptoms of recurrent bleeding.

LASER PEARLS FOR PYOGENIC GRANULOMA OR ELEVATED VASCULAR PAPULES When the vascular target of the PDL is thicker than 1.5  mm it exceeds the depth of penetration of the laser, limiting the laser’s ability to injure the underlying blood vessels. Elevated vascular lesions can be readily compressed with a glass microscope slide (diascopy) flattening the surface to allow for better penetration. Pressing on the lesions with a glass-slide blanches the lesion removing the blood which is the target of the laser. By pressing lightly with the slide, most pyogenic granulomas can be flattened without complete blanching, allowing for optimal treatment. Elevated lesions often require multiple pulses of the laser for adequate injury. Since the spot size of the laser often exceeds the size of the papule that is being pulsed there is risk of injury to the surrounding normal skin which can blister with repeat laser pulsing. One way to avoid this problem is to take a skin punch that is the size of the pyogenic granuloma and use it to make a circular hole in a small piece of foam tape. The tape can then be placed on top of the pyogenic granuloma with the PG centered

583. West TB, Alster TS. Comparison of the long-pulsed dye and KTP lasers in the treatment of facial and leg telangiectasia. Dermatol Surg. 1998;24:221–226. 584. Goldberg DJ, Sciales CW. Pyogenic granulomas in children: treatment with the flashlamp-pumped pulsed dye laser. J Dermatol Surg Oncol. 1991;17:960. 585. Gonzalez S, Vibhagool C, Falo LD Jr, et al. Treatment of pyogenic granulomas with the 585 nm pulsed dye laser. J Am Acad Dermatol. 1996;35:428–431. 586. Tay YK, Weston WL, Morelli JG. Treatment of pyogenic granuloma in children with the flashlamp-pumped pulsed dye laser. Pediatrics. 1997;99:368–370. 587. Lapidoth M, Ad-El D, David M, et al. Treatment of angiokeratoma of Fordyce with pulsed dye laser. Dermatol Surg. 2006;32:1147–1150. 588. Pfirrmann G, Raulin C, Karsai S. Angiokeratoma of the lower extremities: successful treatment with a dual-wavelength laser system (595 and 1064 nm). J Eur Acad Dermatol Venereol. 2009;23:186–187.

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in the cut out hole. Repeat pulses of the laser can then be safely used since the surrounding skin is protected by the foam tape. Vascular malformations, other than superficial PWS, are not usually amenable to treatment with the pulsed dye laser. These lesions are typically deeper than the depth of penetration of the laser and present as an overlying bluish hue to the tissue. On palpation, the skin often has a doughy appearance and expansion can occur with increased orthostatic pressure. PDL can lighten the surface color of these lesions but most require more extensive treatment with debulking by sclerotherapy followed by surgical intervention. In general, small lesions are amenable to complete resection but there is a tendency for recurrence. Conservative management is usually preferred unless there are symptoms of pain or functional limitations.490 One exception to this is small angiokeratomas or the superficial angiokeratoma-like vascular blebs that develop on the surface of extremities in Klippel–Trenaunay syndrome. Bleeding from these lesions is readily treated by this laser. Resolution of the more keratotic plaque is unusual. Angiokeratoma of Fordyce has been successfully treated with pulsed dye laser.587 A recent report of successful treatment of angiokeratoma of the lower extremities treated with a dual-wavelength laser system (595 PDL and 1064 frequency doubled Nd:YAG) shows promise in elimination of these lesions more completely.588 Similarly, lymphatic malformations that are localized such as lymphangioma circumscriptum can be treated with PDL to help control the leakage of blood stained lymphatic fluid.589 Treatment does not remove the lesion in its entirety and new areas can develop adjacent to treated areas since these arise on a field of skin that has defective lymphatic channels. CO2 laser in combination with PDL/Nd:YAG is a better choice for more symptomatic and elevated lesions since these laser systems penetrate more deeply and the superficial scar that can result is minimal but can prevent recurrence.490 Non-vascular cutaneous lesions with prominent erythema and significant vascularity can also be treated with pulsed dye laser. Vascular angiofibromas are an example of a cutaneous lesion that is not primarily vascular in origin, but whose vascular component is very amenable to treatment with this laser system. The laser removes the erythema associated with early central facial lesions effectively.590,591 It does not, however, remove the underlying fibrous papule. Adolescents often opt for initial treatment with pulsed dye laser since it is the erythema that is most noticeable during early development of angiofibromas. More definitive treatment can be obtained with the carbon dioxide or KTP lasers.591–594

589. Lai CH, Hanson SG, Mallory SB. Lymphangioma circumscriptum treated with pulsed dye laser. Pediatr Dermatol. 2001;18:509–510. 590. Sharma VK, Khandpur S, Khanna N. An interesting case of unilateral angiofibromas successfully treated with pulsed dye laser. J Eur Acad Dermatol Venereol. 2004;18:641–642. 591. Papadavid E, Markey A, Bellaney G, et al. Carbon dioxide and pulsed dye laser treatment of angiofibromas in 29 patients with tuberous sclerosis. Br J Dermatol. 2002;147:337–342. 592. Belmar P, Boixeda P, Baniandrés O, et al. Long-term follow up of angiofibromas treated with CO2 laser in 23 patients with tuberous sclerosis. Acta Dermosifiliogr. 2005;96:498–503. 593. Bittencourt RC, Huilgol SC, Seed PT, et al. Treatment of angiofibromas with a scanning carbon dioxide laser: a clinicopathologic study with long-term follow-up. J Am Acad Dermatol. 2001;45:731–735. 594. Tope WD, Kageyama N. ‘Hot’ KTP-laser treatment of facial angiofibromata. Lasers Surg Med. 2001;29:78–81.

A

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Surgical techniques

B

Figure 5.32  Periungual wart (A) before treatment with pulsed dye laser. (B) After two treatments with pulsed dye laser.

Warts, like angiofibromas, have a prominent vascularity that can readily be targeted by the pulsed dye laser. Since warts are common in the pediatric population, pulsed dye laser is used with some frequency to treat symptomatic warts.595–598 Studies suggest that this laser offers no advantage over conventional therapy with liquid nitrogen in the treatment of warts.599 Patients in this study, however were treated at 1 month intervals and optimal treatment of warts using the pulsed dye laser requires treatment at 2–3 week intervals to avoid regrowth of the warts between treatment sessions. The pulsed dye laser is not recommended as a first-line treatment for warts in children. However, for some children who have failed conventional therapy, especially those who have >20 warts on the hands or on the plantar surface of the feet, the pulsed dye laser is a good alternative (Fig. 5.32). This author reserves the use of laser in the treatment of warts for those patients who have failed treatment with oral cimetidine, immunotherapy, and topical therapy with 5-fluorouracil in salicylic acid. Many of the children treated are on immunosuppressive therapy post-organ transplantation and have both disfiguring and functionally impairing warts.595 Extensive warts cannot be treated in most children without some form of anesthetic. For acral warts in adolescents, digital blocks can be helpful. For younger children, however, the use of a general anesthetic will be necessary, since topical anesthetics are not sufficient to reduce the pain of pulsed dye laser or cryotherapy

for wart treatment. For immunocompromised patients, combination therapy with cryotherapy, paring, and pulsed dye laser may yield the best results. Many of these patients never achieve cure but treatments reduce the disability and disfigurement of severe viral infection. Flat warts respond the best to the pulsed dye laser, requiring one or two treatments only in most cases. Caution must be taken in the treatment of facial lesions on pigmented skin because the transient post-inflammatory hypopigmentation is more noticeable and disfiguring than the warts themselves. For larger, periungual or plantar warts, 3–4 treatments is more typical for resolution. It is recommended that the warts be aggressively pared prior to laser treatment to allow better penetration of the tissue for vascular injury. High fluence (8.5–10  J/ cm2) and multiple pulses to each wart to produce purpura are recommended. A minimum of three pulses is usually required per wart. The risk of scarring and the pain and length of postoperative healing are markedly reduced with the pulsed dye laser compared with the carbon dioxide laser. The latter is no longer considered an appropriate treatment in the pediatric population because of the associated morbidity and availability of superior treatments. A study of use of CO2 laser to treat warts in pediatric patients demonstrated a 27.5% incidence of post-treatment hypopigmentation.600 The pulsed dye laser has also been used in the treatment of scars. Both the 585 nm and 595 nm lasers have been shown to

595. Sethuraman G, Richards KA, Hiremagalore RN, et al. Effectiveness of pulsed dye laser in the treatment of recalcitrant warts in children. Dermatol Surg. 2010;36:58–65. 596. Park HS, Choi WS. Pulsed dye laser treatment for viral warts: a study of 120 patients. J Dermatol. 2008;35:491–498. 597. Schellhaas U, Gerber W, Hammes S, et al. Pulsed dye laser treatment is effective in the treatment of recalcitrant viral warts. Dermatol Surg. 2008;34:67–72.

598. Park HS, Kim JW, Jang SJ, et al. Pulsed dye laser therapy for pediatric warts. Pediatr Dermatol. 2007;24:177–181. 599. Kauver AN, Geronemus RG. Pulsed-dye laser versus conventional therapy in the treatment of warts. J Am Acad Dermatol. 2001;45:151. 600. Serour F, Somekh E. Successful treatment of recalcitrant warts in pediatric patients with carbon dioxide laser. Eur J Pediatr Surg. 2003;13:219–223.

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improve the vascularity and pliability of surgical scars. Low energies (3.5 J/cm2, 450 µm, 10 mm spot size) are recommended with repeat treatments monthly for 3 months. The 585 nm laser may be preferred since height improved significantly more with this laser than with the 595 nm PDL.601,602 PDL has been shown to improve redness in many skin conditions with minimal risk of epidermal damage and hyperpigmentation. Interestingly, PDL appears to be effective in the treatment of hypertrophic scars and keloids, as well as atrophic scars and striae.603,604 PDL has been shown to induce reduction in TGF beta 1, fibroblast proliferation and collagen type III deposition in treated keloids. For keloids, six PDL treatments at 2-month intervals using fluence of 10–18 J/cm2 is recommended.605 Lower fluences (7 J/cm2) and a short pulse width (0.45 ms) is recommended in dark-skinned individuals.606 Recurrence of keloid after treatment has been reported.607 Striae rubra have also been improved with the use of PDL. Treatment with the laser is purported to increase the amount of collagen in the extracellular matrix as well as diminish erythema.608 Low fluences (2.0–4.0 J/cm2) are recommended and phototypes V and VI should not be treated. One study attempted to reduce the pigmentary alteration seen in pigmented skin with PDL treatment of striae by combining low fluence PDL (3.0 J/cm2) with 10 mm spot size with radiofrequency (Thermage) at 53–97 J/cm2. Skin biopsies demonstrated increase in the amount of collagen and elastic fibers after one Thermage treatment and three treatments with PDL at 1 month intervals.609 PDL should not be a first-line treatment for scars, keloids or striae in children. Nonetheless, it may provide another tool in the management of these lesions that do not improve with pressure dressings, silicon sheeting, massage and time. Other than transient hyperpigmentation, the side-effects of these treatments at low fluences are minimal.610 Another pediatric condition that shares the properties of having increased vascularity with prominent erythema is ILVEN (inflamed linear verrucous epidermal nevus). This congenital epidermal nevus is characterized by marked erythema often accompanied by functionally impairing pruritus that is poorly responsive to standard topical therapy. PDL has been demonstrated to offer relief both for the erythema of these lesions and the underlying pruritus.611 Minimal effect on the thickness of the lesion is noted with these treatments.612

Pigmented lesions are also amenable to laser treatment in children, although the use of these lasers is generally deferred until adolescence. Melanin, the main chromophore of the epidermis, is the target of these lasers. It absorbs energy from about 300– 1000  nm. For this reason, a number of different lasers can be used for selective treatment of a multitude of benign pigmented lesions.613 Two types of pigmented laser systems are available to treat pigmentary lesions: highly selective lasers, and nonselective or somewhat selective lasers. In general, the highly selective laser systems are preferred for treatment in children. Like the pulsed dye laser, these lasers have pigmentary specificity based on the theory of selective photothermolysis. The target of selective pigmentary lasers is melanin in melanosomes. Selective injury to melanosomes and pigment cells occurs with highintensity light at short pulse durations of 0.1  µs. The thermal relaxation time of a melanosome, which ranges in size from 0.5–1.0  µm, is between 250 and 1000  ns. For laser injury to be specific for melanin and avoid injury to the surrounding tissue, short impulses of light in these ranges must be used.614 The pigment-specific lasers are listed in Table 5.7. The longer the wavelength, the deeper the laser penetrates into the skin. Lasers with longer wavelengths are preferred for lesions that have dermal melanin. The choice of pigmentary laser depends on the pigmented lesion being targeted and the depth of melanin in the lesion. The spectrum of pigmentary lesions amenable to laser in children includes epidermal pigmented lesions (café-au-lait macules, nevus spilus, ephelides and lentigines), dermal pigmented lesions (nevus of Ota, nevus of Ito and tattoos) and lesions with combination of epidermal and dermal components (Becker’s nevus, congenital pigmented nevi, junctional or compound acquired melanocytic nevi and epidermal nevi) (Table 5.8). Despite this, the treatment of pigmented lesions in the pediatric population is not commonplace.402,615 With the exception of nevus of Ota, significant recurrence of congenital pigmented lesions after multiple laser treatments is a frequent occurrence. Availability of these laser systems in a setting that can provide adequate anesthesia for the pediatric patient is also limited. Most treatment is deferred until adolescence or young adulthood,

601. Nouri K, Rivas MP, Stevens M, et al. Comparison of the effectiveness of the pulsed dye laser 585 nm versus 595 nm in the treatment of new surgical scars. Lasers Med Sci. 2009;24:801–810. 602. Kono T, Erçöçen AR, Nakazawa H, et al. Treatment of hypertrophic scars using a long-pulsed dye laser with cryogen-spray cooling. Ann Plast Surg. 2005;54:487–493. 603. Bernstein EF. The pulsed-dye laser for treatment of cutaneous conditions. G Ital Dermatol Venereol. 2009;144:557–572. 604. Alster TS, Handrick C. Laser treatment of hypertrophic scars, keloids, and striae. Semin Cutan Med Surg. 2000;19:287–292. 605. Kuo YR, Jeng SF, Wang FS, et al. Flashlamp pulsed dye laser (PDL) suppression of keloid proliferation through down-regulation of TGF-beta1 expression and extracellular matrix expression. Lasers Surg Med. 2004;34:104–108. 606. Manuskiatti W, Wanitphakdeedecha R, Fitzpatrick RE. Effect of pulse width of a 595-nm flashlamp-pumped pulsed dye laser on the treatment response of keloidal and hypertrophic sternotomy scars. Dermatol Surg. 2007;33:152–161. 607. Shih PY, Chen HH, Chen CH, et al. Rapid recurrence of keloid after pulse dye laser treatment. Dermatol Surg. 2008;34:1124–1127.

608. Jiménez GP, Flores F, Berman B, et al. Treatment of striae rubra and striae alba with the 585-nm pulsed-dye laser. Dermatol Surg. 2003;29:362–365. 609. Suh DH, Chang KY, Son HC, et al. Radiofrequency and 585-nm pulsed dye laser treatment of striae distensae: a report of 37 Asian patients. Dermatol Surg. 2007;33:29–34. 610. Smit JM, Bauland CG, Wijnberg DS, et al. Pulsed dye laser treatment, a review of indications and outcome based on published trials. Br J Plast Surg. 2005;58:981–987. 611. Sidewell RU, Syed S, Harper JI. Pulsed dye laser treatment for inflammatory linear verrucous epidermal naevus. Br J Dermatol. 2001;144:1267–1269. 612. Alster TS. Inflammatory linear verrucous epidermal nevus: successful treatment with the 585 nm flashlamp-pumped pulsed dye laser. J Am Acad Dermatol. 1994;31:523–524. 613. Carpo BG, Grevelink JM, Grevelink SV. Laser treatment of pigmented lesions in children. Semin Cutan Med Surg. 1999;18:233–243. 614. Anderson RR. Lasers in dermatology – a critical update. J Dermatol. 2000;27:700–705. 615. Morelli JG. Use of lasers in pediatric dermatology. Pediatr Dermatol. 1998;16:489–495.

Laser treatment of pigmented lesions and tattoos in children

Surgical techniques

5

Table 5.7  Highly selective lasers for treating pigmented lesions in children LASER

WAVELENGTH (NM)

PULSE DURATION (NS)

LOCATION OF TARGETED PIGMENT

Flashlamp pumped pulsed dye (PDL)

504, 510

300–500

Epidermis, superficial dermis

QS Nd:YAG

532

5–20

Epidermis, superficial dermis

QS Ruby (QSR)

694

20–40

Epidermis, dermis

QS Alexandrite

755

50–100

Epidermis, dermis

QS Nd:YAG

1064

5–20

Deep dermis

Long-pulsed Ruby (LPR)

694

300–3000

Dermis (larger targets)

Long-pulsed alexandrite (QSA)

755

200–20 000

Dermis (larger targets)

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

Freq, frequency; QS Nd:YAG, Q-switched, neodymium-yttrium, aluminum-garnet laser; QS, Q-switched.

Table 5.8  Pigmented lesions amenable to laser in children LESION

DEPTH OF MELANIN IN SKIN

LASER OF CHOICE

Café au lait macule

Epidermal

Nd:YAG (532), Q-switched ruby (694), Q-switch alexandrite (755), pigment PDL (510)

Nevus spilus

Epidermal and dermal

Nd:YAG (532), Q-switch ruby (694)

Lentigines

Epidermal

Nd:YAG (532), Q-switch ruby (694)

Congenital nevus

Epidermal and dermal

None (Er:YAG for unresectable lesions)

Nevus of Ota

Deep dermis

Q-switched ruby, Nd:YAG (1064), Q-switch alexandrite

Becker nevus

Epidermal (target also hair)

Long pulsed rubya + Q S ruby Nd:YAG (532) + long-pulsed alexandrite

Epidermal nevus

Epidermal (target is water)

Erbium:YAG or CO2 resurfacing

a

No longer available.

when the patient is invested in the removal of the lesion, usually for cosmetic purposes.

Café-au-lait macules Café-au-lait macules (CALMs) are common, occurring in 10– 20% of patients. Most are small and inconspicuous. Facial lesions are most likely to present for laser therapy, especially when they are large, such as those seen in McCune–Albright syndrome. The pigment in CALMs is present at the basal layer in giant macromelanosomes. Several lasers have been used to treat these lesions, including the Q-switched ruby laser, the frequencydoubled neodymium YAG laser, and the pulsed dye laser at 510 or 504 nm, and the Q-switched alexandrite, all of which can penetrate to the basal layer.613 Response to laser treatment is variable, however, and similar lesions treated with the same laser can lighten, clear with recurrence, remain unchanged or be tran-

616. Grossman MC, Anderson RR, Farinelli W, et al. Treatment of café-au-lait macules with lasers: a clinicopathologic correlation. Arch Dermatol. 1995;131:1416–1420. 617. Shimbashi T, Kamide R, Hashimoto T. Long-term follow-up treatment of solar lentigo and café-au-lait macules with Q-switched ruby laser. Aesthet Plast Surg. 1997;21:445–448. 618. Alster TS. Complete elimination of large café-au-lait birthmarks by the 510-nm pulsed dye laser. Plast Reconstr Surg. 1995;96:1660–1664.

siently or permanently darkened.616,617 Side-effects of treatment such as transient hyper- and hypopigmentation, prolonged hypopigmentation or hyperpigmentation (higher risk with the Q-switched ruby),502 scarring and recurrence of the entire lesion are seen.613,616 The best results have been reported with the pulsed dye laser at 510 or 504 nm. Alster successfully cleared 34 CALMs in an average of 8.4 treatments with no recurrence at 1 year with the 510 nm pulsed dye laser.618 This laser is not commonly used or available, however. Most authors recommend the Q-switched 532 nm Nd:YAG laser.619 Use of this laser results in purpura and postoperative abradement of the treated lesion that requires some wound care for 5–14 days.502 Typically, 5–10 treatments result in the best treatment and recurrence is present in one-third to one-half of patients.620 Facial lesions may be more responsive to laser treatment than lesions in other areas. It is essential to discuss the limitations of treatment and the potential darkening of lesions that can occur with the patient and parents prior to

619. Wheeland R, Schmults C. Pigmented lesions and tattoos. In: Dover JS, Goldberg DJ, eds. Procedures in cosmetic dermatology, laser and lights. Vol 1. 2005. 620. Downs AM, Pickard A, Palmer J. Laser treatment of benign pigmented lesions in children: effective long-term benefits of the Q-switched frequency doubled Nd:YAG and long-pulsed alexandrite lasers. Pediatr Dermatol. 2004;21:88–90.

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undergoing any laser therapy for CALMs in the pediatric population.621 Treatment of CALM is not recommended in skin types IV–VI due to the risk of permanent pigment change.502

demonstrated effectiveness in the treatment of lentigines without the risk of pigmentary changes and may be the treatment of choice in this population, although many treatments are necessary to obtain the same results.628

Nevus spilus

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

Nevus spilus is a congenital or acquired pigmented lesion that frequently begins as a CALM that becomes studded with smaller more darkly hyperpigmented macules that histologically consist of lentiginous melanocytic hyperplasia or lentiginous junctional, dermal or compound nevi, or Spitz nevi. Lesions can range in size of 1–20 cm and are most frequently found on the trunk or extremities. Although rare, malignant melanoma has developed within these lesions and any suspicious area should be biopsied.622 Treatment should be avoided in any pediatric patient with a family history of melanoma.402,623 Moreover, lesions treated with laser should be followed indefinitely for any recurrence and suspicious areas immediately biopsied. Numerous lasers have been used in the treatment of nevus spilus.402 Like other CALMs, the background pigmentation is the most difficult to eradicate completely. Most reports demonstrate successful removal of the junctional nevi within the plaques using Q-switched ruby laser or the frequency-doubled Q-switched neodymium YAG laser.624 Removal of the background pigmentation is less predictable. Reports indicate that 1–7 treatments are needed for maximum improvement or clearance.623

Lentigines Lentigines can also be treated with the Q-switched ruby, and frequency-doubled neodynium YAG.625,626 Similar efficacy is noted with both of these lasers and results are preferable to those obtained with liquid nitrogen.626 Children with Peutz–Jeghers, Laugier–Hunziker syndrome, or other multiple lentigines syndromes can be effectively treated with these lasers. Patients with pigmented skin are at increased risk of post-inflammatory hyperpigmentation that can be very persistent. It has been hypothesized that the photomechanical effect of the Q-switched lasers may contribute to this persistent pigmentation in Asian patients.626 The long-pulse 532 nm Nd:YAG had a lower incidence of pigmentary abnormalities than the Q-switched version of this laser in one study.627 Intense pulsed light sources have

621. Idorn LW, Hædersdal M. Paradoxical postoperative hyperpigmentation from Q-switched YAG laser treatment of pigmented lesions in children with fair skin types. J Eur Acad Dermatol Venereol. 2009;23:856–857. 622. Weinberg JM, Schutzer PJ, Harris RM, et al. Melanoma arising in nevus spilus. Cutis. 1998;61:287–289. 623. Graeme LM, Anderson RR. Lasers in dermatology. 6th ed. New York: McGraw-Hill; 2003:2493–2509. 624. Tse Y, Levine VJ, McClain SA, et al. The removal of cutaneous pigmented lesions with the Q-switched ruby laser and the Q-switched neodymium:yttrium aluminum-garnet laser. J Dermatol Surg Oncol. 1994;20:795–800. 625. Todd MM, Rallis TM, Gerwels JW, et al. A comparison of 3 lasers and liquid nitrogen in the treatment of solar lentigines: a randomized, controlled, comparative trial. Arch Dermatol. 2000;136:841–846. 626. Chan HH, Kono T. The use of lasers and intense pulsed light sources for the treatment of pigmentary lesions. Skin Therapy Lett. 2004;9:5–7. 627. Chan HH, Fung WKK, Ying Sy, et al. An in vivo trial comparing the use of different types of 532 nm Nd:YAG lasers in the treatment of facial lentigines in Oriental patients. Dermatol Surg. 2000;26:743–749. 628. Kawada A, Shiraishi H, Asai M, et al. Clinical improvement of solar lentigines and ephelides with an intense pulsed light source. Dermatol Surg. 2002;28:504–508.

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Congenital nevi The treatment of congenital nevi with laser is controversial. Congenital nevi of all sizes have an increased risk of malignant melanoma. Treatment with lasers alters the clinical appearance of these nevi by lightening or removing the superficial cutaneous pigment without destroying the melanocytes deeper within the skin. Histologic evidence of persistent melanocytes has been demonstrated following laser treatment with the normal-mode ruby laser, the QS ruby laser, and the QS neodymium YAG laser (1064 nm).629,630 Moreover, recurrence of pigmentation occurs in most treated lesions.630 Laser therapy of congenital nevi carries the risk of altering the clinical appearance of the nevus in a manner that may lead to the delayed recognition of malignant change. Laser does not remove the malignant risk, since there is histologic evidence that even in the absence of clinically detectable pigmentation following laser, S-100, HMB-45 and Massonpositive cells persist deep in the dermis and around adnexal structures.631 The separate issue of whether or not laser surgery can impact the risk of malignant transformations has not yet been determined.553 For these reasons, the author feels that superficial laser treatment of congenital nevi in pediatric patients is contraindicated. The treatment of choice for these lesions is surgical excision. A small subset of patients have large congenital nevi that are in locations, such as the central face, where they are inoperable. Recently, investigators in Europe have attempted to reduce the melanocytic load in these patients, while improving cosmesis with a resurfacing laser. The Er:YAG laser was used in neonates in the first weeks of life with minimal postoperative complications. Follow-up at 36 months showed little or no repigmentation.632–634 Multiple other modalities have been attempted in patients like this, including dermabrasion, curettage, chemical peeling, cryosurgery and CO2 laser dermabrasion.632 The sideeffect profile of Er:YAG laser appears preferable to these other modalities.

629. Duke D, Byers HR, Sober AJ, et al. Treatment of benign and atypical nevi with the normal-mode ruby laser and the Q-switched ruby laser: clinical improvement but failure to completely eliminate nevomelanocytes. Arch Dermatol. 1999;135:290–296. 630. Waldorf HA, Kauvar AN, Geronemus RG. Treatment of small and medium congenital nevi with the Q-switched ruby laser. Arch Dermatol. 1996;132:301–304. 631. Kopera D, Hohenleutner U, Stolz W, et al. Ex vivo quality-switched ruby laser irradiation of cutaneous melanocytic lesions: persistence of S-100-, HMB-45- and Masson-positive cells. Dermatol. 1997;194:344–450. 632. Ostertag JU, Quaedvlieg PJ, Kerchoffs FE, et al. Congenital naevi treated with erbium:YAG laser (Derma K) resurfacing in neonates: clinical results and review of the literature. Br J Dermatol. 2006;154:889–895. 633. Ostertag JU, Quaedvlieg PJ, Kerchoffs FE, et al. Congenital naevi treated with erbium: YAG laser (Derma K) resurfacing in neonates: clinical results and review of the literature. Br J Dermatol. 2006;154:889–895. 634. Rajpar SF, Abdullah A, Lanigan SW. Er:YAG laser resurfacing for inoperable medium-sized facial congenital melanocytic naevi in children. Clin Exp Dermatol. 2007;32:159–161.

Surgical techniques

A Becker nevus is a hamartoma of smooth muscle that develops in adolescence. It occurs more frequently in males than females (4 : 1) and is typically a unilateral, hyperpigmented patch on the shoulder, anterior chest or scapular region with hypertrichosis. Smooth muscle hamartoma is considered by most to be the congenital variant of this benign entity. Successful treatment of Becker nevus requires two separate laser systems. The greatest success has been attained using a combination of the long-pulsed ruby laser which penetrates to the deeper hair follicles, eliminating the hypertrichosis followed by Q-switched ruby laser to target the epidermal pigment that persists.613,620 The frequency-doubled neodymium YAG laser also improves the appearance of this lesion, but the superficial penetration of the laser does not allow for effective treatment of the hypertrichosis.624 and the risk of recurrence is higher since the pigmented keratinocytes and melanocytes of the deep hair follicle act as a reservoir for repigmentation. Theoretically, this system could be combined with the long-pulsed alexandrite but no studies have yet been done looking at these two lasers in combination.

Epidermal nevus Epidermal nevi are benign hamartomas of the epidermis. They are usually congenital, but delayed appearance and extension throughout the early childhood years are common. Typical lesions are flat and velvety at birth with gradual increase in thickness and hyperpigmentation with time. The most dramatic changes are usually noted around adolescence when filiform and warty papules develop in many patients. Lesions are mostly symptomatic in the intertriginous areas where the thickened plaques harbor bacteria and become malodorous. For solitary small plaques, or symptomatic lesions such as the inflamed linear verrucous epidermal nevus (ILVEN) variant, surgical resection is often the treatment of choice and the small scar that results is usually considered a good trade by the pediatric patient.635 In symptomatic areas like the axilla where thickening of these lesions is more problematic, superficial shave resection can be an effective way to flatten the lesions without the risk of contracture from full-thickness scars over a joint. For larger areas, this is not practical. Unfortunately, laser therapy of epidermal nevi has not been very successful. Recurrence is common and scarring is a frequent side-effect.613 The thickness of the lesion usually precludes effective use of the Q-switched laser systems that do not penetrate deeply enough into the skin to eradicate the lesion. The newer

635. Lee BJ, Mancini AJ, Renucci J, et al. Full-thickness surgical excision for the treatment of inflammatory linear verrucous epidermal nevus. Ann Plast Surg. 2001;47:285–292. 636. Losee JE, Serletti JM, Pennino RP. Epidermal nevus syndrome: a review and case report. Ann Plastic Surg. 1999;43:211–214. 637. Kang W, Lee E, Choi GS. Treatment of Ota’s nevus by Q-switched alexandrite laser: therapeutic outcome in relation to clinical and histopathological findings. Eur J Dermatol. 1999;9:639–643. 638. Kono T, Nozaki M, Chan HH, et al. A retrospective study looking at the long-term complications of Q-switched ruby laser in the treatment of nevus of Ota. Lasers Surg Med. 2001;29:156–159. 639. Kono T, Chan HH, Ercocen AR, et al. Use of Q-switched ruby laser in the treatment of nevus of Ota in different age groups. Lasers Surg Med. 2003;32:391–395.

pulsed and scanned CO2 and erbium:YAG resurfacing lasers allow for more precise control of the depth of tissue ablation.636 This reduces the risk of scarring, but also results in a higher rate of recurrence than the older continuous wave CO2 and argon lasers. Most authors recommend use of the Er:YAG infrared resurfacing laser.553 This system has less risk of hypopigmentation than the CO2 resurfacing laser. Test areas are recommended prior to treatment of the entire lesion to ensure that any pigmentary alteration is acceptable. The object is to flatten the lesions so it can be more easily camouflaged. Treatment of localized recurrences is expected and patients should be warned of the possible need for additional procedures.

Nevus of Ota and Ito Nevus of Ota (nevus fuscoceruleus ophthalmomaxillaris) is the presence of deep dermal melanocytosis, typically in an irregular patch along the distribution of the first and second divisions of the trigeminal nerve. Patchy blue-gray or greenish pigmentation elsewhere on the skin (excluding the transient Mongolian spots seen in pigmented races) is termed nevus of Ito. In both cases, lesions can be congenital or acquired and histologically demonstrate pigment laden, spindle-shaped dendritic melanocytes deep in the dermis.637 Laser treatment of nevus of Ota is accomplished with Q-switched lasers that have longer wavelengths to target the dermal melanin. Early studies demonstrated the efficacy of the Q-switched ruby laser in effective treatment of these lesions. Typically, several treatments (3–7) at 4–8 week intervals are required. A retrospective study of long-term complications of treatment with this laser demonstrated a 16.8% incidence of persistent hypopigmentation and a 5.9% incidence of persistent hyperpigmentation. Recurrence of the lesion was noted in only 1% of treated patients.638 Use of this laser for the treatment of nevus of Ota in children has been shown to achieve excellent results in fewer treatment sessions than adults and with a lower complication rate.639 Early treatment of these lesions is therefore recommended.626 The Q-switched alexandrite and neodymium YAG (1064 nm) are also effective in the treatment of nevus of Ota.640,641 Chan has demonstrated a slightly increased efficacy of the QS-neodymium YAG over the QS-alexandrite but a patient preference for use of the QS-alexandrite, a difference which may be more relevant in pediatric patients.642,643 Transient hyperpigmentation is noted in 50% of patients lasting 4–6 months that is usually treated with hydroquinone and tretinoin cream.640 Persistent hypopigmentation and hyperpigmentation were seen in 3% of patients treated with both lasers. Texture changes and

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

Becker nevus

5

640. Lam AY, Wong DS, Lam LK, et al. A retrospective study on the efficacy and complications of Q-switched alexandrite laser in the treatment of acquired bilateral nevus of Ota-like macules. Dermatol Surg. 2001;27:937–942. 641. Chan HH, Leung RS, Ying SY, et al. A retrospective analysis of complications in the treatment of nevus of Ota with the Q-switched alexandrite and Q-switched Nd:YAG lasers. Dermatol Surg. 2000;26:1000–1006. 642. Chan HH, Ying SY, Ho WS. An in vivo trial comparing the clinical efficacy and complications of Q-switched 755 nm alexandrite and Q-switched 1064 nm Nd:YAG lasers in the treatment of nevus of Ota. Dermatol Surg. 2000;26:919–922. 643. Chan HH, King WW, Chan ES, et al. In vivo trial comparing patients’ tolerance of Q-switched Alexandrite (QS Alex) and Q-switched neodymium:yttrium-aluminum-garnet (QS Nd:YAG) lasers in the treatment of nevus of Ota. Lasers Surg Med. 1999;24:24–28.

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scarring occurred in 2.9% and 1.9%, respectively.641 The risk of recurrence is estimated to be between 0.6% and 1.2%.626 Incomplete and poor responses are noted in a significant number of patients (10–20%). Some authors feel that this is related to the color of the lesions with browner lesions responding better than more violaceous lesions.623,644 Others feel that response to laser treatment is determined by the depth of pigment rather than the color, with lesions containing melanocytes to the depth of 1 mm or less achieving the best results.637

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

COLOR OF SOURCE

LASER OPTIONS

SIDE-EFFECTS

Traumatic

Q S ruby, alexandrite or Nd:YAG (1064)

Microexplosions if made from gun powder

Black, blue, dark brown

Q S ruby, alexandrite or Nd:YAG (1064)

Tattoos

Green

Q S ruby, alexandrite

Allergic reaction to chromium

An increasing number of pediatric patients are obtaining tattoos in late adolescence and early adulthood as ‘body-art’ continues to gain popularity. Studies of adults who return for tattoo removal have shown that most obtained their tattoos impulsively and cite poor decision making and personal regret as their main reasons for seeking removal.645 This highlights the importance of educating adolescents to dissuade them from tattoo placement. Tattoo removal is painful, costly and frequently incomplete and accompanied by undesirable scarring. It is important to emphasize these facts to our adolescents whom we see for unrelated issues. Traumatic tattoos are the most common form of tattoo encountered in younger pediatric patients. Tattoo with lead from pencils, or foreign body materials such as metal, glass, dirt, sand, and asphalt are common. Pencil point tattoos typically clear with one treatment with QS ruby, QS alexandrite or QS neodymium YAG.646,647 More treatments are needed for most other forms of traumatic tattoo removal but all of these lasers have demonstrated effective treatment. Decorative tattoos are more difficult to remove than most traumatic tattoos. Amateur tattoos are usually easier to treat since they generally consist of a single pigment at variable depths in the skin.402,648 Older tattoos are also easier to clear probably due to the migration of pigment particles deeper into the skin or out of the dermis by the action of phagocytic cells.626 For professional decorative tattoos many treatments are generally required. Quantitative chemical analysis of professional tattoo pigments found that the most common elements were aluminum, titanium, and carbon. Poor response to treatment relates to the overrepresentation of titanium in the tattoo ink.626 When tattoos are lasered, the pigment specific laser injury alters the tattoo ink particle which stimulates phagocytosis by macrophages and slow removal of the pigment from the skin.402 In recent prospective trials of the QS Nd:YAG (532 and 1064 nm) versus the QS ruby laser and QS alexandrite laser in the treatment of decorative tattoos, the QS ruby produced the greatest degree of lightening.649,650 However, treatment with this laser is also associated

Red, orange, yellow, violet, white, tan

Q S Nd:YAG (532), pigment PDL (510)

Tattoo rack darkening Allergic reactions (mercury sulfide, azo dyes, cadmium)

644. Ueda S, Isoda M, Imayama S. Response of naevus of Ota to Q-switched ruby laser treatment according to lesion colour. Br J Dermatol. 2000;142:77–83. 645. Armstrong ML, Stuppy DJ, Gabriel DC, et al. Motivation for tattoo removal. Arch Dermatol. 1996;132:412–416. 646. Knoell KA, Schreiber AJ, Kutenplon M, et al. Q-switched ruby laser treatment of traumatic tattooing induced by pencil point puncture in children. Pediatr Dermatol. 1997;14:325–326. 647. Kilmer SL. Laser eradication of pigmented lesions and tattoos. Dermatol Clin. 2002;20:37–53. 648. Alster TS, ed. Laser treatment of tattoos. In: Manual of cutaneous laser techniques. Philadelphia: Lippincott-Raven; 1997:64–68.

274

Table 5.9  Lasers for tattoo removal

All laser treatments can result in hypo-pigmentation. All Type IV–VI skin should be treated with Nd:YAG (1064 nm) only to avoid pigment alteration.

with a higher risk of permanent hypopigmentation and textural changes. This is especially true in darkly pigmented patients who should optimally be treated with the QS Nd:YAG to minimize side-effects. Although the QS ruby laser is the most effective overall in removing decorative tattoos, the laser of choice depends to some degree on the colors present in the tattoo. Black pigment absorbs red and infrared light well, so any one of the Q-switched lasers (775 nm alexandrite, 694 nm ruby or 1064 nm Nd:YAG) will be effective.651 Blue and green ink absorbs best in the 600– 800 nm range (Q-switched ruby or alexandrite), and yellow, orange, and red ink absorbs best in the green light range (532 nm frequency-doubled Nd:YAG) (Table 5.9). In general, yellow and orange pigment are the most difficult to remove because they absorb minimally at any of the commercially available laser wavelengths. Green pigment is also very difficult to remove despite the use of the Q-switched ruby laser, where it absorbs energy well. This is felt to be an inherent quality of the ink mixture.623 To improve clinical outcome in tattoo removal, the external application of magnets has been used to facilitate the removal of magnetite skin tattoos after Q-switched laser.652 The use of intradermal focusing to the Q-switched laser treatment is also being developed.653 Complications of laser removal of tattoos are frequent. Transient or long-lasting hypopigmentation, transient postinflammatory hyperpigmentation, textural changes and atrophic

649. Goyal S, Arndt KA, Stern RS, et al. Laser treatment of tattoos: a prospective, paired, comparison study of the Q-switched Nd:YAG (1064 nm), frequency doubled Q-switched Nd:YAG, and Q-switched ruby lasers. J Am Acad Dermatol. 1997;36:122–125. 650. Leuenberger ML, Mulas MW, Hata TR, et al. Comparison study of the Q-switched alexandrite, Nd:YAG, and ruby lasers in treating blue-black tattoos. Dermatol Surg. 1999;25:10–14. 651. Bailin PL, Ratz JL, Levine HL. Removal of tattoos by CO2 laser. J Dermatol Surg Oncol. 1980;6:997. 652. Huzaira M, Anderson RR. Magnetite tattoos. Lasers Surg Med. 2002;31:121–128. 653. Hu XH, Wooden WA, Vore SJ, et al. In vivo study of intradermal focusing for tattoo removal, Lasers Med Sci. 2002;17:154–164.

Surgical techniques

Laser hair removal Unfortunately, the amount and distribution of hair play an important role in the cultural definition of beauty. Having plentiful scalp hair is desirable. Conversely, the presence of hair on the face, axillae and legs is often deemed socially unacceptable in women. Adolescents are often severely emotionally distressed by the presence of excessive hair in certain body regions and seek advice about hair removal.652 The pediatric dermatologist is wise to keep abreast of the rapid progress in laser technology that is ongoing, as this cosmetic market is being aggressively developed by laser companies. Traditional approaches to hair removal have been primarily temporary. Shaving, plucking, waxing, chemical depilatories, and bleaching remain the methods used most frequently by adolescents to control unwanted hair growth. Electrolysis, the use of a direct current or electrothermolysis, the use of a radio­ frequency current, were the only methods available to provide permanent hair removal prior to the use of laser systems. Unfortunately, these techniques were inconvenient, painful, operatordependent and carried a significant risk of scarring. In addition, they were impractical for removal of large numbers of hair. Improved hair removal can now be provided with the use of lasers and intense pulsed light sources, but there remains little scientific evidence that any of the currently available systems is effective in permanent hair removal for the majority of patients. Aggressive marketing has led to public belief that this is a reasonable goal and many adolescents approach laser treatment with false expectations of treatment outcome. It is the pediatric dermatologist’s job to ensure that the expectation of the patient

654. Olsen EA. Methods of hair removal. J Am Acad Dermatol. 1999;40:143–155. 655. Dierickx C, Aora MB, Dover JS. A clinical overview of hair removal using lasers. Dermatol Clin. 1999;17:357–366. 656. Goldberg DJ. Laser hair removal. Dermatol Clin. 2002;20:561–567. 657. Morley S, Gault D. Hair removal using the long-pulsed ruby laser in children. J Clin Laser Med Surg. 2000;18:277–280.

is consistent with the limitations of currently available treatments. Adolescents seeking permanent hair removal should be informed that long-standing hair removal is only possible for patients with dark hair. Moreover, those patients with dark hair and dark skin are unlikely to achieve good results since the target of most laser systems is melanin, and the use of sufficient energy to permanently destroy the hair follicles in these patients can cause permanent injury to the skin pigment. Individuals with blonde, red, gray or white hair should understand that laser treatment is unlikely to effect permanent hair removal. If the adolescent is willing to undergo repeat laser treatments at 2–4 month intervals, temporary hair removal is attainable and may be a more acceptable alternative to traditional hair removal methods. Even for those ideal patients with dark hair and light skin, treated at high fluences (>30 J/cm2) using a large spot size (7 mm diameter), the average long-term hair loss per treatment is only 20–30%.653–656 There are multiple hair removal systems now commercially available and FDA approved for hair removal. Table 5.10 lists the properties of the currently available systems. No one system is optimal for removal of hair in all patients. The most effective hair removal lasers target melanin found in the melanosomes. When laser energy is absorbed, heat is released that injures the hair follicle preventing hair growth.657 The long-pulsed ruby (694 nm, 2 ms), the long-pulsed alexandrite (755 nm, 3–20 ms) and the diode (810 nm, 50–250 ms) have wavelengths and pulse durations targeted to melanin in the hair bulb and shaft. A study of hair removal in children using the long-pulsed ruby laser demonstrated suppression of hair growth lasting 3–6 months that was well tolerated.657 More recently, hair removal in children using the long-pulsed alexandrite and long-pulsed Nd:YAG was reported with minimal side-effects.401 Children that had skin types I–IV were treated with the alexandrite and those with skin types IV–VI were treated with the Nd:YAG. Intolerable discomfort requiring reduction of the laser fluence was the only reported side-effect with no dyspigmentation, infection, blistering or scarring reported. The Nd:YAG laser (1064 nm, 5–18 ms) has insufficient melanin absorption to provide for permanent hair removal. It does offer the advantage of safety for patients with pigmented skin. Typical delay in hair regrowth with this laser is 3–6 months.658 Intense pulsed light systems have also been reported to be effective in hair removal.652 Like the Nd:YAG, this system has fewer side-effects and is a better choice for patients with pigmented skin. The long pulsed alexandrite and diode lasers are preferable to the long-pulsed ruby in this patient population. Side-effects of hair removal include redness and edema of the hair follicles and surrounding skin, and occasional pigmentary alterations or even scarring if high fluences are used.659 Optical hair removal is painful and adolescents should be prepared for discomfort when they seek this treatment.

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

scarring can be seen.648 Immediate post-treatment pigment darkening may occur in tattoos with skin-colored tones containing iron or titanium dioxide through reduction of ferric oxide to ferrous oxide. This darkening can be very difficult to remove.613 Repeated Q-switched laser treatment and the use of a resurfacing laser may be necessary to rectify this pigmentation.626 Prior to the development of pigment-selective lasers, the carbon dioxide laser (10 600 nm) was used in the treatment of tattoos.651 This non-specific laser targets intra- and extracellular water and vaporizes tissue. In the defocused mode, many benign cutaneous lesions including warts, epidermal nevi, vascular lesions, and adenoma sebaceum were frequently treated with this destructive laser. Injury from this laser always produces scarring and healing, especially on the lower extremities, where it was used to treat plantar warts, was prolonged and painful. It did not prevent recurrence of these lesions. The use of this laser in the pediatric population is inappropriate. There is no benign cutaneous lesion for which there is not an alternative laser or excisional therapy that has a better outcome. Use of this laser should be limited to the second-line treatment of lesions resistant to these better therapies with a full discussion of the scarring that will likely result.

5

658. Nanni CA, Alster TS. A practical review of laser-assisted hair removal using the Q-switched Nd:YAG, long-pulsed ruby, and long-pulsed alexandrite lasers. Dermatol Surg. 1998;24:1–7. 659. Verplancke P, Beele H, Monstrey S, et al. Treatment of dystrophic epidermolysis bullosa with autologous meshed split-thickness skin grafts and allogeneic cultured keratinocytes. Dermatology. 1997;194:380–382.

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Table 5.10  Hair removal lasers and light-based devices TYPE

WAVELENGTH (NM)

PULSE DURATION (MS)

FLUENCE (J/CM2)

SPOT SIZE (MM) 7–10

EpiLaser

755

2

5–50

5–10

EpiTouch Alex

Ruby laser Alexandrite laser

COMMERCIAL NAME

COMMENTS

Fast

3

10–100

7–15

Gentle lase

Slow

5, 10, 20

5–20

7–10

PhotoGenic a LPIR

Requires multiple pulses

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

Diode laser

800

5–30

10–40

9×9

Light Sheer

Fewer side-effects

NeodyniumYAG

1064

10–20

2–3

7–10

SoftLight

? Permanent hair removal; carbon solution unnecessary, less painful, less skin pigmentation injury

400–1200

2.5–100

10–150

10×45

EpiLight

Slow

Intense pulsed Light source Flashlamp

Multiple pulses Operator experience Need for efficiency May be safe for dark skin

Satisfaction with therapy is possible, but only with realistic expectations.

TISSUE EXPANDERS

276

A relatively new technique, known as tissue expansion, uses the gradual expansion of normal skin and soft tissue adjacent to a birthmark to develop excess skin for the repair of an anticipated defect.660,661 This technique uses one or more sterile inflatable silicone bags placed beneath the adjacent normal skin surface near the anticipated surgical site or defect. Each expander, which is capable of massive inflation two or three times its normal volume, its attached to a self-sealing injection port by way of silicone tubing. After an incision is made under general anesthesia, the expander is placed in proper position and the wound is sutured closed (Fig. 5.33). Once this heals, usually after 7–10 days, the expansion process can begin. At weekly intervals, sterile saline is injected without anesthesia into the buried injection port. This can be accomplished painlessly with the application of topical anesthetic cream to the skin surface overlying the injection port. The volume injected is dependent on the anatomic location and size of the expander. Usually the quantity injected at each visit is 10–20% of the total volume of the expander. This sequential injection process gradually expands the silicone bag and results in a slow stretching of the overlying soft tissue and skin to accommodate the increase in size in a manner analogous to the expansion of skin that occurs during pregnancy. This injection and expansion process is continued until sufficient excess soft tissue has been created to cover the proposed surgical defect. In most cases, this can be accomplished within 6–8 weeks.

This process stimulates the growth of new skin from the adjacent normal tissue. The resulting advancement flap that is created provides an ideal color-and-texture match with the surrounding skin, while maintaining normal sensation. Prior to the development of this technique, wounds that could not be closed primarily or with a reasonable number of staged excisions were closed with either skin grafts or local cutaneous flap

660. Unlu RE, Sensöz O, Uysal AC. Re: the use of serial tissue expansion in pediatric plastic surgery. Ann Plast Surg. 2001;47:679.

661. Rivera R, LoGiudice J, Gosain AK. Tissue expansion in pediatric patients. Clin Plast Surg. 2005;32:35–44.

Figure 5.33  Tissue expansion for excision of a large congenital nevus of the scalp.

Surgical techniques

surgery. The former was a poor color and texture match and the latter was limited by the anatomy of the area and usually resulted in sensation alteration. In addition, tissue expansion eliminates the secondary defect created by a skin graft donor site and the resultant care of the donor site. The expanded tissue is sufficient to cover both the primary and secondary defects at one time. Expanders are especially optimal in areas like the scalp where hair-bearing tissue can be expanded in a similar fashion. Expanded scalp skin, unlike skin grafts, is hairbearing and much larger areas can be replaced than with local flaps with excellent hair coverage and with fewer scars and less trauma to the underlying hair follicles. Tissue expanders provide an excellent cosmetic result not obtainable with either skin grafts or flaps for treatment of scalp defects. Placement of tissue expanders in children is generally accomplished with an outpatient anesthetic. Tension on the wound from placement of the expanders minimizes postoperative bleeding. Rarely, drains are placed and removed after several days. Most patients go home within hours of the surgery and resume normal activities avoiding trauma to the areas. All expansion injections are carried out in a painless manner with topical anesthetic cream placed over the injection port 1 hour before the time of injection. This procedure has been successfully employed in the treatment of burn wounds, removal of large congenital nevi,662,663 nevus sebaceus, aplasia cutis, hemangiomas,664 lymphangiomas, linear epidermal nevi,665 and scarring alopecia. Serial expansions can be performed to allow for removal of extremely large lesions covering large areas of the trunk and extremities. Since pre-expanded skin is under less tension, scars heal with minimal spreading. The uses for tissue expansion continue to be expanded. Tissue expanders should not be used where primary closure in one or two stages is possible. The complication rate of tissue expansion is not insignificant. The most common complications are infection 6%, deflation 3% and exposure 2%.666 Complications are greatest in older patients, burn patients, with the use of internal expander ports and for serial expansion patients.667 Lower extremity lesions have the highest rate of complication.666

Even when complications occur, however, further expansion and successful reconstruction are still possible. One recent retrospective review of over 215 children who underwent tissue expansion reported successful treatment of the diagnosed wound infection without removal of the expander in 13 of 16 children in whom infection occurred.668 Good outcomes are dependent on meticulous technique, close follow-up and patient compliance. Infants and young children are ideal candidates for expansion. Older children have higher complication rates and should be expanded when not in school to avoid significant psychologic trauma. The use of tissue expansion has revolutionized the approach to giant congenital nevi in pediatric patients.663

662. Bauer BS, Few JW, Chavez CD, et al. The role of tissue expansion in the management of large congenital pigmented nevi of the forehead in the pediatric patient. Plast Reconstr Surg. 2001;107:668–675. 663. Bauer BS, Corcoran J. Treatment of large and giant nevi. Clin Plast Surg. 2005;32:11–18. 664. Chang CJ, Achauer BM, VanderKam VM. Reconstruction of head and neck hemangiomas with tissue expansion in the pediatric population. Ann Plast Surg. 1997;38:15–18. 665. Lee BJ, Mancini AJ, Renucci J, et al. Full-thickness surgical excision for the treatment of inflammatory linear verrucous epidermal nevus. Ann Plast Surg. 2001;47:285–292. 666. LoGiudice J, Gosain AK. Pediatric tissue expansion: indications and complications. J Craniofac Surg. 2003;14:866–872. 667. Friedman RM, Ingram AE Jr, Rohrich RJ, et al. Risk factors for complications in pediatric tissue expansion. Plast Reconstr Surg. 1996;98:1242–1246. 668. Adler N, Dorafshar AH, Bauer BS, et al. Tissue expander infections in pediatric patients: management and outcomes. Plast Reconstr Surg. 2009;124:484–489. 669. Gosain AK, Santoro TD, Larson DL, et al. Giant congenital nevi: a 20 year experience and an algorithm for their management. Plast Reconstr Surg. 2001;108:622–636. 670. Chung C, Forte AJ, Narayan D, et al. Giant nevi: a review. J Craniofac Surg. 2006;17:1210–1215.

671. Arneja JS, Gosain AK. Giant congenital melanocytic nevi of the trunk and an algorithm for treatment. J Craniofac Surg. 2005;16:886–893. 672. Warner PM, Yakuboff KP, Kagan RJ, et al. An 18-year experience in the management of congenital nevomelanocytic nevi. Ann Plast Surg. 2008;60:283–287. 673. Organek AJ, Klebuc MJ, Zuker RM. Indications and outcomes of free tissue transfer to the lower extremity review. J Reconstr Microsurg. 2006;22:173–181. 674. Kaźmierski M, Mańkowski P, Jankowski A, et al. Comparison of the results of operative and conservative treatment of deep dermal partial-thickness scalds in children. Eur J Pediatr Surg. 2007;17:354–361. 675. Herlin C, Louhaem D, Bigorre M, et al. Use of Integra in a paediatric upper extremity degloving injury. J Hand Surg Eur Vol. 2007;32:179–184. 676. Fujimori Y, Ueda K, Fumimoto H, et al. Skin regeneration for children with burn scar contracture using autologous cultured dermal substitutes and superthin auto-skin grafts: preliminary clinical study. Ann Plast Surg. 2006;57:408–414. 677. Whitaker IS, Prowse S, Potokar TS. A critical evaluation of the use of Biobrane as a biologic skin substitute: a versatile tool for the plastic and reconstructive surgeon. Ann Plast Surg. 2008;60:333–337. 678. Supp DM, Boyce ST. Engineered skin substitutes: practices and potentials. Clin Dermatol. 2005;23:403–412. 679. Earle SA, Marshall DM. Management of giant congenital nevi with artificial skin substitutes in children. J Craniofac Surg. 2005;16:904–907.

5

SKIN GRAFTS SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

Skin grafting is not a common procedure performed by officebased dermatologic surgeons, especially when treating children. However, a brief review of the various skin grafting techniques may serve as useful information for the physician caring for patients who may require this type of procedure for the correction of some cutaneous condition or defect. Skin grafts are used to provide closure of those defects where primary closure cannot be accomplished because of size or limited quantity of adjacent tissue. With the advent of tissue expansion techniques, the need for skin grafting has been markedly reduced in the pediatric population. The most common uses for skin grafts include removal of giant congenital nevi,669–672 removal of large nevi or other tumors on the lower extremities,673 and removal of nevi or other tumors or the treatment of burns of the hands, feet, post-auricular scalp or ears. Grafts may also be used to protect deeper underlying structures from desiccation or to prevent contraction of soft tissues on the extremities. Occasionally, they provide a means of wound healing in severely ulcerated skin areas from scalding or burn injury.674 Split-thickness skin grafts are used most often to repair larger defects resulting from ablative surgery, burns, or other injuries. Tissue expansion techniques together with composite grafts of human skin equivalent have markedly reduced the need for these procedures in young children.675–679

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Split-thickness grafts

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

278

placed. Meshed grafts can be used to double, triple, or increase the surface even ninefold over the original size of the splitthickness skin graft. While the cosmetic appearance from this process is inferior to that obtained with a regular split-thickness graft, it does permit coverage of large areas with greater ease and will generally improve satisfactorily with time. When large defects are present, ultra-thin or meshed splitthickness grafts can be used in combination with artificial skin.679 Non-healing skin defects in dystrophic epidermolysis bullosa have been successfully treated with a combination of autologous meshed split-thickness grafts from the non-involved skin that was covered with allogeneic keratinocytes.685 More recently, tissue-engineered skin alone has been successfully used in these patients with improved cosmesis obviating further the need for split-thickness grafts.686,687

The traditional split-thickness skin graft employs the use of a sharp knife, or dermatome, to remove large thin sheets of tissue.680 One instrument, the Davol dermatome, is a rechargeable battery-powered dermatome that will harvest mediumthickness grafts of 0.015 inch in thickness and 1 516 inch in width. This is frequently adequate for the treatment of many dermatologic conditions. Other instruments used to harvest split-thickness skin grafts include the Brown and Padgett dermatomes; these electrically powered machines are capable of harvesting grafts of variable thickness and width. Regardless of the instrument chosen, the technique used to harvest split-thickness grafts is essentially the same. The donor site may be any part of the body, but most commonly, the anterior thigh, buttocks, abdomen, and back are used. After infiltration with a local anesthetic agent, the area to be removed is coated with mineral oil or sterile surgical ointment to facilitate the harvesting of tissue. For larger grafts, tumescent anesthesia may offer a benefit, especially in children where the amount of local anesthetic that can be safely administered is limited.681 A graft of suitable length and width is cut using a dermatome. It is then laid into the recipient area and sewn or stapled into place and covered with a suitable dressing, to immobilize it and prevent shearing forces that could disrupt the new blood vessels that are growing into the graft.682 The donor site is covered with a synthetic surgical dressing and allowed to heal by second intention. Most split-thickness skin grafts develop a sufficient vascular supply within 2 weeks to permit limited function by the patient. Over a period of several months, the graft gradually begins re­ pigmenting to provide a more satisfactory cosmetic result. Since the texture of a split-thickness graft almost never is an ideal match with the normal skin, and the sensation of the graft is abnormal, this type of graft may always remain visible and produce cosmetic difficulties. Recently, a technique has been developed to improve the color of skin flaps and grafts on the face. A thin, split-thickness skin graft of scalp epidermis was overgrafted onto the surface of facial flaps and grafts in 15 patients with significant improvement in the color match and aesthetics of the transplanted skin. This technique may improve the color aesthetics when grafts are necessary in pediatric patients in cosmetically important areas, such as the face.683 In cases in which a large defect is present, like a burn wound in a small child or infant, and there is only a limited amount of donor area available, meshed split-thickness grafts are often used.684 The mesher mechanically cross-hatches a standard splitthickness skin graft to increase the area over which it can be

Full-thickness skin grafts are used to cover small defects that cannot be closed primarily without creating tension on the wound edges or distorting the adjacent normal anatomy. This type of graft has a much higher nutritional requirement and has a higher failure rate than that of split-thickness grafts. However, since a full thickness of soft tissue is transferred from one site to another, the improved color, texture, and presence of appendageal structures will normally provide an improved cosmetic result over that obtained with other grafts.688,689 The key to performing ideal full-thickness skin grafting is the proper selection of the donor tissue.682,690,691 The closer the donor site resembles the recipient site in color, texture, hair, and sebaceous gland activity, the better will be the final cosmetic result. With that in mind, the surgeon can select the best possible match from a number of available donor sites. The most common sites used for this purpose include the supraclavicular area, pre- and postauricular skin, upper eyelid, glabella, posterior neck, inguinal fold, and antecubital fossa. It is crucial to remember that skin taken from below the mammary line will not blush when placed on the face. As a consequence of this, if the primary defect is located on the face, the best donor site should be superior to this line. The technique for full-thickness skin grafting begins with the creation of a template that is based upon the actual size of the defect. Since some shrinkage of the graft is expected after harvesting, the template is placed on the appropriate donor tissue and a fusiform excision is designed to remove an adequate amount of tissue that can be used as the graft. Once the excision has been made, the graft is defatted and cut to fit the size of the defect

680. Beer GM, Widder W, Cierpka K, et al. Malignant tumors associated with nevus sebaceous: therapeutic consequences. Aesthet Plast Surg. 1999;23:224. 681. Field LM, Hrabovszky T. Harvesting split-thickness grafts with tumescent anesthesia. Dermatol Surg. 1997;23:62. 682. Rudolph R, Fisher JC, Ninnemann JL. Skin grafting. Boston: Little Brown; 1979. 683. Walton RL, Cohn AB, Beahm EK. Epidermal overgrafting improves coloration in remote flaps and grafts applied to the face for reconstruction. Plast Reconstr Surg. 2008;121:1606–1613. 684. Kirsner RS, Eaglstein WH, Kerdel FA. Split-thickness skin grafting for lower. 1997. 685. Verplancke P, Beele H, Monstrey S, et al. Treatment of dystrophic epidermolysis bullosa with autologous meshed split-thickness skin grafts and allogeneic cultured keratinocytes. Dermatol. 1997;194:380–382.

686. Falabella AF, Valencia IC, Eaglstein WH, et al. Tissue engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds. Arch Dermatol. 2000;136:1225. 687. Phillips J, Rockwell WB. Surgical treatment of recessive dystrophic epidermolysis bullosa in the hand: use of tissue-engineered skin (Apligraf). Ann Plast Surg. 2003;50:441–442. 688. Ratner D. Skin grafting. From here to there. Dermatol Clin. 1998;16:75–90. 689. Valencia IC, Falabella AF, Eaglstein WH. Skin grafting. Dermatol Clin. 2000;18:521–532. 690. Harley S, Walsh N. A new look at nevus-associated melanomas. Am J Dermatopathol. 1996;18(2):137–141. 691. Gloster HM Jr. The use of full thickness skin grafts to repair nonperforating nasal defects. J Am Acad Dermatol. 2000;42:1041–1050.

Full-thickness grafts

Surgical techniques

precisely. It is then sutured into place, and a large immobilizing bulky dressing is tied over the surface to prevent any inadvertent shearing action from disrupting the normal healing process. The donor site is then repaired in a simple linear manner with appropriate suture material. To prevent injury to the full-thickness skin graft, most surgeons do not examine it for 2–7 days. Specialized dressing to minimize pressure on the grafted tissue may be needed to minimize injury during sleep.692 When examined, there is almost always some vascular congestion present that results in a cyanotic appearance. Sometimes the epidermis becomes blistered and separates from the graft with the first dressing change. Neither of these findings is indicative of graft failure; rather, they are normal expected changes.692 The sutures are usually removed from the graft at 9–10 days, but diligent wound care is required for an additional 10 days, to ensure graft survival. If there is a suboptimal cosmetic result due to poor color or texture match, additional improvement can often be obtained by lightly dermabrading the surface at the end of 8 weeks. Relatively normal sensation and color can be expected in most cases within 4–6 months.

5

Primary

SPECIALIZED FORMS OF DERMATOLOGIC SURGERY IN CHILDREN

Secondary

Both

Composite skin grafts Composite skin grafts that contain cartilage in addition to skin and subcutaneous tissue are primarily used for reconstruction of defects on the nose and ear. While no more difficult to perform than standard skin-grafting procedures, failure of this graft is not uncommon, due to the tremendous nutritional requirements. This is especially common when grafts are larger than 2 cm in diameter. The donor area for this procedure is most often the superior or anterior helical rim of the ear.

SIMPLE CUTANEOUS FLAPS The alternatives to wound closure for those defects that cannot be closed primarily in a simple side-to-side fashion include both skin grafting and skin flaps. The prime advantage of skin flaps over grafting is the improved final cosmetic result. Since simple skin flaps move adjacent loose tissue into a defect, the color match, texture, sensation, and presence of appendageal structures tend to be much closer to that of the original tissue than can be obtained with use of skin grafts of any type.

Common simple skin flap The common simple skin flaps consist of advancement, rotation, transposition, and rhomboid flaps.693,694 Each derives its name from the type of motion involved in the transfer of adjacent tissue to fill the primary defect. Each flap has some unique properties that may give certain advantages and disadvantages. In performing proper flap surgery, the surgeon must be familiar with each type of flap in order to select the most appropriate one to use in any given situation.

692. Mast BA. Healing in other tissues. Surg Clin North Am. 1997;77:529–547. 693. Shpall S, Frieden I, Chesney M, et al. Risk of malignant transformation of congenital melanocytic in nevi in blacks. Pediatr Dermatol. 1994;11:204–208.

Figure 5.34  Schematic drawing of a rotation flap showing its three separate movements. The pucker that is formed by the rotation of the skin is shown on the pedicle of the flap nearest the defect. The size and direction of this pucker change depending on the amount of primary and secondary movement.

Rotation flap The appearance of a rotation flap suggests that the movement consists entirely of rotation about a given pivot point. However, there is also a component of transposition and advancement involved (Fig. 5.34). This flap is intrinsically safe to perform, even in the movement of large amounts of tissue, due to the maintenance of a large pedicle through which the vascular structures remain intact. This flap can be used to mobilize the entire cheek to close a large nasal defect, or much of the scalp may be mobilized with this flap to close a forehead or temple defect. At the same time, a much smaller version of this flap can also be successfully used to close defects of lesser size. The curved lines that are created in the movement of this type of flap are often beneficial in that they are easier to conceal by placing them within one of the naturally curved folds or creases, which will improve the cosmetic results that are obtained.

Advancement flap The advancement flap uses a sliding movement of tissue to fill a void (Fig. 5.35). This flap is probably the easiest one to plan and perform in a satisfactory manner. However, because of the design of this flap, necrosis of the tip may occur if the vascular supply, determined by the width of the flap, is impaired by excessive stretching or if the metabolic demands, determined by the length of the flap, outstrip the supply. The linear nature of this

694. Pletcher SD, Kim DW. Current concepts in cheek reconstruction. Facial Plast Surg Clin North Am. 2005;13:267–281.

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Primary

Primary

Secondary

Secondary

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Both

Both

Figure 5.35  Schematic drawing of an advancement flap showing its three

separate movements. It should be noted that the flap and the triangle of skin created by the flap interchange with one another in a similar manner to that in a Z-plasty.

flap creates straight lines that may, in certain areas of the body, be obvious. When used on the forehead, where naturally straight lines exist, the cosmetic result can be exceptionally good. Advancement flaps can also be used to reduce the contraction of scars that have adversely distorted normal anatomy. This type of advancement flap is known as the V-Y flap; it is used to lengthen a scar and reduce tension.695,696 This is commonly used for scars on the eyelids, where ectropion has resulted from previous injury or surgery.

nevi or residual hemangiomas are essentially round, this flap can be very useful on the central face and nose.698

Rhomboid flap

The transposition flap can be characterized by the most common type, the Z-plasty.697 This type of flap is used to change the directions of a scar by reversing or transposing the two arms of the flap. It is often used for long linear scars to break up the line and make it more cosmetically acceptable, by reducing its visibility. This flap also can be used to effectively lengthen a scar. If tension across a joint or other mobile part of the body, like the neck, has resulted from a linear incision, by using a series of small Z-plasties the direction and length of the scar can be changed to reduce the tension. Another useful transposition flap on the face is the bilobed transposition flap. Since many pediatric skin lesions like Spitz

Without doubt, the rhomboid flap is the most difficult flap to visualize as far as the movement of tissue is concerned (Fig. 5.36). However, once the proper geometric shape of this flap has been designed, it offers significant advantages over the other flaps. This has to do with its versatility, since any one of four different quadrants around the original defect can be rotated into position to close the defect. This has the greatest utility in the scalp for removal of larger birthmarks like congenital nevi or aplasia cutis. When these lesions occur on the occipital scalp, hair coverage is often a problem postoperatively. A carefully designed rhomboid flap can allow for redirection of the adjacent hair so that it will grow in a direction that covers the scalp scar. Before flap surgery is performed for wound closure, the physician must have a thorough knowledge of the procedure. The best results will only be obtained when the dynamics of flap movement are understood. With this knowledge, the correct decision can be made as to whether or not a flap should be used, and which type of flap is the best choice to provide the most satisfactory technique for wound repair.

695. Peled IJ, Wexler MR. The usefulness and versatility of V-Y advancement flaps. J Dermatol Surg Oncol. 1983;9:1003. 696. Clark JM, Wang TD. Local flaps in scar revision. Facial Plast Surg. 2001;17:295–308.

697. Rohrer TE, Bhatia A. Transposition flaps in cutaneous surgery. Dermatol Surg. 2005;31:1014–1023. 698. Aasi Sz, Leffell DJ. Bilobed transposition flap. Dermatol Clin. 2005;23:55–64.

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280

Figure 5.36  Schematic drawing of a rhomboid flap showing its three

movements. The vertical line indicates the center of the defect, while the eyebrow is also shown as a fixed anatomical structure to compare how the various movements of the flap alter the location of each. The darker sutures represent key stitch placement.

Surgical techniques

Since most dermatologists perform minor surgical procedures routinely, even on a daily basis, very little additional equipment is required for the effective treatment of children. Certain types of dermatologic surgical procedures require the purchase of special instruments, but few other tools are necessary for their adaptations to treat children, since virtually all the surgical instruments and local anesthetics used in the surgical treatment of children and adolescents are identical to those used in the treatment of adults. For those physicians who like to employ restraints, the purchase of a papoose board or similar restraining device might be worthwhile, but this is certainly not mandatory. More humane methods of restraining children, such as wrapping with an office sheet, are effective and far less traumatic than commercially available restraining devices (Fig. 5.37).699 If the surgical procedure takes longer than 5 min, the use of restraining devices is contraindicated. Excisional surgery should never be performed using restraints. Children too young to cooperate during these procedures should have the benefit of outpatient anesthesia.

When purchasing surgical instruments, it is important to keep in mind that pediatric patients are smaller than adult patients. Closing wounds in confined spaces in children can be facilitated by the use of smaller instruments. Pick-ups that are 3 inches long and shorter needle holders allow for more precise control in small spaces. The use of a 15-C blade or a Beaver blade can facilitate small excisions (Fig. 5.38). Availability of proper suture removal equipment is also essential since pediatric patients are often uncooperative at suture removal. Suture removal scissors with fine but blunt tips are ideal for removing 6-0 suture on the face (Fig. 5.39). Since all invasive surgical procedures are associated with some risk of secondary infection, the physician performing proper dermatologic surgery must use strict aseptic technique, and this requires the use of sterile instruments. The most ideal method for sterilizing surgical tools is steam heat with pressurization. This can best be achieved for the office-based physician with an autoclave, which becomes an important piece of equipment essential for performing surgery on the skin. In order for the surgeon to perform the best possible technical procedure, comfort is a requirement. An electrically powered

A

B

C

D

SPECIAL EQUIPMENT

SPECIAL EQUIPMENT

5

Figure 5.37  Immobilization of a child using a sheet. (A) The child is placed on a sheet folded in half on the table. One half of the sheet is wrapped around the arm. (B) The child is lifted and the sheet is wound behind the back. (C) The sheet is passed beneath the second arm and wrapped over the arm and under the back again as in (A) and (B). (D) The other edge of the sheet is wrapped around the child to secure the restraint.

699. Lyon VB, Palmer CM, Wagner AM, et al. Toddler wrap for abdominal biopsy or excision. Pediatr Dermatol. 2008;25:109–111.

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SPECIAL DERMATOLOGIC SURGERY PROBLEMS

Figure 5.38  Comparison of blade types. Left to right: Beaver blade; 15-C blade; 15 blade; 10 blade.

come stocked with the necessary medications to handle various levels of office emergencies. The types and kinds of emergency medications and intravenous fluids included in the emergency kits should be determined by the training and expertise of the personnel in the office and the availability of emergency technicians in the community. Dosages of all medications for both adults and children should be placed in the emergency kit for immediate use. All medications contained in the kits should be checked periodically to ascertain that they have not become outdated. At a minimum, all office personnel should be familiar with basic cardiopulmonary resuscitation emergency techniques, as well as the necessary steps to take in the event of an emergency. In addition to the emergency kit, an emergency supply of oxygen and ventilation breathing bags fitted with both pediatric and adult sizes of masks should be available. Plastic oropharyngeal airways and endotracheal tubes in a full range of sizes should also be present. Infant and child-sized blood pressure cuffs and a stethoscope with pediatric head should also be kept in the surgery suite. If conscious sedation is carried out, a cardiac monitor and pulse oximeter should be used. A physician or physician assistant independent of the person performing the surgery should be responsible to monitor the cardiopulmonary status and level of consciousness of any pediatric patient undergoing sedation for a procedure. Office staff should be well versed in the appropriate action in the event that an emergency should occur.

SPECIAL DERMATOLOGIC SURGERY PROBLEMS

Figure 5.39  Suture removal scissor with small pick-up.

adjustable surgical table facilitates positioning of the patient for maximum exposure and greatest comfort possible. An adjustable stool can also make a long procedure more tolerable for the surgeon. Adequate lighting is also a requirement for performing cutaneous surgical procedures. Additional lighting can be suspended from the ceiling, attached to the surgical table, or mounted on rollers, depending upon the space available in the operating room suite. It is equally important during surgery to keep the patient comfortable. Pediatric patients are most comfortable surrounded by familiar objects: a pillow or blanket from home, a parent, a stuffed animal and a DVD player or iPod. There is no more effective distraction than a movie. A hand held DVD player is a worthwhile investment in the pediatric surgery suite. Having patients bring something familiar that they enjoy is invaluable. The louder the volume, the more distracting the video player will be. Minimizing adult conversation in the room during the procedure is also important to encourage the patient to pay attention to the video. One area of common neglect in many physicians’ offices is an emergency kit. Prepackaged kits are now widely available and 282

The pediatric dermatologic surgeon is rarely called upon to excise skin cancers. Most excisional surgery in this field is performed because of the risk of malignant transformation that is present in some birthmarks or to improve the cosmetic appearance of a child by removing the birthmark. These surgeries are elective and therefore choosing the optimal time for excision is important. Many factors enter into a decision to perform an elective surgery in a child. The goal of every procedure is to minimize surgical risk while providing the best surgical outcome. For many lesions, postponement until the age of preadolescence is recommended when excisions can be accomplished readily with a local anesthetic. For some lesions, such as large congenital nevi, the risk of malignancy is sufficiently great that earlier intervention is usually recommended. In addition, in some body locations, such as the scalp and face, early excision is advisable to maximize the cosmetic appearance of the resultant scar. Table 5.11 outlines the recommended timing of surgical excision in the pediatric dermatologic population. This section reviews the more common pediatric dermatologic surgery entities, indications for treatment of these conditions, and surgical treatment options.

NEVUS SEBACEOUS OF JADASSOHN The nevus sebaceous of Jadassohn is an uncommon congenital hamartoma of the skin and adnexa with a predominance of sebaceous glands, abortive hair follicles, and ectopic apocrine glands. It is most commonly located on the scalp and face where

Surgical techniques

5

Table 5.11  Recommended timing of surgical excision LESION

LOCATION

SIZE

AGE

COMMENTS

Nevus sebaceous

Scalp

1 cm

6–12 months

1° excision, staged excision or tissue expansion under general anesthetic

Face

All

6–12 months

Early excision recommended

All locations

Small, 20 cm

>6 months

Tissue expansion 20 cm

3–6 months

Tissue expansion

All

>1 cm

6–12 months

For cosmetic improvement

4 cm

6–12 months or preschool

Large JXGs leave fibrofatty deposition with involution

Body

>4 cm

7–10 years

Face, scalp

>3 cm

6–12 months

Excision for symptoms of severe recurrent blistering or pain or if lesion fails to involute by age >7

Body

>3 cm

7–10 years

Ulcerated hemangioma

All

Amenable to 1° closure

Infancy

Consider excision when significant scarring or if failure of medical therapy to heal ulcer

Non-ulcerated hemangioma

All

>1 cm

>4 years

For cosmetic improvement of fibrofatty deposition

Pyogenic granulomas

All

7 mm

When diagnosed

Electrodesiccation with curettage for pedunculated lesion; if base ≥8 mm excision is preferred Excision for cosmetic purposes only

Epidermal nevi Acquired nevi

Face Face

>1 cm

6–12 months

16 years

Cosmetic removal should be deferred in early adolescence

Atypical nevi

All

All

When diagnosed

Excision for changes

Spitz nevi

Face

>2 mm

When diagnosed

Early excision improves scar

Body

>6 mm

When diagnosed

Observation unless atypical appearance. Excision for changes when they occur

Vascular malformation

Larger lesions more likely to recur

Angiokeratoma

Excise early if painful or enlarging All

Lymphangioma circumscriptum

SPECIAL DERMATOLOGIC SURGERY PROBLEMS

Congenital nevi

1 cm on the scalp or for any obvious lesion of cosmetic importance on the face, removal of nevus sebaceous under a general anesthesia in infancy will give the best scar. Scalp flexibility is maximal in the first year of life and large areas can be primarily resected without the need of tissue

707. Turner CD, Shea CR, Rosoff PM. Basal cell carcinoma originating from a nevus sebaceus on the scalp of a 7-year-old boy. J Pediatr Hematol Oncol. 2001;23:247–249. 708. Xin H, Matt D, Burg G, et al. Deletions of the PCTH gene in sebaceous nevi. J Invest Dermatol. 1999;112:387. 709. Aszterbaum M, Epstein J, Oro A, et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med. 1999;5(11):1285–1291. 710. Santibanez-Gallerani A, Marshall D, Duarte AM, et al. Should nevus sebaceus of Jadassohn in children be excised? A study of 757 cases, and literature review. J Craniofac Surg. 2003;14:658–660. 711. Correale D, Ringfeil F, Rogers M. Large, papillomatous, pedunculated nevus sebaceus: a new phenotype. Pediatr Dermatol. 2008;25:355–358. 712. Terenzi V, Indrizzi E, Buonaccorsi S, et al. Nevus sebaceus of Jadassohn. J Craniofac Surg. 2006;17:1234–1239.

Surgical techniques

B SPECIAL DERMATOLOGIC SURGERY PROBLEMS

A

5

Figure 5.41  (A) Preoperative appearance of large nevus sebaceous of the scalp and face. (B) Postoperative appearance of the scar 1 year after resection.

expansion and with decreased spreading of the scars in this period (Fig. 5.41). Most small areas of nevus sebaceous can be readily approached in the pre-adolescent years using a local anesthetic in the clinic. All excisional surgery leaves a scar that will not grow hair and significant spreading of scars can occur in certain locations on the scalp, especially the occiput. The parents should be informed of this prior to making a decision to proceed with excision or to postpone excision in early infancy. Laser destruction of nevus sebaceous is not recommended. There is a high rate of recurrence of these lesions when treated with more superficial laser systems and the risk of malignancy is not altered by this therapy due to the failure of the laser systems to penetrate deeply and fully remove the tumor. Patients who have undergone surgical resection of nevus sebaceous in the early years of life require close follow-up until puberty. Extension of nevus sebaceous with skip areas is a commonly described occurrence. If new areas of nevus sebaceous develop after primary surgical resection, these can be approached as an outpatient local procedure in a pre-adolescent. Larger areas of nevus sebaceous should be excised with the aid of tissue expansion techniques to minimize the spreading of the postoperative scar. For intermediate size nevi, staged excisions can also be beneficial.

Figure 5.42  Malignant melanoma in a garment-type, giant congenital nevus.

CONGENITAL NEVUS Nevocellular nevi are present at birth in 1% of the population. The risk of development of malignant melanoma in a congenital nevus is unknown, but clearly increased over acquired nevocellular nevi.713,714 Removal of congenital nevi to prevent malignant deterioration is therefore controversial. It appears that the size of the congenital nevus is the most important contributing factor to increased risk (Fig. 5.42).715 Although studies are ongoing to better define the risk of melanoma in these lesions, it is unlikely that an appropriate prospective trial of the efficacy of prophylac-

tic excision of large congenital nevi in preventing malignant change will ever be performed. Size of these lesions often precludes complete resection and decision to pursue aggressive resection is more often motivated by the psychosocial challenges of living with such disfiguring lesions than the medical benefits of the therapy. Moreover, the rarity of large nevi coupled with the low incidence of melanoma would prohibit a trial of sufficient size to answer the question. The prospective studies of large

713. Schaffer JV. Pigmented lesions in children: when to worry. Curr Opin Pediatr. 2007;19:430–440. 714. Kinsler VA, Birley J, Atherton DJ. Great Ormond Street Hospital for children registry for congenital melanocytic naevi: prospective study

1988–2007. Part 1 – epidemiology, phenotype and outcomes. Br J Dermatol. 2009;160:143–150. 715. Krengel S, Hauschild A, Schäfer T. Melanoma risk in congenital melanocytic naevi: a systematic review. Br J Dermatol. 2006;155:1–8.

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congenital nevi (>20 cm2) currently reported estimate the risk of melanoma at 2.4–14%.714,716–720 Retrospective studies and an internet registry-based study show an even lower incidence of malignant change (0.3–2.9%).721–725 For small congenital nevi, the risk is estimated as ≤1%. Nonetheless, histologic evidence of malignant melanoma occurring in small pre-existing nevi that have features of congenital nevi continues to be reported.726,727 There is some racial variation in the risk of malignant deterioration. Patients of African-American descent with small congenital nevi are believed to have a much lower risk than Caucasian patients. The risk has been estimated at 1 in 20 000 in this population.728 Intermediate-size nevi are extrapolated to have an intermediate risk, although little data is available looking at this subset of nevi.692,729 SPECIAL DERMATOLOGIC SURGERY PROBLEMS

Many congenital nevi are excised to prevent deterioration into malignancy, although the exact risk is unknown. Congenital nevi are flat at birth, but develop a carpet-like thickness or a cerebriform surface texture with time. In addition, hypertrichosis is common within these. Variation in pigmentation and in nodularity can make observation difficult. The cosmetic appearance of large congenital nevi may also contribute to the decision for removal as well as the appropriate timing of surgical excision when excision is desired.730,731 Most pediatric dermatologists recommend observation of small congenital nevi rather than excision. Exceptions to this include nevi in cosmetically disfiguring areas such as the central face, nevi in locations that are difficult to follow such as the scalp, groin, palms or soles, or nevi that have atypical features that make elective observation difficult and risky. Any small congenital nevus that undergoes a clinical change in color, shape, or nodularity should be evaluated by a pediatric dermatologist. Changes that are concerning for malignancy should precipitate full excision of the nevus when they occur. In the absence of concerning changes, all small congenital nevi should be observed at least until puberty. A decision to remove a small congenital nevus for cosmetic or prophylactic reasons at this

time will allow for the use of a local anesthetic. The exception to this is lesions on the face where early surgical excision in the first year of life may improve the final appearance of the scar. For medium-sized congenital nevi, a larger proportion of practicing pediatric dermatologists recommend excision. This relates to a perceived increase in the risk for malignancy as well as an increased concern for the cosmetics of these lesions. Many factors enter into recommendations for excision and the timing of recommended excision of medium-sized congenital nevi. Lesions that are present in areas with minimal skin mobility such as the anterior lower legs or forearms, the palms and soles, and the scalp are generally recommended for early excision in the first year of life. The flexibility of tissue is greatest at this time and excision during the active period of pre-adolescence and adolescence results in poor cosmetic results due to a high level of activity. This also eliminates the need for two-staged procedures in many nevi. The risk of developing a poor scar must be balanced against the risk of developing melanoma in larger nevi. For large congenital nevi, most practitioners recommend early excision when this is possible. Plastic surgical techniques including partial-thickness skin grafting and tissue expansion have allowed for complete removal of giant congenital nevi in many patients.731–734 This requires many procedures and is best approached early in life. The risk of malignancy in giant congenital nevi is greatest in the first 5 years of life. For nevi that cannot be completely excised, a discussion of partial removal is indicated to improve the cosmesis of these disfiguring lesions. In a recent prospective 19-year-study from Great Ormond Street Hospital, this practice was questioned. Published data failed to demonstrate any reduction in the risk of malignancy for routine excision of large congenital nevi. No advantage was noted to perform surgery early and many nevi followed prospectively seemed to lighten spontaneously. It was recommended that all routine surgery be delayed for at least 1 year, that serial photos to document change, including lightening, be done yearly, and that patients with facial nevi, whether they were the primary or satellite lesions, as well as patients with single, easily excisable medium sized nevi be offered surgery primarily for cosmetic

716. Ruiz-Maldonado R, Tamayo L, Laterza AM, et al. Giant pigmented nevi: clinical, histopathologic, and therapeutic considerations. J Pediatr. 1992;120:906–911. 717. Egan CL, Oliveria SA, Elenitsas R, et al. Cutaneous melanoma risk and phenotypic changes in large congenital nevi: a follow-up study of 46 patients. J Am Acad Dermatol. 1998;39:923–932. 718. Hale EK, Stein J, Ben-Porat L, et al. Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevi: results from the NYU-LCMN registry. Br J Dermatol. 2005;152:512–517. 719. Dawson HA, Atherton DJ, Mayou B. A prospective study of congenital melanocytic naevi: progress report and evaluation after 6 years. Br J Dermatol. 1996;134:617–623. 720. Marghoob AA, Schoenbach SP, Kopf AW, et al. Large congenital melanocytic nevi and the risk for the development of malignant melanoma: a prospective study. Arch Dermatol. 1996;132–175. 721. Bett BJ. Large or multiple congenital melanocytic nevi: occurrence of cutaneous melanoma in 1008 persons. J Am Acad Dermatol. 2005;52:793–797. 722. Ka VS, Dusza SW, Halpern AC, et al. The association between large congenital melanocytic naevi and cutaneous melanoma: preliminary findings from internet-based registry of 379 patients. Melanoma Res. 2005;15:61–67. 723. Swerdlow AJ, English JS, Qiao Z. The risk of melanoma in patients with congenital nevi: a cohort study. J Am Acad Dermatol. 1995;32:595–599. 724. Berg P, Lindelöf B. Congenital melanocytic naevi and cutaneous melanoma. Melanoma Res. 2003;13:441–445.

725. Zaal LH, Mooi WJ, Klip H, et al. Risk of malignant transformation of congenital melanocytic nevi: a retrospective nationwide study from the Netherlands. Plast Reconstr Surg. 2005;116:1902–1909. 726. Mackie RM, Watt D, Doherty V, et al. Malignant melanoma occurring in those aged under 30 in the west of Scotland 1979–1986: a study of incidence, clinical features, pathological features and survival. Br J Dermatol. 1991;124:560–564. 727. Harley S, Walsh N. A new look at nevus-associated melanomas. Am J Dermatopathol. 1996;18:137–141. 728. Shpall S, Frieden I, Chesney M, et al. Risk of malignant transformation of congenital melanocytic in nevi in blacks. Pediatr Dermatol. 1994;11:204–208. 729. Sahin S, Levin L, Kopf AW, et al. Risk of melanoma in medium-sized congenital melanocytic nevi: a follow-up study. J Am Acad Dermatol. 1998;39:428–433. 730. Marghoob AA, Agero AL, Benvenuto-Andrade C, et al. Large congenital melanocytic nevi, risk of cutaneous melanoma, and prophylactic surgery. J Am Acad Dermatol. 2006;54:868–870. 731. Arneja JS, Gosain AK. Giant congenital melanocytic nevi. Plast Reconstr Surg. 2009;124:1e–13e. 732. Tannous ZS, Mihm MC Jr, Sober AJ, et al. Congenital melanocytic nevi: clinical and histopathologic features, risk of melanoma, and clinical management. J Am Acad Dermatol. 2005;52:197–203. 733. Tromberg J, Bauer B, Benvenuto-Adrade C, et al. Congenital nevi needing treatment. Dermatol Ther. 2005;18:136–150. 734. Bauer BS, Corcoran J. Treatment of large and giant nevi. Clin Plastic Surg. 2005;32:11–18.

Surgical indications

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Surgical techniques

reasons.735 For patients who underwent surgical intervention for their congenital nevus, a high level of satisfaction was reported for facial nevi removal and for the removal of nevi > Functionally impairing lesion non-responsive to medical therapy >> Post-involution fibrofatty tissue or tissue redundancy >> Ulcerated hemangiomas non-responsive to medical or laser therapy

>> Significant lip or nasal tip hemangiomas non-responsive to medical therapy

>> Large disfiguring hemangiomas (controversial)

SPECIAL DERMATOLOGIC SURGERY PROBLEMS

Figure 5.44  Recurrence of hemangioma after resection at 4 months of age. Note significant glabellar scarring.

Surgical indications The surgical indications for removal and treatment of hemangiomas are controversial. There is no doubt that aggressive surgical intervention early will result in unnecessary scarring for some patients whose hemangiomas undergo rapid involution with very acceptable cosmetic outcomes (Fig. 5.44). Proliferating hemangiomas are ill-defined, highly vascular tumors. It is difficult to remove these in their entirety without sacrificing some normal tissue. This is particularly a problem for large deep hemangiomas such as those in the parotid area of the face. Deep resection can result in injury to the facial nerve as well as removal of subcutaneous tissue that leads to a severe contour defect on the face. Early excision is contraindicated in this location. There is regression of the vascular channels, and the multilaminated basement membranes that are interspersed between the pockets of endothelial proliferation are replaced by adipocytes and fibrous tissue that is better defined and more readily resected without risking injury to or removal of the surrounding normal tissue. Moreover, it is possible and sometimes beneficial to leave some of this residual deep scar tissue to provide contour in the deep tissue and perform a more superficial resection removing only the atrophic and redundant or scarred skin on the surface. There are circumstances, however, under which surgical excision may be preferable to awaiting natural involution to minimize the morbidity of these lesions or to impact functional impairment. Current recommendations for primary excision of hemangiomas are: (1) removal of all functionally impairing hemangiomas that are non-responsive to medical therapy; (2) removal of tissue redundancy and fibrofatty residual that remains after involution of hemangiomas; (3) removal of ulcerated hemangiomas that are amenable to primary closure and poorly responsive to medical therapy and pulsed dye laser therapy; (4) removal of significant lip and nasal tip hemangiomas that fail to

767. Williams EF 3rd, Stanislaw P, Dupree M, et al. Hemangiomas in infants and children. An algorithm. Arch Facial Plast Surg. 2000;2:103–111. 768. Demiri EC, Pelissier P, Genin-Etcrhberry T, et al. Treatment of facial hemangiomas: the present status of surgery. Br J Plast Surg. 2001;54:665–674. 769. Finn MC, Glowacki J, Mullikan JB. Congenital vascular lesions: clinical application of a new classification. J Pediatr Surg. 1983;18:894–900.

290

respond to medical therapy; and (5) removal of large and disfiguring hemangiomas in cosmetically important areas to decrease the psychologic morbidity of growing up with these lesions, including non-involuting congenital hemangiomas (controversial) (Box 5.9). For larger lesions on the face and scalp, where residual tumor and tissue redundancy is assured, it is recommended that excision be accomplished in the preschool years, optimally between the ages of 4 and 5.767,768 Finn et al. demonstrated in a retrospective review that only 50% of hemangiomas completely involuted by 6 years of age.769 Of the remaining 50% that did not involute, 80% left a substantial residual cosmetic deformity. Of the 50% that were completely involuted by age 6 years, 38% left a substantial cosmetic residual. These statistics have led to a more aggressive surgical approach by some physicians who advocate surgical excision in the second year of life, or even during the proliferative phase.767,770,771 Delaying excision until age 4–7 allows the surgeon to take advantage of the benefit of natural involution. Intervention is critical before the age of 7, since children suffer severe psychosocial trauma once they reach the developmental stage where they identify body image and distinguish differences between themselves and others.772 Preschoolers are curious; first-graders are mean. Resection before age 7 allows for as much natural involution as possible and minimizes the extent of the surgical procedure that is undertaken. Care should be taken to resect only the abnormal skin in early resection. Staged excision with purse-string closure can markedly decrease the size of the final scar (Fig. 5.45). Laser treatment can be used as an adjunct to surgical excision after debulking of large tumors to improve the cosmetic appearance.551,553,555,560,767 For tumors on the trunk and extremities that are asymptomatic, postponement of resection until the age of 7–10 years, when this can be accomplished as a local procedure without the need for a general anesthetic, is recommended. Early excision of hemangiomas in the rapid proliferative phase of the first year of life can result in partial resection and recurrence. The best surgical results are obtained when the proliferative phase has ended and the tumors have entered involution. Excision is not recommended for small superficial

770. Waner M, Suen JY, Dinehart S. Treatment of hemangiomas of the head and neck. Laryngoscope. 1992;102:1123–1132. 771. Waner M, Suen JY. Management of congenital vascular lesions of the head and neck. Oncology. 1995;9:989–994, 997. 772. Tanner JL, Dechert MP, Frieden IJ. Growing up with a facial hemangioma: parent and child coping and adaptation. Pediatrics. 1998;101:446–452.

Surgical techniques

A

B

5

C

Figure 5.45  (A) Appearance of a hemangioma in a 7-year-old boy. (B) Purse-string closure. (C) Scar 1 month after surgery demonstrating reduced scar length

hemangiomas on the face or scalp, where early intervention will result in unnecessary scarring. Three important exceptions to this are significant lip hemangiomas, nasal tip hemangiomas and non-involuting congenital hemangiomas (NICH). Rapidly enlarging hemangiomas of the lip and nasal tip can have devastating cosmetic outcomes if not approached early.773,774 Medical intervention is always the recommended first-line approach. The recent discovery that propranolol, a non-selective beta-blocker, can stabilize and induce rapid and early regression has markedly reduced the need for early resection of these lesions.576–580,775 This author recommends the use of this medical therapy for all patients with enlarging hemangiomas in these locations, preferably beginning in the first 3 months of life, when treatment is most effective. For patients who require surgery despite this early intervention, multiple surgical procedures are often needed to reduce the deformity of hemangiomas in these locations. Early surgical intervention, within the first year of life, may be indicated. For NICH, early surgical resection will yield the best outcome.776–778 In addition to primary excision, hemangiomas can be approached with the pulsed dye laser. The indication for the use of pulsed dye laser in the treatment of hemangiomas is limited to effecting more rapid healing of ulcerated hemangiomas that are poorly responsive to good topical wound care.562,564 The pulsed dye laser can diminish the pain in these ulcerated hemangiomas and decrease the risk of infection by facilitating earlier healing. The pulsed dye laser is ineffective in treatment of hemangiomas with a deep component. Treatment of superficial hemangiomas results in early involution in the superficial layers of the skin.551,555 Since pulsed dye laser penetrates Pachyonychia congenita (Jadassohn–Lewandowsky or Jackson–Lawler)

>> Pallister–Hall (hypothalamic hamartoblastoma) >> Weidemann–Rautenstrauch >> Natal teeth, patent ductus arteriosus, intestinal pseudo-obstruction

16

From Robson et al. (1969).

93. Parmigiani S, Giordano G, Fellegara G, et al. A rare case of multiple congenital epulis. J Matern Fetal Neonatal Med. 2004;16:55–58. 94. Küpers AM, Andriessen P, van Kempen MJ, et al. Congenital epulis of the jaw: a series of five cases and review of literature. Pediatr Surg Int. 2009;25:207–210. 95. Billeret-Lebranchu V, Martin de la Salle E, Vandenhaute B, et al. Granular cell tumor and congenital epulis. Histochemical and inmunohistochemical study of 58 cases. Arch Anat Cytol Pathol. 1999;47:31–37.

310

Figure 6.13  Sucking callus: diffuse pale thickening of vermilion border in a 4-week-old breast-fed infant. (Courtesy of Dr Antonio Torrelo)

96. Domingues-Cruz J, Herrera A, Fernandez-Crehuet P, et al. Riga-Fede disease associated with postanoxic encephalopathy and trisomy 21: a proposed classification. Pediatr Dermatol. 2007;24:663–665. 97. Leung AK, Robson WL. Natal teeth: a review. J Natl Med Assoc. 2006;98:226–228. 98. Adam R, Schroten H. Picture of the month. Congenital sucking blisters. Arch Pediatr Adolesc Med. 2007;161:607–608.

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6

BENIGN SELF-LIMITING CUTANEOUS LESIONS Margarita Larralde, Paula C. Luna

SUCKING BLISTERS, EROSIONS AND CALLUSES

well, full-term newborn. (Courtesy of Ronald Hansen, MD)

coalesce. Different types of trauma have been described as responsible for these lesions including non-orthodontic teats, pacifiers and vigorous sucking. The differential diagnosis includes diverse infectious diseases such as herpetic stomatitis, herpangina and hand, foot and mouth disease. Abusive trauma must always also be considered. Treatment of these lesions is oriented towards minimizing the causes of trauma.

LYMPHATIC MALFORMATIONS Lymphatic malformations may also be found on lips, buccal mucosa, and palate, and have been described on the floor of the mouth in continuity with cervical lymphatic malformations.99,100 They may also occur on the tongue, causing macroglossia. Airway compromise can occur with these larger malformations, especially when there is bleeding into them or when secondary infection occurs, as can disfigurement of the maxilla and mandible.

MEDIAN ALVEOLAR NOTCH Median alveolar notch is a midline notch in the upper alveolar ridge seen in many neonates. This has been reported in 26% of black infants and in 12% of white infants.101 The rectolabial frenulum is a soft connective tissue structure in the anterior midline of the maxillary arch in continuity with the labial frenulum. When pronounced, this frenulum causes a fissure in the alveolus, producing the median alveolar notch. As teeth erupt, the connective tissue septum and frenular plate ordinarily reabsorb, and the notch reduces in size. Occasionally, the notch persists and may contribute to a space between the central incisors.101

99. Ikemura K, Hidaka H, Fujiwara I, et al. A case of cystic lymphangioma extending from the neck to the tongue. Management of the lesion remaining after surgery. J Craniomaxillofac Surg. 1987;15:369–371. 100. Jasper RD, Goldberg MH, Zborowski RG. Lymphangioma and cystic hygroma. Correction of facial growth disharmony and obstructive sleep. Int J Oral Maxillofac Surg. 1989;18:152–154. 101. Jorgenson RJ, Shapiro SD, Salinas CF, et al. Intraoral findings and anomalies in neonates. Pediatr. 1982;69:577–582. 102. Libow LF, Reinmann JG. Symmetrical erosions in a neonate: a case of neonatal sucking blisters. Cutis. 1998;62:16–17.

MILIA

Figure 6.14  Sucking blisters: two erosions (wrist and base of thumb) in a

Sucking blisters, erosions or calluses may be present at birth, usually located on the fingers, wrists or forearms (Fig. 6.14).101 The primary lesion is a tense vesicle or bulla on non-inflamed skin and erosions that result from blister rupture may also be seen. Calluses (sucking pads) may also be seen in the same areas. All these lesions appear to be the result of vigorous sucking in utero.101 Most frequently they are single, but multiple lesions have been reported19 and some rare cases have been bilateral.102 They spontaneously resolve without sequelae, usually by 2 weeks of age.103 The erosions and blisters may be confused with more serious diseases in the newborn, such as herpes simplex, bullous impetigo, bullous mastocytosis or epidermolysis bullosa. The focal presentation, characteristic morphology, and the failure to develop other blisters during the first few days of life should allow correct diagnosis.

SEBACEOUS GLAND HYPERPLASIA Sebaceous gland hyperplasia occurs in >50% of term newborns and less commonly in preterm infants,104,105 with a nearly 1:1 female/male ratio.104 Multiple, pinpoint, white-yellowish papules are seen at the opening of pilosebaceous follicles in areas in which sebaceous glands are abundant, such as the nose (Fig. 6.15), cheeks, upper lip and forehead. There is no surrounding erythema. They are typically present at birth. Sebaceous hyperplasia results from the influences of maternal androgens on the pilosebaceous follicle. This stimulation occurs during the final month of gestation resulting in an increase in sebaceous cell number and volume.106 Biopsy of these lesions reveals large sebaceous glands with prominent secretory cells surrounding the pilosebaceous follicles. Milia, which are inclusion cysts, are differentiable as they are often solitary, discrete, and whiter in color. Milia may accompany sebaceous gland hyperplasia in approximately half of affected infants. No treatment is necessary as the lesions tend to resolve quite rapidly.105

MILIA Milia are tiny inclusion cysts commonly found on the skin of newborns.107 These white, pearly, firm 1–2 mm globular papules occur particularly on the nose, cheeks, chin and forehead, in

103. Lucky AW. Transient benign cutaneous lesions in the newborn. In: Eichenfield LF, Frieden IJ, Esterly NB, eds. Philadelphia: WB Saunders; 2001:88–102. 104. Moosavi Z, Hosseini T. One-year survey of cutaneous lesions in 1000 consecutive Iranian newborns. Pediatr Dermatol. 2006;23:61–63. 105. Conlon JD, Drolet BA. Skin lesions in the neonate. Pediatr Clin North Am. 2004;51:863–888. 106. Holbrook KA, Smith LT. Ultrastructural aspects of human skin during the embryonic, fetal, premature, neonatal and adult periods of life. Birth Defects. 1981;1:9–38. 107. Berk DR, Bayliss SJ. Milia: a review and classification. J Am Acad Dermatol. 2008;59:1050–1063.

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BOX 6.2 GENODERMATOSES WITH MILIA

MATERNAL AND PLACENTAL HORMONAL EFFECTS: ‘MINIATURE PUBERTY’ OF THE NEWBORN

Figure 6.15  Sebaceous gland hyperplasia: yellowish closely set nasal

>> Bazex–Dupre–Christol syndrome >> Rombo syndrome >> Brooke–Spiegler syndrome >> Orofaciodigital syndrome type 1 >> Atrichia with papular lesions >> Hereditary vitamin D-dependent rickets type IIA >> Pachyonychia congenita type II >> Basal cell nevus syndrome >> Generalized basaloid follicular hamartoma syndrome >> Familial milia and absent dermatoglyphics (FMAD) >> Familial profuse congenital millia >> Nicolau–Balus syndrome >> Hypotrichosis with light-colored hair and facial milia >> KID syndrome >> Loeys–Dietz syndrome.

papules in a neonate. (Courtesy of Dr Antonio Torrelo) Adapted from Berk and Bayliss (2008).107

be present in anhidrotic ectodermal dysplasia and in MarieUnna hypotrichosis.107,109 Milia generally resolve spontaneously over several weeks to months. Incision and expression of keratinous contents are rarely necessary.

MATERNAL AND PLACENTAL HORMONAL EFFECTS: ‘MINIATURE PUBERTY’ OF THE NEWBORN

40% of term newborns.103 The number of milia present can vary from a few to a few hundred. Larger, solitary lesions can be seen on the foreskin, areola, scrotum, labia majora and elsewhere (Fig. 6.16). Lesions may appear at birth or in later infancy, but usually appear and disappear spontaneously during the first month. In some cases, milia may be more persistent. These tiny epidermal inclusion cysts originate from the pilosebaceous apparatus of vellus hair, and contain concentric layers of keratinized stratum corneum. Secondary milia may appear after trauma and may originate from epithelial structures such as sweat ducts, hair follicles, or sebaceous ducts. Milia are numerous and persistent in several genodermatoses (Box 6.2).107–109 In most of these conditions, the onset of the milia is in the neonatal period or in early infancy. Pseudo-milia, lesions that resemble milia clinically but not histologically, may

A number of phenomena occur during the newborn period as a result of the influence of placental and maternal hormones. These have been collectively called ‘miniature puberty of the newborn.’ Hyperpigmentation of the linea alba (linea nigra), scrotum, and external genitalia is frequent and pronounced in dark-skinned newborns. Female genitalia may appear swollen, with an enlarged clitoris. A whitish, creamy vaginal discharge, indistinguishable on vaginal smear from that of a pregnant woman, is common. Within days of birth, desquamation of the hyperplastic vaginal mucosa occurs, leaving a more normal infantile mucosa. Rarely, frank withdrawal bleeding may occur on the third or fourth day of life, lasting several days as a ‘miniature menses.’ Male genitalia appear similarly enlarged and well developed during the newborn period, and both males and females can develop hypertrophy of the mammary glands. In fact, palpable breast tissue hypertrophy is typical of term infants and is used as a measure of gestational maturity in the neonatal Dubowitz scale. The engorged breast tissue can secrete a colostrum-like substance termed ‘witch’s milk’ late during the first week of life. This swelling subsides rapidly and is gone by the end of the first month. Infrequently, stagnant milk in the breast of infants can become infected leading to mastitis (Fig. 6.17) or abscess formation. Staphylococcus aureus is the usual infecting agent. The bacteria are thought to enter the breast tissue through

108. Larralde de Luna M, Raspa ML, Ibargoyen J. Oral-Facial-Digital Type 1 Syndrome of Papillon-Leage and Psaume. Pediatr Dermatol. 1992;9:52–56.

109. Rutter KJ, Judge MR. Profuse congenital milia in a family. Pediatr Dermatol. 2009;26:62–64.

Figure 6.16  Milium: isolated truncal lesion in a 4-week infant.

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6

VASCULAR BIRTHMARKS

Neonatal skin and skin disorders

Figure 6.17  Neonatal mastitis. the hypertrophied ducts. Abscess formation is heralded by the development of redness, swelling, and fluctuance in one breast from 5–20 days after birth. Fever is rare, but systemic antibiotic therapy in this setting is indicated, since untreated infection can lead to bacterial sepsis.

Figure 6.18  Mongolian spot, extensive in Native American infant. (Courtesy of Ronald Hansen, MD)

BIRTHMARKS Margarita Larralde, Paula C. Luna Most birthmarks are collections of highly differentiated cells of one or more of the normal components of the skin. Any of the skin elements can produce a birthmark: melanocytes, blood vessels, lymphatics, epidermis, sebaceous glands, hair follicles, connective tissue, collagen, elastin, and smooth muscle. The congenital malformations produced by these tissue components vary in frequency and importance. For this reason, the term ‘birthmark’ should not be used as a diagnosis. Given that most of these conditions are addressed in detail in other chapters, only a short mention will be made here.

VASCULAR BIRTHMARKS Vascular anomalies are frequently seen in the newborn period (see Ch. 20). They are classified according to the International Society for the Study of Vascular Anomalies (ISSVA) into two main groups: tumors and malformations. Tumors demonstrate cellular hyperplasia while vascular malformations show dysplastic vessels. The first group includes infantile hemangioma, congenital hemangiomas, tufted angioma and Kaposiform hemangioendothelioma. Infantile hemangiomas are the most frequent benign tumor of childhood; completely developed lesions are typically not usually present at birth but tend to grow during the neonatal period. Malformations are divided according to the type of vessel involved into capillary, venous, lymphatic, arteriovenous and

Figure 6.19  Congenital smooth muscle hamartoma. (Courtesy of Dr Antonio Torrelo)

other combined malformations. Capillary and venous malformations are always evident at birth. Lymphatic malformations are usually evident at birth but some deep ones are not evident until bleeding occurs into them at a later stage. Arteriovenous malformations are usually evident to some extent at birth but may remain clinically undiagnosed until they undergo alteration later in childhood or, particularly, after puberty. 313

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Neonatal and Inherited Disorders

Table 6.3  Hyperpigmented lesions that may be present at birth

HYPOPIGMENTED BIRTHMARKS

314

DIAGNOSIS

SHAPE

COMMON LOCATION

COLOR

SIZE

ASSOCIATIONS

Café au lait macule

Round or oval

Trunk and limbs

Tan

2–20 mm

See Table 6.6

Congenital melanocytic nevus

Variable, may be multiple

All areas

Variable brown to black; sometimes red, blue, and white areas

Small to giant

Melanoma risk, neurocutaneous melanosis, posterior cranial fossa anomalies, vertebral column defects

Nevoid (mosaic) hyperpigmentation

Follows Blaschko lines or segmental Represents mosaicism

All areas

Varying shades of brown

From several cm to extensive

Usually none. McCune-Albright syndrome; occasional neurological and skeletal anomalies

Mongolian spot

Irregular

Buttocks

Blue-gray or blue-green

From 2 cm

GM1 gangliosidosis, Hunter syndrome

Nevus of Ota

Irregular

Periocular

Blue-gray

1→10 cm

Glaucoma, melanoma

Nevus of Ito

Irregular

Supraclavicular or scapular

Blue-gray

1→10 cm

None

Congenital smooth muscle hamartoma

Oval

Trunk and extremities

Pale brown, sometimes skin-colored

3–10 cm

None

Non-organoid (keratinocytic) epidermal nevus

Follows Blaschko lines

Trunk and extremities

Variable shades of brown, subtly or obviously raised

Variable

Skeletal abnormalities

Lentigo

Round or oval

All areas

Medium brown

2–3 mm

Part of speckled lentiginous nevus; part of syndromes, see Table 6.7

Speckled lentiginous nevus

Segmental or follows Blaschko lines Represents mosaicism

All areas

Pale brown background with superimposed darker lentigines

Variable

Usually nil

Plexiform neurofibroma

Irregular

All areas

Lesion itself skin-colored, but often superimposed by large irregular café au lait macule

Variable

Neurofibromatosis

Post-inflammatory hyperpigmentation

Spotty, macular following intrauterine inflammatory phase of transient neonatal pustular dermatosis (pustular melanosis)

All areas

Variable brown; mainly in pigmented individuals

1–2 mm

Transient neonatal pustular dermatosis (pustular melanosis), in the rare situation where pustular phase is not the neonatal presentation

HYPERPIGMENTED BIRTHMARKS

HYPOPIGMENTED BIRTHMARKS

Hyperpigmented lesions are commonly present at birth. The most common are presented in Table 6.3 (Figs 6.18, 6.19). Some lesions are frequently seen in newborns and are rarely of significance, such as Mongolian spots, while others may be associated with systemic diseases and genetic syndromes (Box 6.3 and Table 6.4). Hyperpigmented birthmarks are discussed as distinct entities in other chapters (see Chs 7 and 10).

Although less common than hyperpigmented birthmarks, a number of hypopigmented lesions are present in the newborn period. These are listed in Table 6.5 (Fig. 6.20). In addition to these, more generalized hypopigmentation can occur at birth in a variety of congenital syndromes. These are listed in Table 6.6 (for a more detailed discussion, see Ch. 10).

Neonatal skin and skin disorders

6

Table 6.4  Syndromes associated with multiple lentigines SYNDROME

FEATURES

LEOPARD

Lentigines, EKG abnormalities, ocular hypotelorism, pulmonic stenosis, abnormal genitalia, growth retardation, deafness (LEOPARD)

Peutz–Jeghers

Periorificial, mucosal, and acral lentigines; gastrointestinal polyposis

Carneya

Myxomas, spotty pigmentation, endocrine hyperactivity

NAMEa

Nevi, atrial myxomas, myxoid neurofibromas, ephelides (NAME)

LAMB

a

Lentigines, atrial myxomas, mucocutaneous myxomas, blue nevi (LAMB)

Xeroderma pigmentosa

Lentigines, basal cell CA, squamous cell CA, melanoma, UV light sensitivity

a

HYPERPIGMENTED BIRTHMARKS

NAME and LAMB syndromes are now considered variants of Carney syndrome.

Table 6.5  Hypopigmented or depigmented lesions that may be present at birth LESION

SHAPE

USUAL LOCATION(S)

SIZE

DISTINGUISHING FEATURES

IMPORTANT ASSOCIATIONS

Ash leaf macule

Oval or leaf-shaped

Trunk, extremities

1–3 cm at birth

>1 lesion at birth in 70–90% of cases of tuberous sclerosis

Tuberous sclerosis

Nevus depigmentosus, nevoid (mosaic) hypopigmentation

Follow lines of Blaschko

Trunk, extremities

Small to extensive

Linear or swirled; not fully depigmented

When extensive ocular, skeletal and neurological anomalies may occur

Piebaldism

Poorly defined patches, containing macules of normally pigmented skin

Trunk, extremities; spares hands and feet

Variable

White forelock; totally depigmented

Neurologic deficits (Woolf syndrome); deafness, iris heterochromia (Waardenburg syndrome)

Nevus anemicus

Sharp margination, often surrounding erythema

Usually trunk; rarely limbs

1–3 cm at birth

Outline disappears with pressure, no flare on stroking, no reflex vasodilatation after cold

None

Post-inflammatory hypopigmentation

Variable

Any area

Variable

Sites of previous (intrauterine) inflammation

None

Table 6.6  Syndromes associated with generalized hypopigmentation at birth SYNDROME

ASSOCIATED FINDINGS

Albinism

Strabismus, decreased visual acuity

Hermansky–Pudlak

Bleeding diathesis, visual abnormalities, pulmonary fibrosis, inflammatory bowel disease

Chediak–Higashi

Silver-gray hair, recurrent infection, seizures, pancytopenia, lymphoreticular malignancies

Prader–Willia

Neonatal hypotonia, hyperphagia, developmental delay, mental retardation, ocular abnormalities

Angelmana

Abnormal facies, developmental delay, mental retardation, neurologic abnormalities, ocular abnormalities

Griscelli

Silver-gray hair, T and B cell immunodeficiency, recurrent pyogenic infections, hepatosplenomegaly, neutropenia, thrombocytopenia

Cross

Mental retardation, spastic diplegia, ocular abnormalities

Zyorowski–Margolis syndrome

Heterochromic irides, congenital nerve deafness, mutism

a

Skin pigment dilution present, not true depigmentation.

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Figure 6.20  Ash leaf spots on back of an infant with tuberous sclerosis. (Courtesy of Ronald Hansen, MD)

BOX 6.3 SYNDROMES ASSOCIATED WITH CAFÉ-AULAIT MACULES Strong association

>> Neurofibromatosis >> Ring chromosome type I and II

Figure 6.21  Nevus sebaceous: congenital salmon-colored plaque over temporal scalp of a newborn. (Courtesy of Dr Maureen Rogers)

Less strong association

>> Bloom syndrome >> Ataxia telangiectasia >> Fanconi anemia >> Russell–Silver syndrome >> Watson syndrome >> Jaffe–Campanacci syndrome >> Basal cell nevus syndrome >> Gaucher disease >> Turner syndrome >> Hunter syndrome

EPIDERMAL NEVI Epidermal nevi (see Ch. 7) arise from the embryonic ectoderm which differentiates into both keratinocytes and the cells forming the epidermal appendages. Although epidermal nevi may show a mixture of components, they are best classified according to their predominant component into keratinocytic (non-organoid) nevi and organoid nevi such as sebaceous (Fig. 6.21), follicular, and sweat gland nevi. The general term epidermal nevus is often, however, still used for simplicity. It is now accepted that each type of epidermal nevus represents the cutaneous manifestation of a different mosaic phenotype. These are most often evident in the neonatal period, although they may appear later in childhood. 110. Sadler TW. Head and neck embryology. In: Sadler TW, ed. Langman’s Medical Embryology, 6th ed. Baltimore: Williams & Wilkins; 1998: 213-220. 111. Ford GR, Balakrishnan A, Evans JN, et al. Branchial cleft and pouch anomalies. J Laryngol Otol. 1992;106:137–143.

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DEVELOPMENTAL ANOMALIES Margarita Larralde, Paula C. Luna A number of errors of fetal embryogenesis result in developmental anomalies that are first recognized during the newborn period. This section discusses the clinical and histologic appearance, pathologic mechanisms, and differential diagnosis of some of the more common abnormalities that result from errors in morphogenesis.

BRANCHIAL CLEFTS AND AURICULAR SINUSES The development of the branchial system begins in the fourth and fifth embryonic weeks with the formation of four paired pouches (endoderm) in the lateral pharyngeal wall. At the same time, four grooves (ectoderm), the pharyngeal or bronchial clefts, appear in direct apposition on the external surface of the embryo.110,111 In fish and amphibians, these two structures meet to form open communications known as gills, hence the term branchial.112 However, in the human embryo, only the first cleft and pouch remain in direct approximation, forming the tympanic membrane; the remaining ectodermal clefts are separated from the endodermal pouches by mesodermal tissue.111,113 As a result of the cleft formation, five ridges become apparent on the

112. Willshaw HE, Al-Ashkar F. The branchial arch syndromes. Trans Ophthalmol Soc UK. 1983;103:331–337. 113. Al-Fallouji MAR, Butler MF. First branchial cleft anomaly. Postgrad Med J. 1983;59:447–449.

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NAME

ASSOCIATIONS

Mandibulofacial dysostosis (Treacher–Collins)

Malformed ears, a beaked nose, facial dysostosis, and deafness

Oculoauricular vertebral dysplasia (Goldenhar syndrome)

Ocular lipodermoids, accessory tragi, and mandibular and vertebral abnormalities

Oculomandibular dyscephaly (Hallerman–Strieff syndrome)

Dwarfism, hypotrichosis, atrophic skin, a beaked nose, and abnormal dentition

Pierre–Robin syndrome

Micrognathia, glossoptosis, and neonatal respiratory distress

Branchio-otorenal syndrome

Profound deafness, renal anomalies, preauricular pits, branchial cleft sinus tracts or other branchial pouch anomalies

Branchio-oculofacial syndrome

Branchial cleft sinuses, ocular anomalies including coloboma, cataracts, and microphthalmia, pseudocleft or cleft lip and palate, and unusual facies

lateral surface of the embryo; these are known as the branchial arches (mesoderm). Each arch is composed of a cartilaginous core surrounded by components that subsequently develop into the muscular, vascular and neural components of the ear, lower face and neck. During the sixth embryonic week, the second branchial arch grows caudally over the third and fourth arches, fusing with the epipericardial ridge of the lower neck. Remnants of these lower arches form the cervical sinus.110,113 The first pharyngeal pouch becomes the eustachian tube and the middle ear cavity, while the corresponding branchial cleft remains as the external ear canal. Most of the second pouch is obliterated; the rest forms the palatine tonsil. The third and fourth pouches lose their connections with the pharynx, forming tissue of the thymus and parathyroid gland; the fifth pouch is retained as part of the thyroid gland.110,113 Abnormalities of the branchial system occur whenever a cleft or pouch fails to obliterate, as a result of toxic, mechanical or vascular insults to the 4–8-week-old embryo (Table 6.7).112,114,115 Branchial anomalies can present as a cyst, sinus or fistula.116 The branchial fistulae and cysts are lined with stratified or pseudo­ stratified ciliated columnar epithelium and/or stratified non­ keratinizing squamous epithelium.115 Those lined with squamous epithelium become symptomatic earlier in life. Most complete fistulae and some external sinuses are diagnosed during the newborn period. Internal sinuses, although presumably present at birth, are usually discovered later in life.114,117 Defects of the second branchial cleft are the most common (accounting for >95% of the anomalies).111,118 Incomplete fusion of the second arch as it overgrows the third and fourth arches leaves a track connecting the cervical sinus to the external surface of the embryo. This fistulous opening is usually found anterior

to the lower sternocleidomastoid muscle and may provide drainage for a persistent cervical sinus. Such a remnant is called a lateral cervical cyst and is commonly located below the angle of the jaw.119,120 While these are congenital malformations, they often present in the first to third decade of life. Infection is the most frequent complication of this lesion.119 In addition to lateral cervical cysts, sinuses and fistulae of the second branchial cleft can occur.121 An incomplete external fistula (sinus) with a blind inner pouch is most frequently found.119,120,122 These present at birth as pits or blind-ending tracts in the lower third of the neck, along the anterior border of the sternocleidomastoid muscle. A skin tag, sometimes containing cartilage, can occur at the site of the opening, and the entire tract may be palpable beneath the skin. A discharge frequently occurs if the fistula is complete, and there is risk of infection similar to that seen with the branchial cysts. About 33% of these developmental defects are bilateral.119 Anomalies of the first branchial cleft are less common but have been reported as preauricular cysts or sinuses. They occur more commonly in females and may occur alone or in conjunction with hearing loss.111,123 The cleft extends along the superior anterior border of the sternocleidomastoid muscle, ending in or near the external ear canal or the middle ear.111,123 Defects may present at birth as a progressively enlarging mass or draining sinus in the preauricular (rarely retroauricular) area or in the anterior superior neck. The combination of a sinus in the upper neck with discharge from the ear in the absence of otitis media should suggest this diagnosis.119 The diagnosis can be delayed in cases of first branchial cleft anomalies. It is facilitated by the use of CT, which demonstrates the bony structures and the cystic nature of these lesions better than MRI.124

114. Burge D, Middleton A. Persistent pharyngeal pouch derivatives in the neonate. J Pediatr Surg. 1983;18:230–234. 115. Takimoto T, Itoh M, Furukawa M, et al. Branchial cleft (pouch) anomalies: a review of 42 cases. Auris Nasus Larynx. 1991;18:87–92. 116. Schroeder JW, Mohyuddin N, Maddalozzo J. Branchial anomalies in the pediatric population. Otolaryng Head Neck. 2007;137:289–295. 117. Lin JN, Wang KL. Persistent third brachial apparatus. J Pediatr Surg. 1991;26:663–665. 118. Anciero SP, Waldhausen JHT. Congenital cervical cysts, sinuses and fistulae. Otolaryngol Clin N Am. 2007;40:161–176. 119. Bill AH, Vadheim JL. Cysts, sinuses and fistulas of the neck arising from the first and second branchial clefts. Ann Surg. 1955;142:904–909.

120. Kenealy JF, Torsiglieri AJ, Tom LW. Branchial cleft anomalies: a five-year retrospective review. Trans Penn Acad Ophthalmol Otolaryngol. 1990;42:1022–1025. 121. Maran AGD, Buchanan DR. Branchial cysts, sinuses and fistulae. Clin Otolaryngol. 1978;3:77–92. 122. Agaton-Bonilla FC, Gay-Escoda C. Diagnosis and treatment of branchial cleft cysts and fistulae. A retrospective study of 183 patients. Int J Oral Maxillofac Surg. 1996;25:449–452. 123. Cavo JW, Pratt LL, Alonso SA. First branchial cleft syndrome and associated congenital hearing loss. Laryngoscope. 1976;86:739–745. 124. Mukherji SK, Tart RP, Slattery WH, et al. Evaluation of first branchial anomalies by CT and MR. J Comput Assist Tomogr. 1993;17:576–581.

BRANCHIAL CLEFTS AND AURICULAR SINUSES

Table 6.7  Branchial arch defects

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THYROGLOSSAL DUCT CYSTS

Figure 6.22  Accessory tragus. (Courtesy of Dr Antonio Torrelo)

A more common anomaly found in the preauricular area is the accessory tragus (Fig. 6.22). The tragus is derived from the dorsal portion of the first branchial arch. As the arches grow ventrally to join in the midline during embryogenesis, accessory tragi can be found along the entire course of migration. Clinically, this path is reflected by a line drawn between the tragus and the corner of the mouth or on the neck at the anterior edge of the sternocleidomastoid muscle. Accessory tragi can be unilateral, bilateral, single, or multiple.125 Vellus hairs are often present. They can be soft but are usually firm, due to the presence of cartilage.126 Excision should involve careful dissection of the underlying cartilage, which can extend deeply. Rarely, accessory tragi are associated with other defects of the branchial arches in complex syndromes, such as Goldenhar syndrome. Familial occurrence also occurs.127 Congenital midline cervical clefts, with or without other associated midline defects, such as cleft tongue, lip, mandible, or sternum, are also thought to arise from the first branchial arch as a result of imperfect fusion during embryogenesis.128 They may be associated with skin tags or sinus tracts of the anterior lower midline neck.129 Persistent second, third, or fourth branchial pouches have been misdiagnosed in the neonate as acute suppurative thyroiditis,130 cysts,117 neck abscesses,131 cervical lymphadenitis,132 lymphatic malformations,114 or malignant tumors. A simple diagnostic test is a plain radiograph of the neck, revealing an air-fluid level in the lesion.114 Once identified, fistulography can be used to demonstrate the communication between the pyriform sinus and the cystic mass.133,134 Ultrasound and CT scan are the most up-to-date complementary techniques.118

125. Cosman BC. Bilateral accessory tragus. Cutis. 1993;51:199–200. 126. Satoh T, Tokura Y, Katsumata M, et al. Histological diagnostic criteria for accessory tragi. J Cutan Pathol. 1990;17:206–210. 127. Tadini B, Cambiaghi S, Scarabelli G, et al. Familial occurrence of isolated accessory tragi. Pediatr Dermatol. 1993;10:26–28. 128. Bergevin MA, Sheft S, Myer C, et al. Congenital midline cervical cleft. Pediatr Pathol. 1989;9:731–739. 129. Elgart GW, Patterson JW. Congenital midline hamartoma: case report with histochemical and immunohistochemical findings. Pediatr Dermatol. 1990;7:199–201. 130. Abe K, Fujita H, Matsuura N, et al. A fistula from pyriform sinus in recurrent acute suppurative thyroiditis. Am J Dis Child. 1981;135:178. 131. Rosenfeld RM, Biller HF. Fourth branchial pouch sinus: diagnosis and treatment. J Laryngol Otol. 1991;105:44–50.

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Figure 6.23  Thyroglossal duct cyst. Definitive treatment of all these cysts and fistulae consists of careful and complete surgical removal,115,132 although endoscopy with laser has been reported to be an effective alternative.135 Initial drainage and marsupialization may be adequate,114 but recurrences are common unless the tract is completely destroyed.131

THYROGLOSSAL DUCT CYSTS Thyroglossal duct cysts are relatively common; they are said to be the second most frequent cause of pediatric neck masses (after lymphadenopathy).136 Although they are usually a sporadic developmental anomaly of the anterior neck, familial cases have been reported.137 The cysts result from a failure of obliteration of the embryonic thyroglossal duct. They can be found anywhere along the length of this duct, which corresponds clinically to the midline of the neck.138 The diagnosis of thyroglossal duct cysts usually occurs during the first 5 years, but may be delayed until adulthood. They present as small 1–3 cm, soft, midline anterior neck masses over the hyoid bone that move upward on swallowing or protrusion of the tongue (Fig. 6.23). Occasionally, they open into the mouth, producing an unpleasant taste.138

132. Nonomura N, Ikarashi F, Fujisaki T, et al. Surgical approach to pyriform sinus fistula. Am J Otolaryngol. 1993;14:111–115. 133. Godin MS, Kearns DB, Pransky SM, et al. Fourth branchial pouch sinus: principles of diagnosis and management. Laryngoscope. 1990;100:174–178. 134. Feldman JI, Kearns DB, Pransky SM, et al. Catheterization of branchial sinus tracts. A new method. Int J Pediatr Otorhinolaryngol. 1990;20:1–5. 135. Vermeire V, Moreau P. A case of third pharyngeal pouch sinus. Acta Oto-Rhino-Laryngol Belg. 1993;47:55–58. 136. Enepekides DJ. Management of congenital anomalies of the neck. Facial Plast Surg Clin North Am. 2001;9:131–145. 137. Klin B, Serour F, Fried K, et al. Familial thyroglossal duct cyst. Clin Genet. 1993;43:101–103. 138. Heymann WR. Cutaneous manifestations of thyroid disease. J Am Acad Dermatol. 1992;26:885–902.

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BRONCHOGENIC CYSTS Bronchogenic cysts are rare congenital anomalies that usually occur in the chest or mediastinum, but occasionally in the skin. Cutaneous bronchogenic cysts are characteristically located close to the suprasternal notch or over the manubrium sterni (upper part of sternum).144 They are thought to develop from abnormal budding of the ventral segment of the primitive foregut at division into its tracheal and esophageal components in the fifth or sixth week of gestation, before the sternum has fused.145,146 Bronchogenic cysts of the skin are usually present at birth as asymptomatic nodules that enlarge and discharge mucoid fluid through a skin fistula.147,148 Cysts of the mediastinum can present as stridor in the newborn.145 Histologically, they have a mucosal lining consisting of lamina propria and a pseudostratified columnar ciliated epithelium with goblet cells. The cyst wall contains smooth muscle, mucous glands, and occasionally cartilage. The differential diagnosis includes anomalies of the branchial arches, thyroglossal duct cysts, and teratomas. Nuclear imaging or ultrasound can aid in the diagnosis.144 There are rare reports of malignant degeneration of these cysts.149 Treatment is by surgical excision.

APLASIA CUTIS CONGENITA Aplasia cutis congenita (ACC) is a focal, congenital, localized absence of skin. It is reported to occur in 1–2.8 cases in 10 000 139. Colohan DP, Hillborn M. An unusual case of intermittent upper airway obstruction. J Emerg Med. 1993;11:157–160. 140. Vincent SD, Synhorst JB 2nd. Adenocarcinoma arising in a thyroglossal duct cyst: report of a case and literature review. J Oral Maxillofac Surg. 1989;47:633–635. 141. Lyos AT, Schwartz MR, Malpica A, et al. Hürthle cell adenoma arising in a thyroglossal duct cyst. Head Neck. 1993;15:348–351. 142. Yanagisawa K, Eisen RN, Sasaki CT. Squamous cell carcinoma arising in a thyroglossal duct cyst. Arch Otolaryngol Head Neck Surg. 1992;118:538–541. 143. Radkowski D, Arnold J, Healy GB, et al. Thyroglossal duct remnants. Preoperative evaluation and management. Arch Otolaryngol Head Neck Surg. 1991;117:1378–1381. 144. Patterson JW, Pittman DL, Rich JD. Presternal ciliated cyst. Arch Dermatol. 1984;120:240–242. 145. Kuhn C, Kuhn JP. Coexistence of bronchial atresia and bronchogenic cyst: diagnostic and embryologic considerations. Pediatr Radiol. 1992;22:568–570. 146. Lazar RH, Younis RT, Bassila MN. Bronchogenic cysts: a cause of stridor in the neonate. Am J Otolaryngol. 1991;12:117–121.

APLASIA CUTIS CONGENITA

Multiple complications of these cysts have been described, including thyroiditis, thyrotoxicosis, infection, and airway obstruction.139 Malignant degeneration of these embryologic remnants occurs in 2.5 cm from the anal verge, atypical)

Capillary malformation (port-wine stain)

Acrochordons/pseudo-tails/ true tails

Hyperpigmentation

Lipomas

Melanocytic nevi

Hemangiomas

Teratomas

Aplasia cutis or scar Dermoid cyst or sinus After Drolet (2001).152

Spinal dysraphism (SD) is a term coined by Lichtenstein in 1940 to refer to a group of congenital malformations with incomplete fusion of the posterior midline embryonic structures. This failure is thought to be produced by a delay or alteration in the sequence of closure, a reopening, or an incomplete regression of the caudal end of the neural tube.201 A multifactorial etiology is reported. It may occur in various genetic and malformation syndromes or as a result of nutritional and teratogenic factors. The skin and nervous system are intimately related by their common ectodermal origin; between the third and fifth week of intrauterine life the neural groove separates from the ectodermal epithelium and is surrounded by mesodermal structures to form the cerebrospinal axis. Hence, it is not unexpected that an abnormal event in some part of this process produces simultaneous malformations. Spinal dysraphism may be grouped into four types, depending on the developmental anomaly: (1) a simple incomplete fusion

of the elements, e.g., spina bifida; (2) a failure of separation of germinal layers, e.g., a dimple; (3) abnormal growth of cell nests of one germinal layer remaining among the cells of another, e.g., dermoid or epidermoid cyst; (4) a disturbance in the growth of normal tissue leading to the formation of intraspinal or intramedullary tumors, e.g., lipoma.202 Combinations of these anomalies are often found. When overt, SD is easily recognized; but occult forms may be unnoticed until neurological symptoms become apparent. Cutaneous markers are reported to be present in 50–80% of patients.202,203 These lesions are usually already evident at birth, which can point to the underlying pathology. These are most important to recognize, as a delay in diagnosis increases the child’s risk of progressive neurologic and urologic deterioration (Table 6.9). The cutaneous stigmata of SD are located on or near midline and include a wide variety of lesions. A combination of two or more of these lesions has proven to be a strong marker of SD.204 They include depressed lesions, dermal lesions, dyschromic lesions, hairy lesions, neoplasms, polypoid lesions, subcutaneous nodules and vascular lesions.205,206 They occur particularly with spinal deformities in the lumbosacrococcygeal region. Skin dimples are round depressions with a frequency that ranges from 4–23% in different series.203 So-called simple dimples (5 mm, further than 2.5 cm from the anus), and particularly if associated with other cutaneous stigmata, then the possibility of an associated SD rises to 40%. These larger lesions usually represent fixation of the skin to bony or fibrous structures.206 Dermal sinus tracts are often associated with dermoid or epidermoid cysts. The sinus may connect the skin directly with the spinal cord and hence there is a significant risk of infection, including meningitis and epidural, subdural or spinal cord abscesses.205 Large cysts may cause neurological compromise due to compression.206 When the tract is superficial to the sacral fascia and contains hairs, is called a pilonidal sinus, and is almost never accompanied by neurological damage.206 Aplasia cutis congenita, presenting as a congenital scar-like defect over the spinal column, has also been described as a marker of SD. These lesions may have a hair collar and can be associated with other cutaneous markers such as lipoma or localized hypertrichosis.208 Under these circumstances, the possibility of an association with SD is even greater. A hairy patch is the most common cutaneous sign of SD evident at birth and can point to skeletal abnormalities at various levels of the cord. Abnormal lumbar hypertrichosis may present as ‘silky down’ or a ‘faun tail.’ Silky down is represented by tufts of hair with the texture of fine, soft, non-terminal, or lanugo hair. A faun tail is rarer and is a wide, often triangular or lozengeshaped (rhomboidal) patch of coarse hair, usually several inches long.209 It is important to appreciate that mild hypertrichosis on the back, including the lumbar area, is a common normal finding in certain ethnic groups, such as Middle-Eastern.206 Congenital lipomas are manifested as soft swellings consisting of a mass of adipose tissue. They mostly occur in the midline of the lower cervical, upper thoracic and lumbar spine, regions that correspond to the last sites of closure of the embryonic neural arch. In some instances, the lipoma may be slightly lateral to the spinal column. The overlying skin may be normal in appearance, or may be marked by dimpling, abnormal hair, or a vascular lesion (Fig. 6.28).202,205 Congenital lipomas are histologically non-encapsulated and are finely lobulated. They may be superficially located or may penetrate into the intraspinal space; frequently they are attached to the dura by a fibrous stalk and on some occasions, particularly when placed lateral to the midline, are associated with a meningocele (lipomyelomeningocele). Intraspinal lipomas are a marker of a tethered cord. ‘Human tails’ are rare caudal appendages found in the sacrococcygeal or lumbar region; true tails (vestigial tails) and pseudotails can be distinguished.210 The latter are a secondary protrusion caused by various anomalies or neoplasms such as anomalous vertebra, lipoma, teratoma and chondrodystrophy. Both types of ‘tail’ are highly associated with SD.210 Vascular lesions such as sacral hemangiomas are also described in association with spinal lesions; they are usually larger than 4 cm, overlie the midline and may have a central scar-like lesion

208. Calikoğlu E, Oztaş P, Yavuzer AR, et al. Faun tail with aplasia cutis congenita and diastematomyelia. Dermatology. 2004;209:333–334. 209. Senayli A, Sezer E, Sezer T, et al. Coexistence of sacral dimple, solitary collagenoma and mid-dorsal hypertrichosis in a child with occult spinal dysraphism. Br J Dermatol. 2007;156:1065–1066. 210. Muthukumar N. The ‘Human Tail’: A rare cause of tethered cord. A case report. Spine. 2004;29:E476–E478. 211. Albright AL, Gartner JC, Weiner GS. Lumbar cutaneous hemangiomas as indicators of tethered spinal cords. Pediatrics. 1989;31:63–70.

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Figure 6.28  Lipoma associated with meningocele (lipomeningocele). Note papular hemangioma as well. (Courtesy of Dr Maureen Rogers)

associated.211 Capillary malformations in the lumbosacral area are usually unassociated with SD,212 but there are rare reports of the association.213 Other skin lesions such as pigmented macules, congenital melanocytic nevi, hamartomas and neurofibromas, may also occur in association with SD and sacrococcygeal teratomas. Careful investigation should be undertaken prior to embarking upon a surgical procedure. High-resolution ultrasonography of the lesion and spinal cord is particularly useful in infants under 3–4 months of age because until then, the posterior bony elements of the spine are not yet fused.214 MRI provides the most accurate information in a non-invasive manner. CT myelography may be required in the very complex abnormalities. The removal of the skin lesions that are suspected to be associated with spinal dysraphism without a previous diagnostic evaluation is contraindicated; doing a biopsy is hazardous because of the risk of introduction of infection into the spinal canal.215 When a skin lesion that may be related to an underlying spinal dysraphism is detected, referral to a neurosurgeon should occur.

DERMOID CYSTS Dermoid cysts are congenital subcutaneous ectodermal growths that occur along embryonic fusion lines. They are unrelated to

212. Patrizi A, Neri I, Orlandi C, et al. Sacral medial telangiectatic vascular nevus: A study of 43 children. Dermatol. 1996;192:301–306. 213. Ben-Amitai D, Davidson S, Schwartz M, et al. Sacral nevus flammeus simplex: The role of imaging. Ped Dermatol. 2000;17:469–471. 214. Kriss V, Kriss T. Occult spinal dysraphism in the infant. Clin Ped. 1995;34:650–655. 215. Larralde M. Dermatological lesions in the midline. In: Dyall Smith D, Marks R, eds. Dermatology at the millennium. New York: Parthenon; 1998:470–473.

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TUMOR

CLINICAL FEATURES

Dermoid cyst

Mobile, solid, skin-colored tumor May have sinus and hair Does not transilluminate Non-pulsatile Frequent infection

Encephalocele

Blue, soft, pulsatile, compressible tumor Enlarges with crying and compression of jugular veins May transilluminate

Nasal glioma

Mobile, red-blue, firm tumor Non-compressible Does not transilluminate Non-pulsatile

Hemangioma

Mobile, red-blue, doughy tumor Non-compressible

Epidermoid cyst

Mobile, cystic, skin-colored to yellow tumor May have sinus opening

Infiltrative tumors

Firm, fixed tumor Irregular shaped Skin-colored

Figure 6.29  Small midline nasal dermoid cyst.

benign cystic teratomas, which are also referred to as dermoids. While dermoid cysts are congenital, they may not be noted until early childhood; 40% manifest at birth, and 70% by age 5 years. If small, they may not be noticed until they become inflamed in later life. Lesions present as soft or rubbery, round, subcutaneous tumors measuring 1–4 cm in diameter.216 They are non-compressible and do not transilluminate or enlarge with Valsalva maneuvers. They are most common on the upper lateral region of the forehead within or near the outer third of the eyebrow, overlying the anterior fontanelle, in the midline of the nose (from the glabella to the nasal columella) (Fig. 6.29), and in the submental region, although they may occur anywhere on the scalp, face, or spinal axis.216,217 The epidermis is clinically normal and freely moveable over the cyst. They are typically single lesions, but more than one may be present. There is often a sinus opening from which hairs may project. Although most dermoid cysts are superficial, dermal sinuses within these defects can extend intracranially to the extradural or intradural compartments. Up to 45% of cysts have been associated with intracranial connections.218 Such connections are more frequent in the presence of a sinus pit. There is also increased association with other anomalies in children with this defect.217,218 Although these cysts are usually asymptomatic, recurrent infections can occur, including periorbital or nasal cellulitis or abscesses, with rare osteomyelitis or meningitis.218 Pressure erosion of bone is another occasional complication. Histologically, dermoid cysts are encapsulated and differ from other types of cysts in that the wall is composed of keratinizing, stratified, squamous epithelium, complete with hair follicles, sebaceous glands, and frequently eccrine and apocrine glands.219 The lumen contains lipid, keratin and hair.

216. Paller AS, Pensler J, Tomita T. Nasal midline masses in infants and children. Dermoids, encephaloceles, and nasal gliomas. Arch Dermatol. 1991;127:362–366. 217. Szeremeta W, Parikh TD, Widelitz JS. Congenital nasal malformations. Otolaryngol Clin North Am. 2007;40:97–112. 218. Wardinsky TD, Poagon RA, Kropp RJ, et al. Nasal dermoid sinus cysts: association with intracranial extension and multiple malformations. Cleft Palate Craniofac J. 1991;28:87–95.

DERMOID CYSTS

Table 6.10  Differential diagnosis of midline facial lesions

Adapted from Paller et al. (1991).216

The differential diagnosis of these lesions varies with anatomic location. When located on the neck, thyroglossal duct cyst, branchial cyst, submaxillary cyst, and ectopic thyroid tissue should be considered. For this reason, all patients with a midline anterior cervical mass should be evaluated, with thyroid function tests and/or 99mTc or 123I scintillation scanning, to identify any possible ectopic thyroid tissue.220 Nuclear imaging can be used for positive identification and delineation of these anomalies prior to surgery. Central facial lesions raise a differential diagnosis of hemangioma, encephalocele, nasal glioma, epidermoid cysts and infiltrative tumors (Table 6.10). Midline lesions on the face should be evaluated with MRI or axial CT; MRI has greater sensitivity, while CT may be superior for delineation of bony defects.221 High-resolution ultrasound with Doppler has also been used successfully to delineate subtle structural abnormalities of the midline face.222 Biopsy of midline nasal masses should be avoided until intracranial connections are ruled out. The imaging studies may show intracranial masses or bony distortion; the former confirms the presence of an intracranial connection, but in patients with the latter there may be no evidence of a connection on surgical exploration.

219. Acierno SP, Waldhausen JH. Congenital cervical cysts, sinuses and fistulae. Otolaryngol Clin North Am. 2007;40:161–176. 220. Conklin WT, Davis RM, Dabb RW, et al. Hypothyroidism following removal of a ‘thyroglossal duct cyst.’ Plast Reconstr Surg. 1981;68:930–932. 221. Barkovich AJ, Vandermarck P, Edwards MS, et al. Congenital nasal masses: CT and MR imaging features in 16 cases. Am J Neuroradiol. 1991;12:105–116. 222. Glasier CM, Brodsky MC, Leithiser RE, et al. High resolution ultrasound with Doppler: a diagnostic adjunct in orbital and ocular lesions in children. Pediatr Radiol. 1992;22:174–178.

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Figure 6.30  Frontal encephalocele. (Courtesy of Odile Enjolras, MD)

Surgery is essential for all lesions with intracranial connections to avoid the risk of local or ascending infection. Removal may be difficult if the cyst has extended into surrounding structures through the cranial sutures and the patient should be managed by an experienced team often including pediatric otolaryngologist, neurosurgeon, and plastic surgeon. An external rhinoplasty approach can be used to improve the final cosmetic result by avoiding the standard vertical midline scar.223

ENCEPHALOCELE AND MENINGOCELE These are developmental anomalies in which herniation of intracranial tissues occurs secondary to faulty closure of the neural tube so that a connection from the skin to intracranial structures remains via a persistent skull defect. There seems to be a disturbance in the separation of neural and surface ectoderm during the final part of neural tube formation.224 An encephalocele is a herniation of brain tissue and meninges through the skull. These lesions occur in the occipital area or parietal area (cranial encephalocele), or in the frontal area (frontal encephalocele) (Fig. 6.30). Cranial encephaloceles, which are most common in the occipital area, present as cystic swellings which may be extremely large; the surface may be covered with skin or be a glistening membrane. Cranial meningocele is exactly equivalent to cranial encephalocele but the sac contains no neural tissue but only cerebrospinal fluid. The most common type of encephalocele, and that most likely to come to the attention of a pediatric dermatologist, is the frontal midline encephalocele. These lesions can be fronto-­ethmoid,

223. Morrisey MS, Bailey CM. External rhinoplasty approach for nasal dermoids in children. Ear Nose Throat J. 1991;70:445–449. 224. Hoving EW. Nasal encephaloceles. Childs Nerv Syst. 2000;16:702–706. 225. Moore MH, Lodge ML, David DJ. Basal encephalocoele: imaging and exposing the hernia. Br J Plast Surg. 1993;46:497–502. 226. Huisman TA, Schneider JF, Kellenberger CJ, et al. Developmental nasal midline masses in children: neuroradiological evaluation. Eur Radiol. 2004;14:243–249.

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with herniation through the ethmoid plate behind the crista galli, or nasofrontal, with herniation anterior to the crista galli.216 Frontal midline encephaloceles are usually diagnosed in the newborn period. They commonly present as nasal broadening (67%) or as a blue, pulsatile, transilluminating mass on the nasal bridge. The masses are soft and increase in size with Valsalva maneuvers, crying, or compression of the jugular veins. Histologically, the lesion is found to contain astrocytes and interweaving strands of fibrous tissue. Occasionally, neurons or muscle fibers are also present.224 Differential diagnosis of frontal encephalocele includes hemangioma, nasal glioma and dermoid cyst. The deformity of the nasal root may be erroneously interpreted as hypertelorism. Infants should undergo a thorough evaluation for other associated anomalies, especially in the midline. Facial clefting is the most common association. Unsuspected encephaloceles have been reported in cases of median cleft face syndrome after CT or MRI.225 Infection and bony atropy or distortion can result if these lesions are not surgically excised early in life. An adequate preoperative workup is imperative to plan the appropriate therapeutic intervention and to avoid complications.226 CT and MRI are vital to define the extent of the complex tumor mass.221 The combined efforts of a pediatric otolaryngologist and neurosurgeon are usually required for removal of both intracranial and extracranial portions of these developmental defects. Complete excision is essential to prevent recurrence; obliteration of the bone and dural defects is necessary to prevent ascending infection.227

RUDIMENTARY MENINGOCELE AND HETEROTOPIC BRAIN TISSUE Rudimentary meningocele and heterotopic brain tissue (HBT) in the head area result from a similar process to that for true encephaloceles and meningoceles. The tissues are sequestrated from the brain and cranial vault early in developmental life with the skull defect closing and the stalk degenerating or remaining as a fibrous track.228 In HBT there is cerebral tissue, with or without meningeal tissue, in a cutaneous location; in rudimentary meningocele there is meningeal tissue without brain tissue. Nasal glioma, which is discussed below, is the term used for HBT in the nasal area. Rudimentary meningoceles can occur also over the midline posterior spine, by an analogous process of faulty neural tube closure. Rudimentary meningocele and HBT on the scalp occur predominantly in the parietal or occipital areas and the appearances can overlap. They can present as a nodule, cyst or membranous aplasia cutis-like area. Often a collar of longer hair surrounds the lesion. The microscopic features are often subtle, with meningeal tissue simulating the appearance of vascular or connective tissue.

227. Kennard CD, Rasmussen JE. Congenital midline nasal masses: diagnosis and management. J Dermatol Surg Oncol. 1990;16:1025–1036. 228. El Shabrawi-Caelen L, White WL, Soyer HP, et al. Rudimentary meningocele: Remnant of a neural tube defect? Arch Dermatol. 2001;137:45–50.

Neonatal skin and skin disorders

Meningocytes tend to encircle collagen bundles and are sometimes accompanied by psammoma bodies; these signs should be sought as clues to the microscopic diagnosis. When brain tissue is present astrocytes will be found. In the majority of cases, no underlying bony defect or communication to the meninges can be detected. However, in light of the probable pathogenesis, imaging studies to exclude any communication to the central nervous system should precede any invasive evaluation or intervention.

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may be used to distinguish the interfaces among cartilage, bone, brain and fluid, while diffusion MRI will allow detection of other lesions and has the capacity to evaluate the brain for associated cerebral anomalies.229 Appropriate neuroimaging should always be performed prior to biopsy or surgery because it is essential to characterize these lesions to determine the exact location and most importantly to exclude a possible intracranial extension or connection.229 Treatment of these lesions is surgical and should involve experienced pediatric otolaryngologists, often in collaboration with plastic surgeons and neurosurgeons.216

NASAL GLIOMA UMBILICAL POLYP

Nasal glioma is a clinically characteristic form of heterotopic brain tissue, also known as congenital nasal neuroectodermal tumor, nasal cerebral heterotopia and glial heterotopia.229 It is a rare tumor that presents at birth or shortly thereafter as a firm bluish or red swelling of the nasal root,227 usually over the glabella, although it can be located slightly off midline.229 It is composed of ectopic neural tissue and can be regarded as analogous to a frontal encephalocele. Unlike true encephalocele, however, it does not have an intact intracranial connection, it is firmer on palpation, and does not increase in size with crying or the Valsalva maneuver.216 The pathogenesis of nasal glioma is thought to involve evagination of neuroectodermal tissue through the nasofrontal fontanelle during development. Normally, this tissue retracts with formation of the dura, but failure of complete retraction can lead to amputation of tissue with closure of the craniofrontal sutures. A stalk of fibroglial tissue can connect these tumors to the underlying brain through the foramen cecum.230 Nasal glioma is usually external (60%),183 but 30% are intranasal or extend into the oropharynx.216 The latter tumor can be a cause of upper respiratory obstruction in the newborn.231 Ten percent of patients present with both intra- and extra-nasal gliomas.232 Histologically, they are characterized by astrocytes and neuroglial fibers intermixed with a fibrovascular connective tissue stroma. Striated muscle can be found in the dermis.233 Neurons and ependymal cells, as well as focal calcification and inflammatory cells, can also occasionally be present. Immunohistochemical reactivity with glial fibrillary acidic protein and S-100 protein will help to confirm the histologic diagnosis, while collagen type IV and laminin can highlight the reactive fibrosis.232 The differential diagnosis of nasal glioma includes encephalocele, hemangioma, nasal dermoid, lacrimal duct cyst, neuro­ blastoma, and rhabdomyosarcoma. It is most commonly mistaken for a deep hemangioma, as it may be bluish in appearance with overlying telangiectasias.234 Evaluation should include a CT or MRI.221 MRI is the modality of choice for assessing the pediatric frontonasal region because it is more sensitive than CT for soft tissue imaging.230 Helical CT

Meckel’s diverticulum is the most common anomaly and occurs in 1–3% of the population.235,236,237 Umbilical polyp is less common and may occur alone or in association with other omphalomesenteric duct anomalies including Meckel’s diverticulum, a fibrous band from the umbilicus to the intestine, or a vitelline cyst. As a consequence, it may be associated with significant complications such as intestinal obstruction, gastrointestinal bleeding, perforation, intussusception and diverticulitis.235,237 The umbilical polyp is a reddish tumor of a few millimeters in diameter; it seldom bleeds or is exudative and typically does not disappear after silver nitrate cauterization. Histopathology shows ectopic gastrointestinal epithelium with the appearance of gastric, intestinal or colonic mucosa, and in rare instances pancreatic tissue can be seen. The differential diagnosis includes umbilical granuloma and lesions associated with the persistence of the embryonic urachus, a fibrous cord that develops from the urogenital sinus. On some occasions a paraumbilical nodule can be seen related to a urachal

229. Hedlund G. Congenital frontonasal masses: developmental anatomy, malformations, and MR imaging. Pediatr Radiol. 2006;36:647–662. 230. Whitaker SR, Sprinkle PM, Chou SM. Nasal glioma. Arch Otolaryngol. 1981;107:550–554. 231. Puppala B, Mangurten HH, McFadden J. Nasal glioma. Presenting as neonatal respiratory distress. Definition of the tumor mass by MRI. Clin Pediatr. 1990;29:49–52. 232. Khanna G, Sato Y, Smith RJ, et al. Causes of facial swelling in pediatric patients: correlation of clinical and radiologic findings. Radiographics. 2006;26:157–171.

233. Fletcher CDM, Carpenter C, McKee PH. Nasal glioma: a rarity. Am J Dermatopathol. 1986;8:341–346. 234. Levine MR, Kellis A, Lash R. Nasal glioma masquerading as a capillary hemangioma. Ophthalmol Plast Reconstruct Surg. 1993;9:132–134. 235. Larralde M, Ciccioni V, Herrera A, et al. Umbilical polyps. Pediatr Dermatol. 1987;4:341–343. 236. Nix TE, Young JC. Congenital umbilical anomalies. Arch Dermatol. 1964;90:160–165. 237. Armstrong DKB, Thornton C, Bingham A. Infantile umbilical polyp: important diagnostic considerations. Dermatology. 1998;197:94.

UMBILICAL POLYP

Umbilical polyp is an uncommon condition present at birth or arising during infancy, that consists of umbilical remnants of ectopic gastrointestinal mucosa caused by incomplete closure of the omphalomesenteric duct.235 This omphalomesenteric (vitelline) duct, which connects the mid-gut with the yolk sac of the embryo, usually disappears during the seventh week of embryonic life. A remnant of the duct may persist anywhere along its embryonic course from the skin to the intestine, and may give rise to the formation of polyps, sinuses, or cysts with or without connection to the intestine or to the skin surface. Nix and Young236 classified the conditions as: 1. Complete patency (umbilical–enteric fistula) 2. Partial patency a. Peripheral portion (umbilical sinus) b. Intermediate portion (vitelline cyst) c. Enteric portion (Meckel’s diverticulum) 3. Mucosal remnant at the umbilicus (umbilical polyp) 4. Congenital band (obliterated vitellointestinal duct).

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cyst or sinus; there may be drainage of urine from a fistula connecting the umbilicus to the bladder. The parents must be educated regarding the possibility of persistent intra-abdominal remnants. Internal omphalomesenteric duct polyps have been found in up to 60% of the patients with umbilical polyps who have undergone surgical exploration, although the actual frequency is unknown. If significant abdominal symptoms develop during the patient’s lifetime, immediate surgical evaluation is needed.235

UMBILICAL GRANULOMA VESICULOPUSTULAR, BULLOUS AND EROSIVE DISEASES OF THE NEWBORN

This is the most frequent umbilical lesion seen during the neonatal period. It consists of a bright red, friable, velvety tumor within the umbilical region. It usually develops during the first few weeks of life. Granulation tissue may persist at the base of the umbilicus after cord separation. The tissue is composed of fibroblasts and capillaries and can grow to >1 cm. Management is usually straightforward with weekly applications of silver nitrate being the most frequently used treatment. A small randomized controlled study concluded that conservative measures such as air drying with alcohol wipes should be tried before cauterizing with silver nitrate.238 Other interventions sometimes used are cryosurgery, electrocautery and double ligature. Persistence of the lesion through several applications of silver nitrate should warrant further evaluation to rule out other lesions of the umbilicus such as umbilical polyp, umbilical hernia, and persistent urachus.

CONGENITAL PEDAL PAPULES IN THE NEWBORN Congenital pedal papules are characteristically bilateral, symmetrical, subcutaneous nodules on the plantar surfaces of the heels, present from birth. The condition was first described by Larralde et al. in 1990,239 reporting four cases and describing their similarity to adult piezogenic papules. Subsequently, more cases have been reported.240 Although they have been regarded as a rare condition, they were found in 5.9% of 269 newborns evaluated by Greenberg and Krafchik.241 They present as 0.5– 1 cm diameter, skin-colored, non-inflammatory, asymptomatic, soft lesions on the plantar surface of each heel (Fig. 6.31). They tend to persist and grow in proportion to the growth of the child. Rarer variants are unilateral lesions and those which develop several weeks after birth. Histopathological examination demonstrates mature adipose tissue in the reticular dermis and subcutis, enveloped in predominantly collagenous fibrous 238. Daniels J, Craig F, Wajed R, et al. Umbilical granulomas: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2003;88:F257. 239. Larralde de Luna M, Ruiz León J, Cabrera HN. Papulas podálicas en el recién nacido. Med Cut ILA. 1990;18:9–12. 240. Ortega Monzó C, Molina-Gallardo I, Monteagudo-Castro C, et al. Precalcaneal congenital fibrolipomatous hamartoma: a report of four cases. Pediatr Dermatol. 2000;17:429–431. 241. Greenberg S, Krafchik BR. Infantile pedal papules. J Am Acad Dermatol. 2005;53:333–334. 242. Meyer P, Soennichsen K, Buchenau W. Autosomal dominant precalcaneal congenital fibrolipomatous hamartoma. Pediatr Dermatol. 2005;22:355–356.

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Figure 6.31  Congenital pedal papules. These were bilateral and biopsy confirmed lipomatous nature. (Courtesy of Ronald Hansen, MD)

sheaths.240 The epidermis is normal and no inflammatory changes are observed. In the literature this condition can be found under a variety of different names including congenital fibrolipomata, podalic papules in the newborn, bilateral congenital fatty heel pads, precalcaneal congenital fibrolipomatous hamartoma, bilateral congenital adipose plantar nodules, benign anteromedial plantar nodules of childhood and congenital piezogenic-like pedal papules. Although it has been classically regarded as a sporadic disease, at least two familial cases have been reported in the last few years. In one case occurring in a father and two daughters242 and another in two half brothers,243 the possibility is raised of this being inherited as autosomal dominant trait with variable expressivity. The exact pathogenesis of these lesions is unclear but incomplete regression of fetal tissue has been suggested. It is important to separate this benign condition from more serious entities such as juvenile fibromatosis, plantar aponeurotic fibroma and childhood fibrous hamartoma.240

VESICULOPUSTULAR, BULLOUS AND EROSIVE DISEASES OF THE NEWBORN Margarita Larralde, Paula C. Luna Vescicules, pustules, bullae and erosions are common in neonates and are considered together in this section because they may overlap or coincide.244–246 Vesicles and pustules particularly 243. Fangman WL, Prose NS. Precalcaneal congenital fibrolipomatous hamartomas: report of occurrence in half brothers. Pediatr Dermatol. 2004;21:655–656. 244. Frieden IJ. The dermatologist in the newborn nursery: approach to the neonate with blisters, pustules, erosions, and ulcerations. Curr Probl Dermatol. 1992;4:123–168. 245. Wagner A. Distinguishing vesicular and pustular disorders in the neonate. Curr Opin Pediatr. 1997;9:396–405. 246. van Praag MC, van Rooij RW, Folkers E, et al. Diagnosis and treatment of pustular disorders in the neonate. Pediatr Dermatol. 1997;14:131– 143.

Neonatal skin and skin disorders

NEONATAL DISORDERS PRESENTING WITH VESICULOPUSTULAR LESIONS Causes of neonatal vesiculopustular eruptions can be grossly divided into non-infective and infective and further into benign and potentially serious (Box 6.4). In the non-infective group can be found benign transient conditions, the neonatal presentation of certain cutaneous diseases and cutaneous presentations of several important systemic diseases. In the infective group are viral, bacterial and fungal infections and parasitic infestations; these can be divided into conditions which are usually benign those which are serious or potentially so. Many of these conditions, particularly the infections, are discussed elsewhere in this chapter or in other chapters and will not be discussed in detail here. Table 6.11 addresses the characteristics of some of these vesiculopustular disorders and the features which may aid in their distinction from each other.

BOX 6.4 DIFFERENTIAL DIAGNOSIS OF NEONATAL VESICULOPUSTULAR DISEASES

Non-infectious: Benign

>> Acropustulosis of infancy >> Eosinophilic pustular folliculitis >> Erythema toxicum >> Miliaria crystallina, rubra, profunda >> Transient neonatal pustular melanosis >> Neonatal cephalic pustulosis

Non-infectious: Potentially serious

>> Incontinentia pigmenti >> Langerhans cell histiocytosis >> Vesiculopustular eruptions in myeloproliferative disorder and

ERYTHEMA TOXICUM NEONATORUM (TOXIC ERYTHEMA OF THE NEWBORN)

overlap and the term vesiculopustular is often appropriate. Conditions presenting in the neonatal period mainly with a vesiculopustular eruption will be addressed first, followed by those presenting mainly with bullae and erosions. Some conditions, in particular infections, can be in both groups. Many of the conditions are benign, innocuous and self-limiting while others are life-threatening. Prompt and accurate diagnosis is necessary.

6

Down syndrome

>> Eosinophilic pustulosis in hyper IgE syndrome Infectious: Usually benign

>> Candidiasis – neonatal >> Impetigo neonatorum >> Scabies

Infectious: Potentially serious

>> Bacterial infections – Chlamydia trachomatis – Escherichia coli – Haemophilus influenzae

ERYTHEMA TOXICUM NEONATORUM (TOXIC ERYTHEMA OF THE NEWBORN)

– Klebsiella pneumoniae

Erythema toxicum neonatorum is a benign, self-limiting condition of the neonatal period. It was probably first described by Metlinger in 1472.247 It is very common in term infants, but is rare in preterm infants and infants with a birth weight of > Candidiasis: congenital >> Viral infections – Cytomegalic – Herpes – Varicella

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330

INCIDENCE

1%

Rare

Incidence, 1%; equal sex incidence

Incidence approximately 4–5%

Incidence, 1%; possibly increased in blacks and males

Approximately 1/3 of full-term newborns

DISEASE

Impetigo neonatorum

Neonatal scabies

Candidiasis, congenital

Candidiasis, neonatal

Acropustulosis of infancy

Erythema toxicum neonatorum

2 weeks

Until treated

5–10 days

DURATION

24–72 h

Hours after birth to 10 months

1 week

2–3 years

After the first week 2 weeks of life

Birth to 24 h

2–4 weeks

Second day to second week

USUAL AGE OF ONSET

Diffuse generalized

Hands, feet, trunk, genitalia

Diaper area, neck, groin, axilla

Red macules and papules, white to pink pustules, vesicles

Red papules evolving into pustular and vesicular lesions in 1 day

Trunk, extremities, face

Hands, feet, both surfaces

Pink to red macules Oral mucosa, and papules diaper area evolving into pustules and vesicles

Pink to red macules and papules evolving into pustules and vesicles

Vesicles and papules; rare burrows

Vesicles, pustules, plus bullae on an erythematous base

LESIONS

DISTRIBUTION

Subcomal pustules with eosinophils associated with pilosebaceous system

Subcorneal pustules with neutrophils and occasionally eosinophils

Subcorneal pustules with pseudohyphae and spores

Subcorneal pustules with pseudohyphae and spores

Subcorneal burrow with mite, eggs, scybala

Subcorneal pustules with Gram-positive cocci in clusters and neutrophils

PATHOLOGY

ERYTHEMA TOXICUM NEONATORUM (TOXIC ERYTHEMA OF THE NEWBORN)

Table 6.11  Comparison of some vesiculopustular diseases of the neonate and young infant

Gram: eosinophils, no bacteria KOH: negative; Wright and Giemsa: eosinophils

Gram: neutrophils, no bacteria KOH: negative Wright and Giemsa: neutrophils

KOH: pseudohyphae Others: negative

KOH: pseudohyphae and spores Others: negative

Oil prep: mite, eggs, scybala

Gram: Grampositive cocci in clusters and neutrophils, KOH: negative, Wright, Giemsa: neutrophils

STAINS

None

Continued

Potent topical steroids, oral antihistamines; consider dapsone 1–3 mg/kg per day with caution for severe cases

Topical anticandidal agent (e.g., nystatin, clotrimazole, or miconazole for 10 days: nystatin suspension/oral fluconazole for persistent thrush

Topical anticandidal agent (e.g., nystatin, clotrimazole, or miconazole) for 10 days: oral fluconazole if severe, and for Candida sepsis in premature

5% permethrin cream overnight

Dicloxacillin, 12.5–25 mg/kg per day; cephalexin, 40 mg/kg per day; for 10-day course

TREATMENT

ii Neonatal and Inherited Disorders

INCIDENCE

Very rare

Equal among sexes and races

Equal among sexes and races

5% of all black neonates; 1% in Caucasians

Very rare

Very rare

DISEASE

Eosinophilic pustular folliculitis

Miliaria crystallina

Miliaria rubra

Transient neonatal pustular melanosis

Congenital and neonatal Langerhans cell histiocytosis

Myeloproliferative disorder in Down syndrome

Parallels hematologic disease, lasts 1 or 2 months

Variable from weeks to months

Pustules; days; macules: 3 months

Hours to days

Hours to days

Years

DURATION

Pustules and crusts over erythematous base

Congenital: Eroded and crusted papules and nodules. Rare single lesions. Neonatal may simulate seborrheic dermatitis

Vesicles and pustules desquamate leaving brown macules

Grouped erythematous papules

Clear vesicles

Crops of papules, vesicles, and pustules that crust

LESIONS

Face

Anywhere; neonatal may predominate over scalp, retroauricular and diaper areas

All areas

Often mainly face; may be generalized

Generalized with intertriginous prominence

Primarily scalp with some trunk and extremity lesions

DISTRIBUTION

Skin biopsies show leukemic perivascular and dermal infiltrates such as seen in leukemia cutis together with intraepidermal spongiotic vesicles with immature myeloid infiltrates

Mid-dermal CD1 and S-100 positive histiocytes with large cells, irregularly shaped vesicular nuclei and eosinophilic cytoplasm

Macules: basilar hyperpigmentation; Pustule: intracorneal and subcorneal neutrophils and rare eosinophils

Intraepidermal spongiosis and vesicles associated with sweat ducts

Subcorneal vesicles associated with sweat ducts

Epidermal and dermal infiltrates of eosinophils associated with hair follicles

PATHOLOGY

ERYTHEMA TOXICUM NEONATORUM (TOXIC ERYTHEMA OF THE NEWBORN)

Birth or early weeks of life

Birth or early weeks of life

Birth, indicative of intrauterine involvement

First weeks of life

First weeks of life

Birth to 1 year

USUAL AGE OF ONSET

Table 6.11  Comparison of some vesiculopustular diseases of the neonate and young infant (contintued )

Wright-stained smears of the vesicular fluid may show promyelocytes, immature myelocytes and rare myeloblasts

Tzanck: histiocytes with uniform nuclei and abundant cytoplasm

Gram: neutrophils, no bacteria, rare eosinophils, KOH: negative, Wright and Giemsa: neutrophils, rare eosinophils

All stains negative

All stains negative

Gram: eosinophils, no bacteria, KOH: negative, Wright and Giemsa: eosinophils

STAINS

None

Usually none; very rare cases chemotherapy

None

Cooling baths, air conditioning, removal of excess clothing

Cooling baths, air conditioning, removal of excess clothing

Questionable benefit of topical corticosteroid preparations

TREATMENT

Neonatal skin and skin disorders

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A ERYTHEMA TOXICUM NEONATORUM (TOXIC ERYTHEMA OF THE NEWBORN)

C

B

Figure 6.32  Erythema toxicum. Erythematous macules and wheals may predominate (A). In some cases pustules are sparse (B), whereas in others extensive white to yellow papulovesicles with flares of erythema are noted (C).

332

tal events. Intestinal toxins, allergic reactions, mechanical or chemical irritation, hormonal influences on the extracellular matrix, and a transient graft-versus-host reaction from maternal lymphocytes have been suggested in the past as possible causes.254,255 In the last few years, a new theory stating that it might be a cutaneous response to commensal microbes penetrating into the skin of the newborn has gained strength.256,257 Diagnosis is usually made on clinical appearance. Microscopic examination of a Wright stain of the pustular contents will show large numbers of eosinophils, frequently in sheets, and is useful for diagnostic confirmation. Peripheral blood eosinophilia is seen in some cases.253 While biopsy is not usually necessary, histologic examination of erythematous macular lesions shows a perivascular accumulation of eosinophils in the upper dermis. Papular lesions are characterized by upper dermal eosinophils. In addition, an accumulation of eosinophils and some neu-

trophils is found around the outer root sheath of hair follicles extending into the epidermis. In pustular lesions, intrafollicular subcorneal collections of eosinophils are present.253 The differential diagnosis includes, in particular, transient neonatal pustular melanosis, congenital candidiasis, miliaria, bacterial infections, herpes simplex infection, incontinentia pigmenti, scabies, eosinophilic pustular folliculitis and eosinophilic pustulosis (Box 6.4). Erythema and postnatal onset may distinguish erythema toxicum from transient neonatal pustular melanosis, though both are common and can occur simultaneously.258 Pustular bacterial infections are usually due to Staphylococcus aureus, but occasionally neonatal infections with group B streptococcus, Pseudomonas aeruginosa, Listeria monocytogenes, Haemophilus influenzae, and Klebsiella pneumoniae present with pustules. These infections are characterized by the presence of large numbers of neutrophils on Wright stain, the presence of organisms on Gram

254. Stone OJ. High viscosity of newborn extracellular matrix is the etiology of erythema toxicum neonatorum: neonatal jaundice?: hyaline membrane disease? Med Hypoth 1990;33:15–17. 255. Bassukas ID. Is erythema toxicum neonatorum a mild self-limited acute cutaneous graft-versus-host-reaction from maternal-to-fetal lymphocyte transfer? Med Hypoth 1992;38:334–338. 256. Marchini G, Hultenby K, Nelson A, et al. Increased expression of HMGB-1 in the skin lesions of erythema toxicum. Pediatr Dermatol. 2007;24:474–482.

257. Marchini G, Nelson A, Edner J, et al. Erythema toxicum neonatorum is an innate immune response to commensal microbes penetrated into the skin of the newborn infant. Pediatr Res. 2005;58:613–616. 258. Ferrandiz C, Coroleu LW, Ribera M, et al. Sterile transient neonatal pustulosis is a precocious form of erythema toxicum neonatorum. Dermatology. 1992;185:18–22.

Neonatal skin and skin disorders

TRANSIENT NEONATAL PUSTULAR MELANOSIS (TRANSIENT NEONATAL PUSTULAR DERMATOSIS) Transient neonatal pustular melanosis (TNPM) is a benign condition of full-term neonates. It was described by Ramamurthy

et al. in 1976,259 and occurs in approximately 0.2–4% of all term newborn infants and is more commonly seen in black infants.259,260 It is characterized by the presence at birth of neutrophil-containing pustules or vesicles without surrounding erythema (Fig. 6.33A). Lesions measure 1–5 mm and are found in clusters or singly. After birth, new lesions usually do not develop, but existing vesicular or pustular lesions may progress to produce a brownish crust, or rupture, leaving a fine white collarette of scale (Figs 6.33B,C). Vesicopustules resolve within several days leaving hyperpigmented macules in darker-skinned individuals (Fig. 6.33D). As pigmentation is not usually a feature in white infants it has been suggested that transient neonatal pustular dermatosis may be a better terminology. Most commonly affected areas include the forehead, posterior ears, chin, neck, upper TRANSIENT NEONATAL PUSTULAR MELANOSIS (TRANSIENT NEONATAL PUSTULAR DERMATOSIS)

stain, and a positive bacterial culture. Candidiasis may be differentiated on the basis of a positive potassium hydroxide preparation. Miliaria may be excluded on the basis of its extrafollicular location and the presence of lymphocytes on Wright stain. As erythema toxicum is self-limiting, no intervention, other than parental reassurance, is necessary.

6

A

B

C

Figure 6.33  Transient neonatal pustular melanosis first appears as small superficial pustules without inflammation (A). Collarettes of scale, typical of the second stage, are occasionally seen at birth without pustules evident (B) or may develop after pustules have ruptured (C). The final stage is that of small hyperpigmented macules resembling lentils, which gradually fade over weeks to months (D).

259. Ramamurthy RS, Reveri M, Esterly NB, et al. Transient neonatal pustular melanosis. J Pediatr. 1976;88:831–835.

D

260. Merlob P, Metzker A, Reisner SH. Transient neonatal pustular melanosis. Am J Dis Child. 1982;136:521–522.

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MILIARIA

chest, back, buttocks, abdomen, and thighs, but all areas may be affected, including the palms and soles. All types of lesion – vesicles, intact pustules, crusted lesions, ruptured pustules with a collarette of scale, and pigmented macules – may be present singly or in combination at birth, suggesting their in utero formation and evolution. When present, macular pigmentation fades within weeks to months. The cause of transient neonatal pustular melanosis is unknown. Maternal infection, drug use, and primary fetal infection have no influence on its occurrence. Some investigators have proposed that it is a variant of erythema toxicum neonatorum, while others have suggested that this condition is actually a precocious form of erythema toxicum.258 Sterile transient neonatal pustulosis is a term used by some authors to include both erythema toxicum neonatorum and transient neonatal pustular melanosis, indicating that there might not be a clear-cut distinction between them. Others believe that as erythema toxicum neonatorum is such a frequent disorder they might just coexist independently. Wright staining of pustular contents shows neutrophils and occasional eosinophils. No organisms are observed. Skin biopsy shows intracorneal or subcorneal aggregates of neutrophils. There may also occasionally be a predominantly neutrophilic dermal infiltrate. Eosinophils may be present in limited numbers in the dermis as well as in the epidermal infiltrate.261 Biopsy of pigmented macules shows increased basilar melanocytes.261 The differential diagnosis includes erythema toxicum, staphylococcal pustulosis and other bacterial, viral, and candidal infections, miliaria, and acropustulosis of infancy. Onset, morphology, and characteristics of Wright and Gram stain and KOH should allow confirmation of clinical suspicions. However, a clear-cut differentiation between transient neonatal pustular melanosis and erythema toxicum is not always possible. No therapy is necessary.

MILIARIA Miliaria is a term used to describe obstruction of the eccrine duct resulting in rupture of the ducts and sweating into the skin. The level of obstruction determines the clinical manifestations. It can be seen in up to 15% of neonates, occurring more commonly in warm climates, in nurseries without air-conditioning and in febrile infants.262,263 Miliaria crystallina (sudamina) is the most common type of miliaria in the newborn period, manifested by fragile, 1–2 mm clear, non-inflammatory vesicles without surrounding inflammation (Fig. 6.34). These superficial, asymptomatic lesions may

261. Cohen LM, Skopicki BK, Harrist TJ, et al. Noninfectious vesiculobullous and vesiculopustular diseases. In: Elder D, Elenitsas R, Jaworsky C, et al., eds. Lever’s histopathology of the skin. Philadelphia: Lippincott-Raven; 1997:209–252. 262. Hidano A, Purwoko R, Jitsukawa K. Statistical survey of skin changes in Japanese neonates. Pediatr Dermatol. 1986;3:140–144. 263. Nanda A, Kaur S, Bhakoo ON, et al. Survey of cutaneous lesions in Indian newborns. Pediatr Dermatol. 1989;6:39–42. 264. Arpey CJ, Nagashima-Whalen LS, Chren MM, et al. Congenital miliaria crystallina: case report and literature review. Pediatr Dermatol. 1992;9:283–287.

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Figure 6.34  Miliaria crystallina. (Courtesy of Dr Antonio Torrelo)

appear like dewdrops on the skin, and reflect superficial obstruction of the eccrine duct at the level of the stratum corneum. Slight pressure will generally rupture miliaria crystallina lesions. It is more common in the first week of life, with some reports of congenital lesions.264–266 Lesions tend to develop mainly on the forehead and upper trunk. Miliaria rubra (prickly heat, or ‘heat rash’) is due to intraepidermal obstruction of the sweat duct with sweat leakage around the ducts. A secondary local inflammatory response is responsible for the erythema associated with the papules and vesicles. Lesions are 1–3 mm erythematous non-follicular papules, vesicles, or pustules (Fig. 6.35). Commonly affected sites are the face, neck, and trunk. It usually occurs during the second week of life. Although this type of miliaria is usually benign and selflimiting and not indicative of any underlying disease, several cases have occurred with salt-depletion crises in severe autosomal recessive type 1 hypoaldosteronism.267–269 Miliaria profunda is rare in neonates. This disorder presents as a non-erythematous papulopustular eruption, most prominent on the trunk and extremities, reflecting an eccrine ductal occlusion at the dermoepidermal junction. Histologic examination of miliaria crystallina shows subcorneal vesicles adjacent to underlying sweat ducts, often with a keratotic plug overlying the duct. A biopsy of miliaria rubra shows intraepidermal vesicles contiguous with a sweat duct, with an intravesicular and/or dermal

265. Holzle E, Kligman A. The pathogenesis of miliaria rubra. Role of the resident microflora. Br J Dermatol. 1978;99:117–137. 266. Gan VN, Hoang MP. Generalized vesicular eruption in a newborn. Pediatr Dermatol. 2004;21:171–173. 267. Urbatsch A, Paller AS. Pustular miliaria rubra: a specific cutaneous finding of type I pseudohypoaldosteronism. Pediatr Dermatol. 2002;19:317–319. 268. Martín JM, Calduch L, Monteagudo C, et al. Clinico-pathological analysis of the cutaneous lesions of a patient with type I pseudohypoaldosteronism. J Eur Acad Dermatol Venereol. 2005;19:377–379. 269. Akcakus M, Koklu E, Poyrazoglu H, et al. Newborn with pseudohypoaldosteronism and miliaria rubra. Int J Dermatol. 2006;45:1432–1434.

6

EOSINOPHILIC PUSTULAR FOLLICULITIS OF INFANCY

Neonatal skin and skin disorders

Figure 6.35  Miliaria rubra/pustulosa in premature infant. (Courtesy of Ronald Hansen, MD)

Figure 6.36  Eosinophilic pustular folliculitis on the scalp. (Courtesy of Ronald Hansen, MD)

chronic inflammatory infiltrate.270 With special stains, Grampositive cocci may be seen beneath and within the keratinous plug in miliaria rubra and profunda.265 The precise cause of miliaria is not known. There is some support for an extracellular polysaccharide substance produced by some strains of Staphylococcus epidermidis being involved in sweat duct obstruction and poral occlusion by epidermal cellular edema.271 The differential diagnosis includes erythema toxicum, transient neonatal pustular melanosis, candidiasis, HSV infection, neonatal acne/cephalic pustulosis, and bacterial folliculitis. Skin scrapings of vesicular contents and of the base of the vesicle may be examined for hyphae, multinucleated giant cells, eosinophils, bacteria, and neutrophils to help support the diagnosis of miliaria. Minimizing overheating of the infant is the only necessary treatment. Cool baths and air-conditioning are useful. Lesions usually resolve rapidly with no other intervention.

EOSINOPHILIC PUSTULAR FOLLICULITIS OF INFANCY Eosinophilic pustular folliculitis of infancy is an uncommon condition first described in infants by Lucky et al. in 1984.272 A few cases have been reported to be present at birth or develop in the first few days of life with yellowish pustules predominantly on the scalp (Fig. 6.36) and face, but also on the trunk and extremities.272–276 Pustules range from 1 to 3 mm in size and generally crust within 2 or 3 days of onset. They may recur in 270. Feng E, Janniger C. Miliaria. Cutis. 1995;55:213–216. 271. Mowad CM, McGinley KJ, Foglia A, et al. The role of extracellular polysaccharide substance produced by Staphylococcus epidermidis in miliaria. J Am Acad Dermatol. 1995;33:729–733. 272. Lucky AW, Esterly NB, Heskel N, et al. Eosinophilic pustular folliculitis in infancy. Pediatr Dermatol. 1984;1:202–206. 273. Giard F, Marcoux D, McCuaig C, et al. Eosinophilic pustular folliculitis (Ofuji disease) in childhood: a review of 4 cases. Pediatr Dermatol. 1991;8:189–193.

crops, with a waxing and waning course that may last days to weeks, with some reports of relapses over a number of years.274 Pruritus or irritability in younger infants is common. Peripheral eosinophilia is present in many patients. Pustular smears display eosinophils with occasional neutrophils without organisms, and cultures for bacteria, fungus, and viruses are all negative.275 Histopathologic examination of scalp lesions demonstrates eosinophilic spongiosis with an occasional subcorneal pustule. A dense mixed dermal infiltrate with many eosinophils, as well as lymphocytes and histiocytes, is variably perifollicular273,274 or interfollicular.272,273,275 For this reason, some authors think the term eosinophilic pustulosis may be more accurate for those patients previously described as eosinophilic folliculitis with a biopsy sparing the hair follicles.277 Because the distance between hair follicles is so small in neonatal skin, some presentations regarded as eosinophilic folliculitis may simply represent eosinophilic pustules coincidentally impinging on, rather than preferentially involving, follicles. The etiology of this condition is unknown. It has been suggested that it may represent a more persistent form of erythema toxicum, based on the histopathologic similarities.275 Clinical similarities also exist with acropustulosis of infancy. Differential diagnosis includes scalp pyoderma, erythema toxicum, transient neonatal pustular melanosis, acropustulosis of infancy, bacterial or fungal folliculitis, scabies, candidiasis, and Langerhans cell histiocytosis. The clinical presentation, location, and histology of these lesions allow differentiation from all these entities. The strong association with human immunodeficiency virus (HIV) seen in adult patients with this condition (also known as Ofuji disease in adults) is not seen in infants 274. Taieb A, Bassan-Andrieu L, Maleville J. Eosinophilic pustulosis of the scalp in childhood. J Am Acad Dermatol. 1992;27:55–60. 275. Duarte AM, Kramer J, Yusk JW, et al. Eosinophilic pustular folliculitis in infancy and childhood. Am J Dis Child. 1993;147:197–200. 276. Larralde M, Morales S, Munoz AS, et al. Eosinophilic pustular folliculitis in infancy: Report of two new cases. Pediatr Dermatol. 1999;16:118–120. 277. Ladrigan MK, LeBoit PE, Frieden IF. Neonatal eosinophilic pustulosis in a 2-month-old. Pediatr Dermatol. 2008;25:52–55.

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with eosinophilic pustular folliculitis, although immunodeficiency has been described.278,279 Secondary infection resulting in localized pyoderma or sepsis has been observed.276 Antihistamines may be useful in controlling the pruritus. Antibiotics and topical steroids are usually ineffective. Other therapies that have been reported to be useful in some cases include dapsone and oral cimetidine.280 Follow-up of these neonates is recommended, as several cases have been reported of patients in whom this type of eruption preceded the diagnosis of hyper IgE syndrome.281 Although IgE levels in this disorder are usually >2000 IU/mL, they may not rise until after 1 year of age.282

ACROPUSTULOSIS OF INFANCY

ACROPUSTULOSIS OF INFANCY

Figure 6.37  Acropustulosis of infancy. (Courtesy of Dr Maureen Rogers)

Acropustulosis of infancy (infantile acropustulosis) is a chronic or recurrent, benign condition of very pruritic vesicles and pustules occurring on the hands and feet of infants and rarely newborns.283 It was first described in 1979 by Kahn and Rywlin284 and by Jarrett and Ramsdell,285 and its etiology is uncertain.285 Although it can be present at birth or develop during the neonatal period, it usually appears during the first months of life, and may continue throughout infancy and early childhood.284,286 Lesions are 1–2 mm papules or distinct vesicles that rapidly evolve into larger, up to 4 mm, flat vesicopustules. Characteristically, lesions affect palms and soles (Fig. 6.37), with lesser involvement of dorsal hands and feet, and lateral aspects of fingers and toes. Occasionally, scattered lesions on the ankles, wrists, proximal limbs, and trunk may be seen. Postinflammatory hyperpigmentation can be observed in dark-skinned infants. Crops of lesions appear in cycles of 2–4 weeks, with individual lesions lasting 3–7 days. As time goes by, the intervals between each outbreak are longer and the intensity and length of each episode are shorter, with complete resolution at about 3 years of age.287 The etiology remains unclear. Theories include a reaction pattern in predisposed individuals to infection or infestation.288 A history of scabies preceding the diagnosis of infantile acropustulosis is common, although the relationship between the two remains unclear, as often the diagnosis of scabies has been made clinically only.287,289 It is clear, however, that some infants, after eradication of documented scabies infection, may have a condition with clinical manifestations, course, and histologic features identical to those of infantile acropustulosis, as a type of postscabetic reaction.287,289

Clinical characteristics and microscopic evaluation of smears or skin biopsies confirm the diagnosis. Laboratory studies are usually normal in infantile acropustulosis, but peripheral blood eosinophilia has been reported.284 Pustule contents may show prominent neutrophils and occasional eosinophils, without mites, eggs, ova, or feces as would be found in scabies.286,290 Skin biopsy shows intraepidermal or subcorneal pustules filled with neutrophils or eosinophils. Focal vesiculation and degeneration of keratinocytes with cell necrosis may also be seen.284,285,286 The differential diagnosis should include active scabies, eosinophilic pustulosis, candidiasis, erythema toxicum, transient neonatal pustular melanosis, bacterial pustulosis, tinea, dyshidrotic eczema, and pustular palmoplantar psoriasis. Multiple skin scrapings are necessary to differentiate active scabies. Smears for Gram and Wright stains, and potassium hydroxide (KOH) preparations may be indicated. Acropustulosis of infancy will spontaneously remit over 1–2 years. Treatment with potent topical corticosteroids is usually successful in controlling the outbreaks.287 Oral antihistamines may be useful to minimize symptoms of pruritus. Oral dapsone in a dosage of 1–3 mg/kg per day has been reported to speed pustule resolution to within 2–3 days284,291 and has been used as intermittent therapy during pustular phases to control the disease until spontaneous resolution occurs at 2–3 years of age; of course this drug must be used with caution.

278. Buchness M, Lim H, Hatcher V, et al. Eosinophilic pustular folliculitis in the acquired immunodeficiency syndrome. N Engl J Med. 1988;318:1183–1186. 279. Rybojad M, Guibai F, Vignon-Pennamen MD, et al. Eosinophilic pustulosis in an infant accompanied by immune deficit. Ann Dermatol Venerol. 1999;126:29–31. 280. Rogers M. Successful treatment of eosinophilic pustulosis with oral cimetidine. Pediatr Dermatol. 1999;16:335–336. 281. Kamei R, Honig PJ. Neonatal Job’s syndrome featuring a vesicular eruption. Pediatr Dermatol. 1988;5:75–82. 282. Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections – an autosomal dominant multisystem disorder. N Engl J Med. 1999;340:692–702. 283. Larralde M, Luna P. Noninfectious neonatal pustular disorders. Expert Rev Dermatol. 2007;2:1–9. 284. Kahn G, Rywlin AM. Acropustulosis of infancy. Arch Dermatol. 1979;115:831–833.

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285. Jarrett M, Ramsdell W. Infantile acropustulosis. Arch Dermatol. 1979;115:834–836. 286. Lucky AW, McGuire JS. Infantile acropustulosis with eosinophilic pustules. J Pediatr. 1982;100:428–429. 287. Mancini AJ, Frieden IJ, Paller AS. Infantile acropustulosis revisited: history of scabies and response to topical corticosteroids. Pediatr Dermatol. 1998;15:337–341. 288. Dromy R, Raz A, Metzker A. Infantile acropustulosis. Pediatr Dermatol. 1991;8:284–287. 289. Nguyen J, Strobel M, Arnaud JP, et al. Infantile acropustulosis: unusual manifestation of scabies in the infant? Ann Pediatr 1991;38:479–483. 290. Jennings JL, Burrows WM. Infantile acropustulosis. J Am Acad Dermatol. 1983;9:733–738. 291. Findlay RF, Odom RB. Infantile acropustulosis. Am J Dis Child. 1983;137:455–457.

Neonatal skin and skin disorders

6

Acne that is present at, or occurs shortly after, birth is known as acne neonatorum or neonatal acne. There is some degree of controversy regarding the nomenclature of neonatal acne and what has been termed transient neonatal cephalic pustulosis.292 Neonatal acne has been described as usually beginning at a few weeks of life and manifested mainly by multiple open or closed comedones as well as erythematous papules and pustules. Lesions are usually localized over the cheeks and forehead and tend to resolve spontaneously towards the first months of age. While the pathogenic mechanism remains unknown, stimulation of the child’s sebaceous glands by maternal androgens has been implied. Although comedones are a characteristic of acne and are typically absent in neonatal cephalic pustulosis, some authors still use both concepts interchangeably, for they think that these disorders might overlap.292 Given its benign course and spontaneous resolution, no treatment is usually needed. If necessary, therapies such as 2.5% benzoyl peroxide, 1% salicylic acid, 1% resorcin cream or 2% erythromycin in an alcohol solution could be tried.

NEONATAL CEPHALIC PUSTULOSIS Neonatal cephalic pustulosis is a common and benign facial pustulosis.283,292,293 Lesions usually appear between 5 days and 3 weeks of life and are mainly numerous tiny pinpoint papules and pustules over an erythematous base mainly over the forehead, cheeks, scalp and they have also been described on the neck and chest. Comedones are typically absent. Colonization by Malassezia sympodialis has been implicated as the etiology. As this microorganism can be found in 50% of newborns at birth and 80% at 7 days of life,293 other factors that may influence the development of this pustulosis are to be investigated.283 Diagnosis is usually clinical. The absence of comedones distinguishes this entity from true neonatal acne. When needed, direct KOH or culture of a pustule showing Malassezia and failing to reveal Candida or bacteria could be of help. Although it is usually self-limiting, topical antifungal, when needed, may clear the eruption in few days.283

VESICULOPUSTULAR ERUPTION IN DOWN SYNDROME WITH TRANSIENT MYELOPROLIFERATIVE DISORDERS Infants with Down syndrome, as well as phenotypically normal neonates with trisomy 1 mosaicism, have an increased risk of developing both malignant and benign hematological abnor-

292. Bergman JN, Eichenfield LF. Neonatal acne and cephalic pustulosis. Is Malassezia the whole story? Arch Dermatol. 2002;138:255–257. 293. Bernier V, Weill F, Hirigoyen V, et al. Skin colonization by Malassezia species in neonates: a prospective study and relationship with neonatal cephalic pustulosis (neonatal acne). Arch Dermatol. 2002;138:215–218. 294. Nijhawan A, Baselga E, Gonzalez-Ensenat A, et al. Vesiculopustular eruptions in Down syndrome neonates with myeloproliferative disorders. Arch Dermatol. 2001;137:760–763.

VESICULOPUSTULAR ERUPTION IN DOWN SYNDROME WITH TRANSIENT MYELOPROLIFERATIVE DISORDERS

NEONATAL ACNE

Figure 6.38  Pustular and crusted rash on the face in a Down syndrome patient with transient myeloproliferative disease.

malities, such as congenital leukemia, leukemoid reaction and transient myeloproliferative disorder (TMD),294 The latter, TMD, is a rare type of spontaneously resolving leukemia seen almost exclusively in infants with Down syndrome or in phenotypically normal infants with mosaicism for trisomy 21 limited to the megakaryocyte lineage or myeloid progenitor cells.295 A unique rash has been described associated with both TMD and leukemoid reactions in Down syndrome patients (and in phenotypically normal patients with trisomy 21 mosaicism). It consists of a dense vesicopustular, erythematous, crusted rash over the face (especially concentrated over the cheeks) (Fig. 6.38) sometimes accompanied by a few pustular lesions over the trunk and extremities. The lesions often demonstrate pathergy, being prominent at the sites of dressings, intravenous lines and oxygen masks.294 Clinical differential diagnosis includes impetigo and herpes virus infection, both acquired and congenital, as well as eosinophilic pustulosis. Wright-stained smears of the vesicular fluid may show promyelocytes, immature myelocytes and rare myeloblasts. Skin biopsies show leukemic perivascular and dermal infiltrates such as seen in leukemia cutis together with intraepidermal spongiotic vesicles with immature myeloid infiltrates which are unusual in leukemia cutis.295 Complete blood count shows leukocytosis with blast cells on the peripheral smear and bone marrow. In phenotypically normal children, cytogenetic study of the bone marrow blast cells should be performed in search of trisomy of chromosome 21.296 As the TMD involutes, in around 1 or 2 months, dermatologic manifestations also disappear.296 However, close follow-up is indicated, given that 25% of Down syndrome or mosaic trisomy 21 infants with TMD are at risk of developing an acute leukemia within the first 3 years of life.294

295. Solky BA, Yang C, Xu X, et al. Transient myeloproliferative disorder causing a vesiculopustular eruption in phenotypically normal neonate. Pediatr Dermatol. 2004;21:551–554. 296. Wirges ML, Stetson M, Oliver JW. Pustular leukemoid reaction in a neonate with Down syndrome. J Am Acad Dermatol. 2006;52: S62–S64.

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Investigations to rule out TMD should be undertaken in every Down syndrome newborn with vesicopustules and crusted lesions, especially on the face. A karyotype of bone-marrow blast cells in search for mosaicism should be undertaken in any phenotypically normal infant presenting with this rash in whom TMD is confirmed.283

CONGENITAL LANGERHANS CELL HISTIOCYTOSIS

INCONTINENTIA PIGMENTI

Langerhans cell histiocytosis (LCH) is defined as the clonal activation of Langerhans cells. The skin is the most frequently involved organ in children younger than 1 year old.297 The skin may be the sole organ involved or it may be involved as part of multisystem disease.298 Langerhans cell histiocytosis is discussed in detail in Chapter 21. Congenital LCH usually presents as a single, in small numbers, or occasionally multiple eroded and crusted, brown-red or purplish, discrete papules and nodules, varying in size from a few millimeters to a few centimeters (Fig. 6.39).299 Sometimes vesicles are seen and rarely, fairly widespread erosions develop.

Hence, this condition can mimic the other vesiculopustular and erosive conditions seen in the neonate. A rare congenital cutaneous presentation simulates a ‘blueberry muffin’ baby.300 Congenital LCH is usually a single organ disease, limited to the skin and is self-healing over weeks to months. This used to be called ‘self-healing reticulohistiocytosis of Hashimoto–Pritzker’ but it is important to recognize it as a definite LCH and be aware that later recurrence and development of disseminated disease may rarely occur months or even years later.301 Once the diagnosis is made, systemic workup and follow-up are appropriate in all infants.301,302 Diagnosis requires biopsy, which shows mid-dermal CD1 and S-100 positive histiocytes with large cells, irregularly shaped vesicular nuclei and eosinophilic cytoplasm.303 Electron microscopy showing Birbeck granules may also be useful for specific diagnosis. Langerin (CD207) is a relatively new monoclonal antibody directed against a type II transmembrane protein associated with Birbeck granules. It appears to be more sensitive and specific for LC than CD1a, and, in the future, it may be a key component of an immunocytochemical panel to diagnose LCH.304 Tzanck preparation can show histiocytes with uniform nuclei and abundant cytoplasm, which may be incorrectly interpreted as suggestive of herpes by inexperienced personnel.305 The great majority of patients will not need treatment. If multisystem organ involvement is present, chemotherapy will be required as in older children.297 The literature shows few reports of congenital LCH. This might be due to the fact that lesions are self-resolving and sometimes single or small and only a high degree of suspicion and a timely biopsy will enable the diagnosis to be made. During the neonatal period cases of disseminated disease with cutaneous involvement have also been reported. The most classic presentation is that of a seborrheic dermatitis-like distribution of typical lesions involving the scalp and diaper area, as in older infants.

INCONTINENTIA PIGMENTI

Figure 6.39  Langerhans cell histiocytosis in newborn. Erythematous, erosive and crusted lesions.

297. Larralde M, Abad E, Gomar B. Langerhans cell histiocytosis in children under one year. Arch Arg Pediatr. 2008;106:269–272. 298. Kapur P, Erickson C, Rakheja D, et al. Congenital self-healing reticulohistiocytosis (Hashimoto–Pritzker disease): ten-year experience at Dallas Children’s Medical Center. J Am Acad Dermatol. 2007;56:290–294. 299. Zunino-Goutorbe C, Eschard C, Durlach A, et al. Congenital solitary histiocytoma: a variant of Hashimoto–Pritzker histiocytosis. A retrospective study of 8 cases. Dermatology. 2008;216:118–124. 300. Sankilampi U, Huikko-Tarvainen S, Karja V. Congenital Langerhans cell histiocytosis mimicking a ‘blueberry muffin baby’. J Pediatr Hematol Oncol. 2008;30:245–248. 301. Larralde M, Rositto A, Giardelli M, et al. Congenital self-healing Langerhans cell histiocytosis: the need for a long term follow up. Int J Dermatol. 2003;42:245–246. 302. Longaker MA, Frieden IJ, LeBoit PE, et al. Congenital ‘self-healing’ Langerhans cell histiocytosis: the need for long-term follow-up. J Am Acad Dermatol. 1994;31:910–916. 303. Stein SL, Paller AS, Haut PR, et al. Langerhans cell histiocytosis presenting in the neonatal period: a retrospective case series. Arch Pediatr Adolesc Med. 2001;155:778–783.

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Incontinentia pigmenti, or Bloch–Sulzberger syndrome, is a rare, X-linked dominant genodermatosis that is usually lethal in utero for males, although lately there have been several reports of surviving males.306,307 It has been associated with mutations in the NEMO (IKK-gamma) gene.308,309 There are four distinct stages of which the first is seen in the neonatal period. Cutaneous 304. Satter EK, High WA. Langerhans cell histiocytosis: a review of the current recommendations of the Histiocyte Society. Pediatr Dermatol. 2008;25:291–295. 305. Colon-Fontanes F, Eichenfield LF, Krous HF, et al. Congenital Langerhans cell histiocytosis: the utility of the Tzanck test as a diagnostic screening tool. Arch Dermatol. 1998;134:1039–1040. 306. Fysco F, Fimiani G, Tadini G, et al. Clinical diagnosis of incontinentia pigmenti in a cohort of male patients. J Am Acad Dermatol. 2007;56:264–267. 307. Pacheco TR, Levy M, Collyier JC, et al. Incontinentia pigmenti in male patients. J Am Acad Dermatol. 2006;55:251–255. 308. Berlin AL, Paller AS, Chan LS. Incontinentia pigmenti: a review and update on the molecular basis of pathophysiology. J Am Acad Dermatol. 2002;47:169–187. 309. Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000;25:466–472.

Neonatal skin and skin disorders

NEONATAL DISORDERS PRESENTING WITH BULLAE AND/OR EROSIONS A number of conditions, both infectious and non-infectious, present during the newborn period with prominent erosions or bullae or a combination of these (Box 6.5). As mentioned above, some conditions can present with either vesiculopustular lesions or bullae and/or erosions. Many of the conditions presenting with bullae are discussed in detail in other chapters and these will be dealt with only briefly here.

BOX 6.5 DIFFERENTIAL DIAGNOSIS OF PROMINENT BULLAE AND EROSIONS IN THE NEWBORN

Non-infectious

>> Neonatal herpes gestationis >> Bullous mastocytosis >> Epidermolysis bullosa >> Neonatal pemphigus vulgaris >> Epidermolytic hyperkeratoses (bullous congenital ichthyosiform erythroderma)

>> Zinc deficiency >> Congenital erosive and vesicular dermatosis (CEVD) >> Porphyrias – Congenital erythropoietic porphyria – Erythropoietic protoporphyria

>> Transient porphyrinemia in Rh incompatibility Infectious

>> Bullous impetigo >> Congenital syphilis >> Congenital candidiasis

Congenital erosive and vesicular dermatosis is an extremely rare disorder of unknown etiology that presents at birth, with extensive erosions (Fig. 6.40A), intact vesicles, crusts, and fissures covering as much as 75% of the cutaneous surface,311 although a case with 10% and with titers of at least 1:80 of circulating anti-basement membrane antibodies.321 The diagnosis is suggested by the maternal history, but it is established on the basis of histopathology and immunofluorescence. Histologic examination of perilesional skin shows dermal–epidermal separation with a mixed perivascular infiltrate that includes many eosinophils. There may be necrosis of the basal cells. Direct immunofluorescent studies demonstrate C3 in a band-like pattern along the basement membrane in most patients and may show IgG antibodies in this area as well. The HG factor, IgG, may be present in the infant’s serum and demonstrable on indirect immunofluorescence by its ability to fix C3 at the basement membrane area.321 Therapy is symptomatic and includes wet compresses and, if required, treatment for secondary infection.

6

ZINC DEFICIENCY IN THE NEWBORN Zinc is an essential cofactor of several enzymes and its deficiency may occur in different clinical settings. An inherited zinc deficiency disorder is acrodermatitis enteropathica. Zinc deficiency may also be seen in breast-fed preterm infants328,329 and on rare occasions in breast-fed term infants.330 Possible mechanisms include deficiency in zinc secretion of the mammary gland,328 abnormal zinc uptake from plasma by the mammary gland,329 and high zinc demand in premature (due to low zinc stores) and low-birth-weight infants. Clinical manifestations of severe zinc deficiency in the young infant include dermatitis, diarrhea and irritability and, if the deficiency is prolonged, other neurologic symptoms, alopecia and limitation of growth. Skin lesions consist of papules, particularly around orifices and sometimes on extremities, progressing to vesico-bullous eruptions and erosions with a characteristic brown peripheral scale.328 The treatment of choice is the administration of zinc at around 1 mg/kg per day. Cutaneous improvement is noted within days and clearance occurs within 4–28 days.

EPIDERMOLYSIS BULLOSA Neonatal vesicles, bullae, and denuded skin, with friction and trauma-induced blistering are the hallmarks of all subtypes of epidermolysis bullosa (EB). The term comprises a set of diseases with various presentations and genetic etiologies. The clinical presentation and course of EB are quite variable, and depend on the specific subtype. EB is classified by the clinical extent and ultrastructural level of blistering, by inheritance pattern and, more recently, by specific molecular defect,331 with EB simplex, junctional EB, and dystrophic EB being the major subgroups.

328. Kiechl-Kohlendorfer U, Fink FM, Steichen-Gersdorf E. Transient symptomatic zinc deficiency in a breast-fed preterm infant. Pediatr Dermatol. 2007;24:536–540. 329. Chue CD, Rajpar SF, Bhat J. An acrodermatitis enteropathica-like eruption secondary to acquired zinc deficiency in an exclusively breast-fed premature infant. Int J Dermatol. 2008;47:372–373. 330. Haliasos EC, Litwack P, Kristal L, et al. Acquired zinc deficiency in full-term newborns from decreased zinc content in breast milk. Cutis. 2007;79:425–428. 331. Fine JD, Eady RA, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): Report of the third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol. 2008;58:931–950.

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Because infants with all subtypes can present with marked blistering in the newborn period, predicting specific EB subtypes based on clinical findings can be difficult in the first weeks of life. The scalp and face may blister due to the trauma of vaginal birth. The depth of blistering depends on EB subtype. More superficial blisters may rupture easily, while deeper blisters may be tense or hemorrhagic. Some EB subtypes tend to be severe in the neonatal period and may be fatal in the first few weeks of life. EB should be in the differential diagnosis of neonatal localized or diffuse vesicles and bullae, or localized or generalized skin denudation or scarring. Biopsy diagnosis is appropriate, and may be aided by electron microscopy.

INFECTIOUS DISEASES OF THE NEWBORN Lawrence F. Eichenfield, Pristine W. Lee Congenital infections usually present during the newborn period and are often recognized by their cutaneous manifestations. This section describes the most common congenital infections and their associated skin findings.

NEONATAL SCABIES NEONATAL SCABIES

TRANSIENT PORPHYRINEMIA IN HEMOLYTIC DISEASE OF THE NEWBORN Porphyria should always be considered when a blistering rash occurs with phototherapy for hyperbilirubinemia and the appropriate tests should be undertaken (see Ch. 7). A few cases of a photosensitive eruption have been described in patients with transient porphyrinemia associated with hemolytic diseases of the newborn when phototherapy has been undertaken.332–334 Clinically it manifests as erythema, blisters and erosions, as well as purpuric patches with sharp demarcation at sites of maximal exposure to the phototherapy lights, with dramatic sparing at shielded sites, developing within 24 h of the initiation of the phototherapy. When skin biopsy of purpuric lesions was performed, it revealed purpura without significant inflammation or keratinocyte necrosis.334 The eruption tends to clear in about 1 week after cessation of phototherapy. Although the true physiopathogenic mechanism remains unclear, the relation between elevated porphyrin levels and skin exposure to phototherapy is evident, suggesting that porphyrinemia may underlie the light-induced eruption.

BULLOUS CONGENITAL ICHTHYOSIFORM ERYTHRODERMA Also known as epidermolytic hyperkeratosis, this is a bullous type of autosomal dominant ichthyosis that manifests as red, tender skin together with superficial bullae within the first hours of life. As blisters break down, they leave denuded areas. The blistering soon lessens and, as time goes by, thick, grayishbrown scales cover the entire body.335 Histologic features are diagnostic.

332. Mallon E, Wojnarowska F, Hope P, et al. Neonatal bullous eruption as a result of transient porphyrinemia in a premature infant with hemolytic disease of the newborn. J Am Acad Dermatol. 1995;33:333–336. 333. Crawford RI, Lawlor ER, Wadsworth LD. Transient erythroporphyria of infancy. J Am Acad Dermatol. 1996;35:833–834. 334. Paller AS, Eramo LR, Farrell EE, et al. Purpuric phototherapy eruption in transfused neonates: relation to transient porphyrinemia. Pediatrics. 1997;100:360–364. 335. Ross R, DiGiovanna JJ, Capaldi L, et al. Histopathologic characterization of epidermolytic hyperkeratosis: a systematic review of histology from the National Registry for Ichthyosis and Related Skin Disorders. J Am Acad Dermatol. 2008;59:86–90.

342

Scabies, a cutaneous infestation caused by Sarcoptes scabiei, is rare in the neonatal period.336 Congenital scabies has not been reported. Clinical manifestations may occur from postnatal exposure in the early weeks of life and evidence of disease in neonates and infants has been reported.337 Neonates do not have a coordinated scratch response, and they may have no observable symptoms, or be irritable, restless, or feed poorly as signs of pruritus.338 Vesicles, papules, pustules, and excoriations may be present anywhere on the body, often with a generalized pattern. Palm and sole lesions are very common in infants. While the face and scalp are commonly spared in older children and adults, infants and young children will commonly have scabies lesions in these locations. Burrows, thin lines with tiny black dots at one end indicating the location of the female mite, are pathognomonic for scabies, but are often not found because of excoriation or eczematous changes.339 Nodular lesions are common in infants, and scabies mites may be found from scrapings of these lesions. Cases of misdiagnosis as urticaria pigmentosa have been reported.340 Bullae or honey-colored crusting should raise suspicion of bacterial superinfection. Diagnosis should be suspected on the basis of rash morphology and distribution and strengthened by a family history of itching or rash. The diagnosis is confirmed by a skin scraping of a fresh vesicle, pustule, or burrow demonstrating intact mites, mite parts, eggs, larvae, or fecal material. A dermatoscope is useful to identify the position of mites in the skin, giving guidance for the location for scraping. Fluorescence-microscopy is useful in identifying eggs and can enable the diagnosis in the absence of microscopically identifiable mites.341 Infants are infested with many mites; careful selection of the lesion to examine will usually demonstrate evidence of infestation. Biopsy shows a spongiotic dermatitis and is non-specific unless a mite or mite parts are seen. However, the pathology may also include

336. Sterling GB, Janniger CK, Kihiczak G. Neonatal scabies. Cutis. 1990;45:229–231. 337. Quarterman MJ, Lesher JL. Neonatal scabies treated with permethrin 5% cream. Pediatr Dermatol. 1994;11:264–266. 338. Peterson CM, Eichenfield LF. Scabies. Pediatr Ann. 1996;25:97–100. 339. Camassa F, Fania M, Ditano G, et al. Neonatal scabies. Cutis. 1995;56:210–212. 340. Mauleon-Fernandez C, Saez-de-Ocariz M, Rodriguez-Jurado R, et al. Nodular scabies mimicking urticaria pigmentosa in an infant. Clin Exp Dermatol. 2005;30:595–596. 341. Bhutto AM, Honda M, Kudo Y, et al. Introduction of fluorescencemicroscopic technique for the detection of eggs, egg shells, and mites in scabies. J Dermatol. 1993;20:122–124.

Neonatal skin and skin disorders

IMPETIGO NEONATORUM (BULLOUS IMPETIGO) AND STAPHYLOCOCCAL SCALDED SKIN SYNDROME The neonate, especially when premature, is particularly susceptible to nosocomial infection with Staphylococcus aureus. This organism produces a wide variety of skin infections as well as systemic infection in the neonatal intensive care unit (NICU). The most common presentation of these infections is impetigo neonatorum. Group II strains of Staphylococcus aureus, phage type 55 and 71, are most commonly responsible for this presentation, and there have been epidemics of methicillin-resistant strains in many nurseries.343 Lesions of impetigo neonatorum usually appear during the second week of life. The neck creases, periumbilical area, and perineum are most commonly involved (Fig. 6.41). Bullae enlarge rapidly, and rupture easily to produce spreading ero-

sions. Rarely, the condition may be complicated by potentially fatal systemic infections including septicemia, osteomyelitis and pneumonia.344 Hence, early aggressive treatment of neonatal impetigo is imperative. While bullous impetigo is characteristically caused by S. aureus, there is a report of bullous impetigo caused by group A beta-hemolytic streptococcus in an infant with streptococcal toxic shock syndrome.345 Although rare, staphylococcal scalded skin syndrome (SSSS) has also been described in neonates. This begins as a scarlatiniform eruption with rapid progression to tender, deep red, confluent erythroderma with edema, followed by wrinkling and sheet-like desquamation of the skin. Most infants have crusting around the nose and mouth. The mucosae are spared. Distinction from toxic epidermal necrolysis is critical, since the latter has an extremely poor prognosis. Staphylococcal exfoliative toxins (ETA, ETB, or ETD) cause intraepidermal splitting by recognition and cleavage of desmoglein 1, leading to bullous impetigo or SSSS.346 The specific expression of ETs may influence the clinical presentation as the majority of bullous impetigo cases have ETA, but SSSS has a higher incidence of ETB. It is proposed that the more severe SSSS results from lower exposure to ETB in the general population and less anti-ETB neutralizing antibodies.347 Treatment is with systemic antistaphylococcal antibiotics. Systemic steroids should not be used in these infants. The differential diagnosis of bullous impetigo neonatorum and SSSS includes epidermolysis bullosa, incontinentia pigmenti, bullous mastocytosis, bullous congenital ichthyosiform erythroderma, neonatal herpes gestationis, and varicella-zoster and herpes simplex virus infections. The site of predilection of lesions and other clinical features, together with appropriate culture and Gram stain, can help distinguish these entities.

CONGENITAL AND NEONATAL CANDIDIASIS

multiple lymphocytes and histiocytes demonstrating diffuse positive staining for CD1a and S100; this has led to the misdiagnosis of Langerhans cell histiocytosis.342 The differential diagnosis and management are discussed in detail in Chapter 27. Permethrin 5% cream is the treatment of choice in infants, although some prefer to use precipitated sulfur in the very early weeks or in low-birth-weight infants.

6

CONGENITAL AND NEONATAL CANDIDIASIS

Figure 6.41  Bullous impetigo in a neonate. (Courtesy of Dr Antonio Torrelo)

342. Bhattacharjee P, Glusac EJ. Langerhans cell hyperplasia in scabies: a mimic of Langerhans cell histiocytosis. J Cutan Pathol. 2007;34:716–720. 343. Aihara M, Sakai M, Iwasaki M, et al. Prevention and control of nosocomial infection caused by methicillin-resistant Staphylococcus aureus in a premature infant ward – preventive effect of a povidone-iodine wipe of neonatal skin. Postgrad Med J. 1993;69:S117. 344. Dancer SJ, Simmons NA, Poston SM, et al. Outbreak of staphylococcal scalded skin syndrome among neonates. J Infect. 1988;16:87–103. 345. Lin JJ, Wu CT, Hsia SH, et al. Bullous impetigo: a rare presentation in fulminant streptococcal toxic shock syndrome. Pediatr Emerg Care. 2007;23:318–320. 346. Hanakawa Y, Schechter NM, Lin C, et al. Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome. J Clin Invest. 2002;110:53–60.

Candida is the most common fungal pathogen in neonates.348 Infection may be acquired vertically from the mother or horizontally by nosocomial transmission in the nursery. Several types of infection with Candida spp. are seen during the neonatal period. Congenital candidiasis is acquired in utero, presents in the first few days of life, and may be responsible for premature labor and delivery or rarely intrauterine death.349 There is a broad spectrum of disease, from congenital cutaneous candidiasis with a diffuse skin eruption with or without systemic symptoms, to severe lifethreatening candidal systemic infection without cutaneous findings.350 347. Yamasaki O, Yamaguchi T, Sugai M, et al. Clinical manifestations of staphylococcal scalded-skin syndrome depend on serotypes of exfoliative toxins. J Clin Microbiol. 2005;43:1890–1893. 348. Ruiz-Diez B, Martinez V, Alvarez M, et al.(1997) Molecular tracking of Candida albicans in a neonatal intensive care unit: long-term colonizations versus catheter-related infections. J Clin Microbiol. 35:3032–3036. 349. Friebe-Hoffmann U, Bender DP, Sims CJ , et al. Candida albicans chorioamnionitis associated with preterm labor and sudden intrauterine demise of one twin. A case report. J Reprod Med. 2000;45:354–356. 350. Darmstadt GL, Dinulos JG, Miller Z. Congenital cutaneous candidiasis: Clinical presentation, pathogenesis, and management guidelines. Pediatrics. 2000;105:438–444.

343

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CONGENITAL AND NEONATAL CANDIDIASIS

Figure 6.42  Congenital candidiasis. (Courtesy of Ronald Hansen, MD)

Neonatal candidiasis refers to candidiasis acquired during passage through an infected birth canal, or postnatally and presenting after the first few days of life. Perinatal and postnatal acquisition of Candida may be: 1. Localized as thrush or diaper dermatitis 2. Invasive fungal dermatitis in which primary candidal species skin infection presents with erosive, crusted plaques which may lead to systemic disease 3. Systemic infection associated with primary immunodeficiency, immunosuppression, chronic antibiotic therapy, hyperglycemia, hyperalimentation, indwelling catheters, prolonged endotracheal intubation or other invasive procedures with candidal contamination.351 Candida parapsilosis, Candida tropicalis, and Candida stellatoidea can cause congenital or neonatal candidiasis, but Candida albicans is isolated in 95% of cases. The prevalence of Candida is significantly higher among infants of gestational age > Dystopia canthorum >> 1st degree relative affected

WHITE SPOTTING

A

Minor criteria

>> Hypopigmented skin lesions >> Prominent nasal root >> Bushy eyebrows-synophrys Associated criteria

>> Cleft/lip palate >> Spina bifida >> Musculoskeletal anomalies

WS is considered if the patient has two major or one major plus two minor or one major plus a 1st degree relative with WS.

Epidemiology The prevalence of WS among the deaf population is 2–6.8%. The incidence of WS in the general population is 1 per 22 400– 42 000.262 WS2 is reported to be more common than WS1.259,262

Physical examination Waardenburg syndrome 1 The key features are dystopia canthorum, congenital sensory neural deafness, and pigmentary changes of the eyes, skin and hair (Fig. 7.39). Dystopia canthorum or an increase in the inner canthal distance, without change in the interpupillary distance, is the most consistent feature, seen in 98–100%.262,263 Dystopia canthorum may be assessed by dividing the inner canthal distance by the interpupillary distance; a ratio >0.6 indicates dystopia canthorum.264 Arias and Moto developed another useful tool, the W-Index to make the assessment of dystopia canthorum. According to this, patients with W-index of >2.07 are classified as dystopia and a value of > Spotty skin pigmentation with a typical distribution (lips,

conjunctiva and inner or outer canthi, vaginal and penile mucosa)

>> Myxoma (cutaneous and mucosal) >> Cardiac myxoma >> Breast myxomatosis or fat-suppressed magnetic resonance imaging findings suggestive of this diagnosis

>> Primary pigmented nodular adrenocortical disease or

paradoxical positive response of urinary glucocorticosteroids to dexamethasone administration during Liddle’s test

>> Acromegaly due to GH-producing adenoma >> Large cell calcifying Sertoli cell tumor or characteristic calcification on testicular ultrasonography

>> Thyroid carcinoma or multiple, hypoechoic nodules on thyroid ultrasonography, in a young patient

>> Psammomatous melanotic schwannoma >> Blue nevus, epithelioid blue nevus (multiple) >> Breast ductal adenoma (multiple) >> Osteochondromyxoma >> Supplemental criteria

Differential diagnosis LEOPARD syndrome must be differentiated from other disorders characterized by multiple spotty pigmented macules, such as Carney complex, and Peutz–Jeghers syndrome. The lack of mucous membrane involvement, the particular facial and body habitus of those with LS and the absence of myxomas help make this distinction.

Treatment Treatment consists of multisystem evaluation by the concerned specialist and genetic counseling.

CARNEY COMPLEX Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome. It was initially described by Carney et al. in 1985 as ‘the complex of myxomas, spotty pigmentation and endocrine overactivity’. Previously some of the disorders with these manifestations have been described under the acronyms ‘NAME’ (Nevi, Atrial Myxomas and Ephelides) and ‘LAMB’ syndrome (Lentigines, Atrial Myxomas, and Blue nevi).321 Stratakis et al. have analyzed 338 patients with CNC from worldwide and revised the diagnostic criteria (Box 7.3).322 The diagnosis of CNC is considered if a patient has either (1) two of the manifestations of the disease listed, or (2) one of these

321. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation and endocrine overactivity. Medicine (Balt). 1985;64:270–283. 322. Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: Diagnostic criteria and recommendations for patient evaluation. J Clin Endo Metabol. 2001;86:4041–4046.

manifestations and meet one of the supplemental criteria (an affected 1st-degree relative or an inactivating mutation of the PRK ARIA gene).

Physical examination The most common clinical manifestation is the spotty skin pigmentation (mainly lentigines) seen in 77% of cases. Lentigines may be seen at birth and the characteristic periorificial distribution (eyelids, lips, genital mucosa), density and intensity of the lesions are noted around the peripubertal period. Mucosal lesions may be seen. Other pigmented lesions are blue nevi (43%),323 melanocytic nevi including congenital type, and café au lait macules. Both lentigines and café au lait macules tend to fade with time.322 Skin myxomas can be seen in 33% of cases. It is the most specific criterion for the diagnosis of CNC.323 The lesions vary from asymptomatic, small sessile dark pink papules to large pedunculated lesions. The classical sites of involvement are eyelids, external ear, nipple, breast and mucosae (oropharynx and female genital tract).322,323

DISORDERS OF HYPERPIGMENTATION

BOX 7.3 DIAGNOSTIC CRITERIA FOR CNC322

7

Extracutaneous features Cardiac myxomas have been reported in 53% of cases. Among the endocrine neoplasms, primary pigmented adrenocortical disease is the most common, seen in 26% of cases. Large cell calcifying Sertoli cell tumor is reported in 33% of male patients with CNC. Other associations include multiple thyroid nodules and/or carcinoma, psammomatous melanotic schwannoma and breast ductal carcinoma.322,323

Genetics and histogenesis Approximately 50% of CNC kindreds have mutations in PRKAR1A gene on chromosome 17q22–24. Most of the remaining cases are due to genetic changes at chromosome 2p16, but the causative gene has not been identified. PRKAR1A is a tumor suppressor gene, coding for the type 1 alpha regulatory subunit of protein kinase A.322,323

Differential diagnosis Differential diagnosis includes LEOPARD syndrome, Peutz– Jeghers syndrome and neurofibromatosis. In Peutz–Jeghers syndrome there is mucocutaneous pigmentation and GI polyps. In neurofibromatosis the freckling is confined to the axillae, groin and palms.323

Treatment Systemic features/abnormalities should be evaluated by the appropriate specialists.

323. Mateus C, Palangie A, Franck N et al Heterogeneity of skin manifestations in patients with Carney complex. J Am Acad Dermatol. 2008;59(5):801–810.

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GENETIC DISORDERS OF THE IMMUNE SYSTEM Julie Schaffer and Amy Paller Genetic disorders of the immune system are a heterogeneous group of conditions characterized not only by susceptibility to infections, but also by a variety of additional features such as autoimmunity, allergy, excessive inflammation, and

malignancy. The molecular bases have been defined for more than 130 monogenic primary immunodeficiency diseases, providing valuable insights into the function of the human immune system.324–327 The reader is referred to Chapter 1 for more details on the basic science of the immune system. The features of the hereditary periodic fever syndromes (autoinflammatory disorders) are summarized in Table 7.6. Children with genetic immunodeficiency disorders often present with cutaneous abnormalities. Some of these simply

Table 7.6  Hereditary periodic fever syndromes FMF GENETIC DISORDERS OF THE IMMUNE SYSTEM

Ethnicity

Jewish, Arab, Turkish, Italian, Armenian

HIDS

TRAPSa

MWS

FCASb

NOMID (CINCA)

Predominantly Dutch, northern European

Any ethnic group

Any ethnic group

Any ethnic group

Any ethnic group

AD

Inheritance

AR

AR

AD

AD

AD

Gene

MEFV

MVKc

TNFRSF1A

CIAS1

CIAS1

CIAS1

Chromosome

16p13.3

12q24

12p13

1q44

1q44

1q44

Protein

Pyrin

Mevalonate kinase

TNF receptor-1

Cryopyrin

Cryopyrin

Cryopyrin

Attack length

1–3 days

3–7 days

Often >7 days

1–2 days

Minutes–3 days

Continuous + flares

Mucocutaneous lesions

Erysipeloid erythema and edema

Erythematous macules and edematous papules, which may become purpuric; occasional oral and vaginal ulcers

Erythematous patches and edematous plaques (often annular or serpiginous); later ecchymotic in appearance; rarely oral ulcers

Urticarial papules and plaques

Cold-induced urticarial papules and plaques

Urticarial papules and plaques; occasional oral ulcers

Distribution of skin lesions

Favor lower leg, foot

Widespread on face, trunk, and extremities

Migrate distally on an extremity with underlying myalgia; may be more widespread

Widespread on face, trunk, and extremities

Extremities > trunk, face

Widespread on face, trunk, and extremities

Abdominal pain and serositis

Peritonitis → pleuritis → pericarditis

Abdominal pain, but rarely serositis

Peritonitis → pleuritis, pericarditis

Abdominal pain, but rarely serositis

Rare

Rare

Musculoskeletal findings

Monoarthritis → exercise-induced myalgia

Arthralgia → oligoarthritis → myalgia

Migratory myalgia → arthralgia → monoarthritis

Myalgia (‘lancing limb pain’), arthralgia → large-joint oligoarthritis

Arthralgia → myalgia

Epiphyseal and patellar overgrowth, arthritis, deforming arthropathy

Ocular findings

Uncommon

Uncommon

Periorbital edema, conjunctivitis, rarely uveitis

Conjunctivitis, episcleritis, optic disc edema

Conjunctivitis

Conjunctivitis, uveitis, optic disc edema, blindness

324. Geha RS, Notarangelo LD, Casanova JL, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. 2007;120:776–794. 325. Fischer A. Human primary immunodeficiency diseases. Immunity. 2007;27:835–845.

418

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS)

326. Maródi L, Notarangelo LD. Immunological and genetic bases of new primary immunodeficiencies. Nat Rev Immunol. 2007;7:851–861. 327. Knerr V, Grimbacher B. Primary immunodeficiency registries. Curr Opin Allergy Clin Immunol. 2007;7:475–480.

Genodermatoses

7

Table 7.6  Hereditary periodic fever syndromes (continued) HIDS

TRAPSa

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS) MWS

FCASb

NOMID (CINCA)

Sensorineural hearing loss; headache

Headache

Sensorineural hearing loss; aseptic meningitis, seizures

Neurologic findings

Rarely aseptic meningitis

Headache

Headache

Other clinical findings

Acute scrotal swelling; splenomegaly

Cervical LAN, HSM

Scrotal pain; splenomegaly, occasional LAN

Amyloidosis

Most common in M694V homozygotes

Rare

≈15% of cases

≈25% of cases

Uncommon

Late complication

Dermal infiltrate in typical skin lesions

Neutrophils

Neutrophils and/or lymphocytes; mild vasculitis common

Lymphocytes and monocytes

Neutrophils and/or lymphocytes (sparse)

Neutrophils (perivascular)

Neutrophils (perivascular + periadnexal)

Cutaneous vasculitis

LCV/HSP (5–10%), PAN (≈1%)

LCV/HSP

Lymphocytic small vessel (rare)

Laboratory abnormalitiesd

Low C5a inhibitor in serosal fluids

Low serum soluble TNF receptor-1 (100 IU/mL) and IgA1; mevalonate in urine during attacks; low lymphocyte mevalonate kinase TNF inhibitors (e.g., etanercept); simvastatin, anakinraf

Glucocorticoids; anakinraf

Anakinraf

Anakinraf

Glucocorticoids; TNF inhibitors (e.g., etanercept)

LAN, HSM; dysmorphic facies – frontal bossing, protruding eyes

GENETIC DISORDERS OF THE IMMUNE SYSTEM

FMF

a

Includes familial Hibernian fever. Also referred to as familial cold urticaria. c Allelic with mevalonic aciduria, which is characterized by dysmorphology, psychomotor retardation, and progressive cerebellar ataxia as well as periodic fevers and other features of HIDS. d Genetic analysis can be performed to confirm the diagnosis. e IgD levels are occasionally normal; elevated IgD may also be observed in FMF and TRAPS. f Interleukin-1 receptor antagonist. AD, autosomal dominant; AR, autosomal recessive; CINCA, chronic infantile neurologic, cutaneous and articular syndrome; FCAS, familial cold autoinflammatory syndrome; FMF, familial Mediterranean fever; HSM, hepatosplenomegaly; HSP, Henoch–Schönlein purpura; HIDS, hyperimmunoglobulinemia D with periodic fever syndrome; LAN, lymphadenopathy; LCV, leukocytoclastic vasculitis; MWS, Muckle–Wells syndrome; NOMID, neonatal-onset multisystem inflammatory disease; PAN, polyarteritis nodosa; TNF, tumor necrosis factor; TRAPS, TNF receptor-associated periodic syndrome. Affected 1st-degree relative. Inactivating mutation of the PRKARIA gene. b

reflect infection of the skin, while others are non-infectious findings that may represent a specific manifestation of a particular disorder or a common pattern of inflammation, such as eczematous or granulomatous dermatitis,328,329 shared by multiple immunodeficiency syndromes (Table 7.7). The dermatologist

should work together with the immunologist to determine the correct diagnosis and initiate optimal management. Screening laboratory tests that may be helpful for a child with recurrent infections that raise suspicion of a primary immunodeficiency330 are presented in Table 7.8.

328. Mitra A, Pollock B, Gooi J. Cutaneous granulomas associated with primary immunodeficiency disorders. Br J Dermatol. 2005;153:194–199. 329. Torrelo A, Vera A, Portugues M. Perforating neutrophilic and granulomatous dermatitis of the newborn: a clue to immunodeficiency. Pediatr Dermatol. 2007;24:211–215.

330. Slatter MA, Gennery AR. An approach to the patient with recurrent infections in childhood. Clin Exp Immunol. 2008;152:389–396.

419

420 + +

++

+

+

++

Ataxia-telangiectasia

Chédiak–Higashi syndrome

Chronic granulomatous disease

+ + + ++ (Cold)

+

+

+

++

Hyper-IgM syndrome

IgA deficiency

IgM deficiency

IL-1 receptor associated kinase-4 (IRAK4) deficiency

+ ++

++

+

Wiskott–Aldrich syndrome

X-linked agammaglobulinemia

+

+

+

+

+

+

+

++

+

CMC

++

+

+

+

+

WARTS

+

++

+

+

+

++

+

+

+

+

ECZEMATOUS DERMATITIS

+

+

++

+a

+

+

++

(++) (Candidal)

++ (Nodular, necrotic)

+ (Often ulcerate)

GRANULOMATOUS DERMATITIS (NON-INFECTIOUS)

+

+

+

++

+

+

LE

+

+

+

+

+

SVV

+

++

+

+

+

+

+

+

ULCERS (PG-LIKE)

Dermatomyositis-like eruption (due to echovirus); ecthyma gangrenosum

Bleeding diathesis

GVHD, erythroderma (Omenn syndrome)

Poor wound healing, delayed separation of the umbilical stump, gingivitis

Vitiligo, lipodystrophia centrifugalis abdominalis

Oral ulcers

Neonatal eosinophilic folliculitis

Dermatomyositis, urticaria, lipodystrophy (C3), JIA

Dermatophyte infections, vitiligo, alopecia areata

Dermatophyte infections, vitiligo, alopecia areata

DLE in female carriers, Sweet’s syndrome, oral ulcers

Pigmentary dilution, hyperpigmentation in sun-exposed sites, silvery hair, bleeding diathesis, gingivitis

Oculocutaneous telangiectasias, progeric changes, CALM

OTHER FINDINGS

+, Occasional finding; ++ Common finding. a Extensive cutaneous and extracutaneous granulomatous disease has been described in children with hypomorphic RAG1 or RAG2 mutations. CALM, café-au-lait macules; DLE, discoid lesions of lupus erythematosus; GvHD, graft-versus-host disease; IL, interleukin; JIA, juvenile idiopathic arthritis; SVV, small vessel vasculitis; LE, lupus erythematosus; PG, pyoderma gangrenosum; SCID, severe combined immunodeficiency; TAP, Transporter associated with Antigen Processing; WHIM, Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. Adapted with permission from Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, ed 2. London: Elsevier; 2007.

+

+

+

WHIM

TAP deficiency

SCID

Leukocyte adhesion deficiency

+

++ (Cold)

++

Hyper-IgE syndrome

++ (Necrotic)

+

+

Complement deficiencies

DiGeorge syndrome

+

+

Common variable immunodeficiency

Chronic mucocutaneous candidiasis (CMC)

Abscesses

S. AUREUS INFECTIONS

Superficial pyodermas

DISORDER

GENETIC DISORDERS OF THE IMMUNE SYSTEM

Table 7.7  Cutaneous findings in primary immunodeficiency disorders

ii Neonatal and Inherited Disorders

Genodermatoses

7

TEST

FINDING

IMMUNODEFICIENCY IDENTIFIED

Complete blood count with differential, platelet count, and examination of smear

Giant granules within neutrophils, ± neutropenia Neutrophilia Small platelets, thrombocytopenia

Chédiak–Higashi syndrome Leukocyte adhesion deficiency Wiskott–Aldrich syndrome

Hair shaft examination

Small, regular clumps of melanin Large, irregular clumps of melanin

Chédiak–Higashi syndrome Griscelli syndrome (type 2; RAB27A)

Quantitative

All Ig ↓

X-linked agammaglobulinemia

Immunoglobulins

IgA↓, IgG ↓, ± IgM ↓ IgA ↓ or IgM ↓ IgM ↑, all other Ig ↓ IgM ↑, ± IgA ↑, ± IgG↓:

Common variable immunodeficiency Selective IgA or IgM deficiency Hyper-IgM syndrome Hypohidrotic ectodermal dysplasia with immunodeficiency Ataxia telangiectasia Hyper-IgE syndrome Wiskott–Aldrich syndrome

IgA ↓, IgE ↓, IgG2,4 ↓ IgE ↑↑ IgM ↓, ± IgG ↓, IgA ↑, IgE ↑ Total hemolytic complement (CH50)

Marked ↓

Various complement deficiencies

Nitroblue tetrazolium (NBT) reduction assay and/or dihydrorhodamine (DHR) 123 assay

50% develop N. meningitidis infections, which typically begin around puberty and are often recurrent b Most common of the homozygous complement deficiencies. c Very low penetrance. d X-linked recessive. CREST, calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias; DLE, discoid lupus erythematosus lesions; GN, glomerulonephritis; HSM, hepatosplenomegaly; HSP, Henoch–Schönlein purpura; HUS, hemolytic-uremic syndrome; IBD, inflammatory bowel disease; INH, inhibitor; JIA, juvenile idiopathic arthritis; MBL, mannose-binding lectin; MASP, MBL-associated serum protease; PPK, palmoplantar keratoderma; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus.

434

deficiencies develop recurrent neisserial infections in their teenage years, reflecting the importance of both the alternative complement pathway (which requires properdin and factor D) and the bactericidal membrane attack complex (MAC; composed of C5–C9) for destruction of these organisms.407,408 The mortality rate of meningococcal infections in MAC-deficient patients is actually lower than that in immunocompetent individuals, and it is thought that the lack of serum lytic activity limits release of bacterial products such as lipopolysaccharide and thereby decreases the potentially detrimental cytokine

response. In contrast, individuals with a properdin or factor D deficiency are unable to clear Neisseria by opsonophagocytosis and have fulminant disease.

407. Schneider MC, Exley RM, Ram S, et al. Interactions between Neisseria meningitidis and the complement system. Trends Microbiol. 2007;15:233–240.

408. Sprong T, Roos D, Weemaes C, et al. Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections. Blood. 2006;107:4865–4870.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of complement component deficiencies includes hypocomplementemia related to LE, other autoimmune disorders, and active infections. Complement components may be specific targets of autoimmune responses. For example,

Genodermatoses

TREATMENT Conservative therapy is often effective for patients with autoimmune manifestations of complement deficiency. The use of topical corticosteroids and sun protection may be sufficient to treat cutaneous LE. Antimalarial drugs, systemic corticosteroids, and other immunosuppressive medications can be administered to patients with more severe disease, with consideration of the increased risk of infections associated with complement deficiencies. The use of plasma transfusions to replace deficient complement components may actually activate the cascade, accelerating immune complex deposition and promoting inflammation. Infections should prompt early, aggressive antibiotic therapy.

CHRONIC GRANULOMATOUS DISEASE Chronic granulomatous disease (CGD) is a group of disorders characterized by severe, recurrent infections and inflammatory sequelae due to an inability of leukocytes to kill phagocytosed bacteria and fungi by generating oxidative metabolites. Reduced function of the nicotinamide dinucleotide phosphate (NADPH) oxidase complex underlies all forms of CGD.

EPIDEMIOLOGY The incidence of CGD is approximately 1 in 200 000 live births.409,410 Some 90% of patients are male. Three-quarters of patients have the X-linked recessive form of CGD, and the remainder have subtypes with an autosomal recessive pattern of inheritance.411

CLINICAL PRESENTATION The areas of the body that are typically affected in CGD are those that are frequently challenged by bacteria, including the skin, perianal region, and lungs. Organisms that commonly cause infections in CGD patients include S. aureus (especially pyodermas, abscesses, and adenitis), Nocardia spp., Burkholderia cepacia, Klebsiella spp., Serratia marcescens (especially osteomyelitis), Candida spp., and Aspergillus spp. (especially pneumonia). The X-linked form of CGD tends to be more severe and to have a

409. Winkelstein JA, Marino MC, Johnston RB, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine. 2000;79:155–169. 410. Segal BH, Leto TL, Gallin JI, et al. Genetic, biochemical, and clinical features of the chronic granulomatous disease. Medicine. 2000;79:170–200. 411. Malech HL, Hickstein DD. Genetics, biology and clinical management of myeloid cell primary immune deficiencies: chronic granulomatous disease and leukocyte adhesion deficiency. Curr Opin Hematol. 2007;14:29–36.

Table 7.15  Frequency of signs and symptoms in patients with chronic granulomatous disease SYMPTOM Lymphadenopathy Hepatosplenomegaly Bronchopneumonia Underweight Short stature Persistent diarrhea and/or abdominal pain Hepatic/perihepatic abscess Pleuritis/empyema Septicemia or meningitis Osteomyelitis Conjunctivitis and/or chorioretinitis Facial periorificial dermatitis Perianal abscess Lung abscess Ulcerative stomatitis Peritonitis Onset by age 1 year Onset with lymphadenitis

PATIENTS (%) 90 85 80 75 50 40 35 35 35 25 25 20 15 15 15 10 65 25

CHRONIC GRANULOMATOUS DISEASE

anti-C1q antibodies are found in 30–50% of patients with SLE (often with renal involvement) and virtually all of those with hypocomplementemic urticarial vasculitis. The ‘Leiner phenotype’ of exfoliative dermatitis, chronic diarrhea, and recurrent infections associated with a lack of functional C3 and/or C5 is not a specific entity, and it has been described in patients with X-linked agammaglobulinemia, hyper-IgE syndrome, and SCID.

7

younger mean age at diagnosis (3 years) than autosomal recessive forms (8 years).409 The first manifestation of CGD is usually staphylococcal infections of the skin around the ears and nose during the neonatal period.412 These localized pyodermas may progress during infancy to extensive purulent dermatitis with regional lymphadenopathy. Skin abscesses caused by S. aureus occur in 40% of patients. Cutaneous granulomas, which are nodular and often necrotic, occur less frequently than skin infections. Purulent inflammatory reactions also tend to develop at sites of minor cutaneous trauma and heal slowly with scarring. Seborrheic dermatitis, folliculitis, Sweet’s syndrome, and ulcers involving the oral mucosa (resembling aphthous stomatitis), perioral area, and other cutaneous sites have also been described. CGD patients may develop cutaneous features of acute or chronic lupus erythematosus, especially discoid lesions.413 In addition, female carriers of X-linked CGD occasionally present with discoid lupus erythematosus, photosensitive eruptions, Jessner’s lymphocytic infiltrate, Raynaud phenomenon, aphthous stomatitis, and granulomatous cheilitis.414 The extracutaneous organs most frequently involved in CGD are the lymph nodes, lungs, liver, spleen, and GI tract (Table 7.15). Suppurative lymphadenitis occurs in half of patients, commonly affecting cervical nodes and resulting in abscess and fistula formation (Fig. 7.47). Pneumonia, the most prevalent extracutaneous infection, often responds inadequately to antibacterial therapy and leads to abscess formation, cavitation,

412. Windhorst DB, Good RA. Dermatologic manifestations of fatal granulomatous disease of childhood. Arch Dermatol. 1971;103:351–357. 413. De Ravin SS, Naumann N, Cowen EW, et al. Chronic granulomatous disease as a risk factor for autoimmune disease. J Allergy Clin Immunol. 2008;122(6):1097–1103. 414. Cale CM, Morton L, Goldblatt D. Cutaneous and other lupus-like symptoms in carriers of X-linked chronic granulomatous disease: incidence and autoimmune serology. Clin Exp Immunol. 2007;148:79–84.

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soluble, oxidized form; when reduced, the dye precipitates and becomes blue (formosan precipitate). Only 5–10% of leukocytes from patients with CGD are able to reduce NBT during phagocytosis, compared to 80–90% of leukocytes from unaffected individuals. The percentage of leukocytes that can reduce NBT is decreased to a variable extent in female carriers of X-linked CGD, The dihydrorhodamine 123 assay and ferricytochrome C reduction assay are more accurate and quantitative in measuring the respiratory burst, and they can also be performed to verify the diagnosis of CGD.415 Immunoblot analysis may demonstrate lack of the gp91phox and p22phox proteins; however, DNA analysis must still be performed to determine which gene is affected, since mutations resulting in the absence of one of these proteins lead to absence of the other. Lack of p47phox or p67phox protein by immunoblot analysis indicates the defective gene. Figure 7.47  Infant affected by chronic granulomatous disease. Draining suppurative inguinal lymph node in an infant with vomiting, failure to thrive, and recurrent staphylococcal pneumonia (Courtesy A. Ammann).

and empyema. Granulomas of the lungs, liver, spleen, and GI and genitourinary tracts are more likely to develop than those of the skin and may obstruct the gastric outlet, bowel, or urinary tract. Excessive inflammatory responses can result in additional non-infectious complications such as wound dehiscence, pneumonitis, and clinical presentations mimicking inflammatory bowel disease, sarcoidosis, rheumatoid arthritis, and IgA nephropathy.410,414

LABORATORY FINDINGS Laboratory abnormalities in patients with CGD typically include leukocytosis, anemia, a decreased numbers of T cells, hypergammaglobulinemia, an elevated erythrocyte sedimentation rate, and an abnormal chest radiograph. Skin testing for delayed-type hypersensitivity is normal, as are studies of phagocytosis and chemotaxis. Biopsy specimens from cutaneous granulomas in CGD patients show histiocytic infiltrates containing foreign body giant cells and accumulation of neutrophils with necrosis. Lupus erythematosus-like skin lesions in CGD patients and carriers often have histologic features similar to those of discoid lupus erythematosus, but vacuolar degeneration of basal keratinocytes is sometimes absent. Direct immunofluorescence studies of lesional skin are frequently negative. The nitroblue tetrazolium (NBT) reduction assay can be useful in establishing the diagnosis of CGD. NBT is yellow in its

415. Jirapongsananuruk O, Malech HL, Kuhns DB, et al. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. J Allergy Clin Immunol. 2003;111:374–379. 416. Rada BK, Geiszt M, Kaldi K, et al. Dual role of phagocytic NADPH oxidase in bacterial killing. Blood. 2004;104:2947–2953. 417. Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007;5:577–582.

436

PATHOPHYSIOLOGY The molecular defects that underlie CGD involve four components of the phagocyte NADPH oxidase: membrane-bound gp91phox and p22phox, and cytoplasmic p47phox and p67phox (Table 7.16). The deficient microbial killing that characterizes CGD results from failure of the NADPH oxidase system to rapidly generate superoxide by transferring electrons from NADPH to molecular O2 (the respiratory burst) following phagocytosis. Superoxide is normally converted into potent microbicidal reactive oxygen species (ROS, e.g., hydrogen peroxide, oxidized halides). NADPH oxidase activity is also thought to be associated with activation of antimicrobial proteases within the phagosome and formation of microbicidal ‘neutrophil extracellular traps’ (NETs).416,417 Individuals with CGD are predisposed to infections with catalasepositive organisms, which are able to break down endogenous hydrogen peroxide that might otherwise contribute to the microbes’ demise in the absence of NADPH oxidase function. The clinical and laboratory abnormalities that are seen in CGD result not only from failure of phagocytic killing and degradation of microorganisms, but also from exaggerated inflammatory responses. ROS participate in induction of neutrophil apoptosis (which prevents tissue damage at sites of inflammation) and regulate cytokine synthesis. Recent studies in animal models of CGD have shown that the lack of ROS contributes to a hyperinflammatory phenotype via decreased regulatory T cell activity, unrestrained γ/δ T cell activity, and augmented production of cytokines such as IL-8 and IL-17.418,419

DIFFERENTIAL DIAGNOSIS Laboratory tests documenting a defective respiratory burst allow differentiation of CGD from other disorders characterized by

418. Romani L, Fallarino F, De Luca A, et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature. 2008;451:211–216. 419. Lekstrom-Himes JA, Kuhns DB, Alvord WG, et al. Inhibition of human neutrophil IL-8 production by hydrogen peroxide and dysregulation in chronic granulomatous disease. J Immunol. 2005;174:411–417.

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Table 7.16  Genetic defects affecting components of the phagocyte NADPH oxidase

GENE

PROTEIN

phox

LOCATION WITHIN NADPH OXIDASE

% OF CGD PATIENTS

Resting state

Active state

Membrane-bound subunits of flavocytochrome b558

Same

70

X-linked recessive chronic granulomatous disease

CYBB

gp91

Autosomal recessive chronic granulomatous disease

CYBA NCF1 NCF2

p22phox p47phox p67phox

Cytosolic complex

Associated with flavocytochrome b558

≤5 20 ≤5

Neutrophil immuno-deficiency syndrome

RAC2

Rac2 GTPasea

Cytosolic complex with RhoGDI

Membrane- and GTP-bound



CHRONIC GRANULOMATOUS DISEASE

DISORDER

a

Also has a role in actin cytoskeletal dynamics, integrin-dependent adhesion and neutrophil migration; see Table 7.17. RhoGDI, Rho GDP-dissociation inhibitor. Adapted with permission from Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, ed 2. London: Elsevier; 2007.

increased susceptibility to bacterial and fungal infections. Additional inherited phagocyte disorders are described in Table 7.17.

TREATMENT The use of antibiotics has substantially reduced the morbidity and mortality of CGD.420,421 Cutaneous and nodal infections are often readily apparent, but small, localized areas of inflammation, with or without associated fever, may be difficult to detect. Vigorous investigation of the lungs, liver, and bones by routine screening radiographs, ultrasounds, or CT, MRI, positron emission tomography (PET), and bone scans often uncovers occult foci of inflammation. Cultures should be performed to determine the microbial agent, which may require invasive procedures to obtain adequate tissue samples. While awaiting culture results or in instances where culture is not possible, patients with evidence of infection should be treated empirically with broadspectrum parenteral antibiotics that cover S. aureus and Gramnegative organisms. Intravenous therapy should be continued for at least 10–14 days and followed by a several-week course of oral antibiotics. Surgical interventions such as debridement, irrigation, and drainage can be important for deeper infections. Long-term prophylactic trimethoprim-sulfamethoxazole therapy has been shown to decrease the incidence of bacterial infections in CGD patients.422 Likewise, the rate of Aspergillus infections has been reduced by prophylaxis with itraconazole.423 Patients with X-linked and autosomal recessive forms of CGD have shown clinical improvement after administration of γ-interferon.424 The interferon likely augments oxidant420. Kang EM, Malech HL. Advances in treatment for chronic granulomatous disease. Immunol Res. 2009;43(1–3):77–84. 421. Seger RA. Modern management of chronic granulomatous disease. Br J Haematol. 2008;140:255–266. 422. Margolis DM, Melnick DA, Alling DW, et al. Trimethoprimsulfamethoxazole prophylaxis in the management of chronic granulomatous disease. J Infect Dis. 1990;162:723–726. 423. Gallin JI, Alling DW, Malech HL. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med. 2003;348:2416–2422. 424. International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med. 1991;324:509. 425. Seger RA, Gungor T, Belohradsky BH, et al. Treatment of chronic granulomatous disease with myeloablative conditioning and an

independent antimicrobial pathways, since superoxide release is not enhanced and levels of cytochrome b are unchanged. Leukocyte transfusions have also been used in patients with rapidly progressive, life-threatening infections.421 Short courses of systemic corticosteroids can be helpful for patients with obstructive granulomas of the bronchopulmonary, GI, and genitourinary tracts.420,421 Hematopoietic stem cell transplantation represents a potentially curative therapy for CGD, and its use in patients with this condition has increased in recent years.420,421,425–427 Although younger patients without infection at the time of transplantation have better outcomes (survival >90–95%), utilization of reducedintensity conditioning regimens has allowed successful treatment of high-risk adults with incurable fungal infections. In children with CGD complicated by recurrent serious infections or corticosteroid-dependant inflammatory disease, especially those who have an HLA-identical family member, transplant should be considered before irreversible organ damage occurs. Gene therapy was first performed in five adults with the p47phox-deficient form of CGD. A single infusion of transduced CD34+ peripheral blood stem cells led to peak levels of corrected granulocytes in 3–6 weeks, with persistence for as long as 6 months.428 More recently, treatment of two young men with X-linked recessive CGD with non-myeloablative conditioning prior to the infusion of CD34+ peripheral blood stem cells transduced ex vivo with a retroviral vector expressing gp91phox led to sustained engraftment of functionally corrected phagocytes and substantial clinical improvement.429 In vivo expansion of phagocyte clones containing insertionally activated growth-promoting

426. 427. 428. 429.

unmodified hematopoietic allograft: a survey of the European experience, 1985–2000. Blood. 2002;100:4344–4350. Del Guidice I, Iori AP, Mengarelli A, et al. Allogeneic stem cell transplant from HLA-identical sibling for chronic granulomatous disease and review of the literature. Ann Hematol. 2003;82:189–192. Gungor T, Halter J, Klink A, et al. Successful low toxicity hematopoietic stem cell transplantation for high-risk adult chronic granulomatous disease patients. Transplantation. 2005;79:1596–1606. Malech HL, Mapels PB, Whiting-Theoblad N, et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc Natl Acad Sci USA. 1997;94:12133–12138. Ott MG, Schmidt M, Schwarzwaelder K, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006;12:401–409.

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Table 7.17  Inherited defects in phagocytes and Toll-like receptor signaling

CHRONIC GRANULOMATOUS DISEASE

DISORDER

INH

GENE

PROTEIN (DEFECT OR FUNCTION)

CLINICAL FEATURES

Severe congenital neutropenia

AD

ELA2

AD

GFI1

AR

HAX1

Neutrophil elastase (abnormal elastase trafficking and accumulation) Transcriptional repressor of elastase (abnormal elastase accumulation) Mitochondrial HS1-associated protein X1 (protects against apoptosis in myeloid cells)

Neutropenia MDS, AML Neutropenia, lymphopenia Circulating myeloid progenitors Neutropenia Increased apoptosis of myeloid cells

Cyclic neutropenia

AD

ELA2

Neutrophil elastase

Alternating 21 days cycles of neutropenia and monocytopenia Fever and oral ulcers at nadir

X-linked neutropenia

XL

WASP

WASP (gain of function; see text, Wiskott–Aldrich syndrome)

Neutropenia

Specific granule deficiency

AR

CEBPE

C/EBPε transcription factor (granulocyte differentiation)

Bilobed neutrophils Recurrent bacterial infections

p14 deficiency

AR

MAPBPIP

MAP binding partner 1-interacting protein (p14; endosomal biogenesis)

Neutropenia Pneumococcal infections Diffuse pigmentary dilution of the skin and hair Short stature, coarse facies

Myeloperoxidase deficiency

AR

MPO

Myeloperoxidase (microbial killing by granulocytes)

Candida and S. aureus infections Often asymptomatic

Shwachman–Bodian– Diamond syndrome

AR

SBDS

SBDS protein (ribosomal RNA metabolism)

Pancytopenia, MDS, AML Exocrine pancreatic insufficiency Chondrodysplasia

Leukocyte adhesion deficiency-I

AR

ITGB2

β2 integrin subunit of LFA-1, CR3, and p150 (see text)

Leukocyte adhesion deficiency-II

AR

SLC35C1 (FUCT1)

GDP-fucose transporter 1 (sialyl-Lewis X expression; see text)

Leukocyte adhesion deficiency-III

AR

RASGRP2

RAS guanyl releasing protein 2 (defective integrin activation; see text)

Rac2 deficiency

AD

RAC2

Rac2 GTPase (dysfunctional NADPH oxidase, integrin-dependent adhesion, and neutrophil migration

Neutrophilia; ↓ tissue neutrophils Necrotic abscesses, ulcers Poor wound healing, delayed umbilical stump separation Gingivitis Bleeding diathesis (LAD-III) Osteopetrosis (LAD-III)

Defects of the interleukin (IL)-12/interferon (IFN)-γ axis

AR

IL12B

AR AR, AD AR AR, AD

IL12RB1 IFNGR1 IFNGR2 STAT1a

Severe mycobacterial and Salmonella infections Disseminated BCG infection Viral infections (STAT1, TYK2) Hyper-IgE syndrome (TYK2; see text)

AR

TYK2

Subunit of IL-12 and IL-23 (stimulation of IFN-γ production) IL-12 and IL-23 receptor β1 chain IFN-γ receptor (ligand binding) IFN-γ receptor (signaling) Signal transducer and activator of transcription (IFN receptor signaling)b Tyrosine kinase 2 (IFN/IL-12/other cytokine receptor signaling)b

AD AR

TLR3 UNC93B1

Herpes simplex encephalitis

AR

IRAK4

AR

MYD88

TLR3 (signals IFN-α/β production) UNC-93B (endoplasmic reticulum protein required for TLR3 signaling) IL-1 receptor associated kinase-4 (IL-1 receptor & TLR signaling) Myeloid differentiation primary response gene 88 (recruits IRAK4 to the IL-1 receptor and TLRs)

Defects in toll-like receptor (TLR) signalingc

Recurrent pyogenic sinopulmonary and skin infections with Streptococcus pneumoniae and S. aureus, respectively

See text for Chédiak–Higashi syndrome and chronic granulomatous disease. Defects in STAT3 underlie AD hyper-IgE syndrome (see text), and defects in STAT5B (involved in IL-2 and growth hormone receptor signaling) lead to an AR syndrome of growth hormone insensitivity, decreased regulatory T cells, viral infections and eczematous dermatitis. b Affect IFN-α/β receptor signaling, which is important to defense against viral infections, in addition to IFN-γ receptor signaling c Downstream signaling occurs via nuclear factor-κB; see Table 7.20 for hypohidrotic ectodermal dysplasia with immunodeficiency due to nuclear factor-κB defects. AML, acute myeloid leukemia; BCG, bacillus Calmette–Guérin; IFN, interferon; MAP, mitogen-activated protein kinase kinase 1. MDS, myelodysplastic syndrome; LFA-1, lymphocyte function-associated antigen-1; SBDS, Shwachman–Bodian–Diamond syndrome; STAT, signal transducer and activator of transcription; WASP, Wiskott–Aldrich syndrome protein; XR, X-linked recessive. a

438

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genes augmented the therapeutic efficacy in this first successful use of gene transfer to correct a myeloid immunodeficiency. Dihydrorhodamine 123 assays can be used in determining the carrier status of the sisters and other female relatives of patients with X-linked CGD, which is important to enable genetic counseling prior to pregnancy. Prenatal diagnosis of CGD is also possible.

CGD can have devastating effects on affected children. Patients frequently require augmented caloric intake due to an increased metabolic rate and GI involvement resulting in malabsorption. Many children exhibit poor growth and are small for their age. The recurrent infections of the skin and other organs can lead to disfigurement and frequent absences from school.

DIGEORGE SYNDROME DiGeorge syndrome belongs to a group of disorders (including velocardiofacial syndrome) caused by hemizygous deletion of chromosome 22q11.2. In addition to abnormalities of the thymus and parathyroid glands, which result from defective development of the third and fourth pharyngeal pouches, prominent features of DiGeorge syndrome include conotruncal heart anomalies (most often tetralogy of Fallot), facial dysmorphism, and cleft palate.430 The underlying chromosome 22q11.2 deletion leads to haploinsufficiency of the TBX1 gene,431 which encodes a T-box transcription factor that is required for development of the fourth pharyngeal arch arteries; mice heterozygous for a null mutation in Tbx1 also have conotruncal cardiac defects. The thymic shadow is absent or reduced at birth in patients with DiGeorge syndrome, and affected neonates often present with hypocalcemia and resultant tetany due to their aplastic parathyroid glands. T-cell abnormalities in patients with DiGeorge syndrome are of variable severity and can be mild (‘partial DiGeorge’), but they do not tend to improve with advancing age.432 Humoral immunity is usually normal. Patients have recurrent mucocutaneous candidal infections, which often begin during the neonatal period, and increased susceptibility to viral, Pneumocystis jiroveci, and other fungal infections. Graftversus-host disease (GvHD) may develop in infants who receive nonirradiated blood products. Non-infectious cutaneous granulomas (Fig. 7.48) and eczematous eruptions characterized histologically by spongiotic dermatitis, satellite-cell necrosis, and an infiltrate of eosinophils and oligoclonal autologous T cells have been described.433 Facial features of DiGeorge syndrome include hypertelorism, a short philtrum, and low-set malformed ears.

430. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007;370:1443–1452. 431. Lindsay EA, Vitelli F, Su H, et al. Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature. 2001;410:97–101. 432. Markert ML, Hummell DS, Rosenblatt HM, et al. Complete DiGeorge syndrome: persistence of profound immunodeficiency. J Pediatr. 1998;132:15–21. 433. Selim MA, Markert ML, Burchette JL, et al. The cutaneous manifestations of atypical complete DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol. 2008;35:380–385.

HYPERIMMUNOGLOBULIN E SYNDROME

PSYCHOLOGICAL/SOCIAL CONSIDERATIONS

Figure 7.48  Non-infectious, persistent cutaneous granulomas in a patient with DiGeorge syndrome. The granulomas are indistinguishable clinically from cutaneous granulomas associated with other immunodeficiencies.

Hematopoietic stem cell or thymic transplantation is recommended for patients with complete DiGeorge syndrome.

HYPERIMMUNOGLOBULIN E SYNDROME Hyperimmunoglobulin E syndrome (HIES) is characterized by repeated cutaneous and sinopulmonary infections, eczematous dermatitis from birth or early childhood, and extremely elevated immunoglobulin E (IgE) levels.434,435 Job syndrome represents a subgroup of HIES that was originally described in female patients with fair skin, red hair, and hyperextensible joints in addition to the other features of HIES.

EPIDEMIOLOGY The classic form of HIES is an autosomal dominant disorder that has variable expressivity, with many patients showing a partial phenotype. A clinically and molecularly distinct autosomal recessive form of HIES has also been described in consanguineous families from Turkey and Mexico.436

CLINICAL PRESENTATION Patients with HIES typically present during the first month of life with a noninfectious papulopustular eruption involving the face, scalp, axillae, upper trunk, and diaper area.437,438 Chronic

434. Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections: an autosomal dominant multisystem disorder. N Engl J Med. 1999;340:692–702. 435. Paulson ML, Freeman AF, Holland SM. Hyper IgE syndrome: an update on clinical aspects and the role of signal transducer and activator of transcription 3. Curr Opin Allergy Clin Immunol. 2008;8:527–533. 436. Renner ED, Puck JM, Holland SM, et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr. 2004;144:93–99. 437. Chamlin SL, McCalmont TH, Cunningham BB, et al. Cutaneous manifestations of hyper-IgE syndrome in infants and children. J Pediatr. 2002;141:572–575. 438. Eberting CL, Davis J, Puck JM, et al. Dermatitis and the newborn rash of hyper-IgE syndrome. Arch Dermatol. 2004;140:1119–1125.

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candidiasis of the oral mucosa, the periungual area, other mucocutaneous sites, and the nails is often the initial infectious manifestation during infancy and eventually develops in >80% of affected individuals. Cutaneous infections with S. aureus also begin during infancy and can present as crusted plaques, retroauricular fissures, folliculitis, furunculosis, abscesses, cellulitis, lymphangitis, and paronychial infections with resultant nail dystrophy. Cutaneous abscesses, which may be extremely large, most commonly affect the neck, scalp, periorbital area, axillae, and groin. These lesions tend to be less erythematous, warm, and tender than expected, and are therefore referred to as ‘cold abscesses.’ Patients are frequently afebrile but sometimes develop a low-grade fever. Recurrent cutaneous infections with other organisms, including Strep. pyogenes as well as Candida spp., may also be observed. Most patients with HIES have recurrent bronchitis and pneumonias, which are usually due to S. aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Empyema, bronchiectasis, and pneumatocele formation represent frequent complications. The pneumatoceles tend to persist and become the site of further infections with bacterial or fungal (e.g. Aspergillus) organisms. Rarely, massive hemoptysis ensues. Other common sites of infection include the ears, oral mucosa, sinuses, and eyes. Visceral infections other than pneumonia are unusual. The eczematous rash of HIES shares many clinical features with atopic dermatitis, including intense pruritus, lichenification (Fig. 7.49), and staphylococcal superinfection. When present, the eczematous dermatitis affects infants and young children with HIES, but frequently clears by adolescence. In contrast to individuals with atopic dermatitis, HIES patients do not have a propensity to develop hay fever, asthma, or other cutaneous signs of atopy. As a consequence of chronic facial abscesses and bone abnormalities, HIES patients experience progressive facial coarsening.439 Manifestations include thick doughy skin, large follicular ostia, pitted scarring, a broad nose, deep-set eyes, a prominent forehead, and irregularly proportioned cheeks and jaw (Fig. 7.50). Osteopenia is often present and patients have an increased risk of fractures of the long bones, ribs, and pelvis. More than half of adolescents and adults with HIES have had at least three fractures, often caused by minor trauma. Scoliosis occurs in three-quarters of patients 16 years of age or older, and hyperextensibility of the joints affects two-thirds of patients. A variety of dental abnormalities have been associated with HIES, including retention of primary teeth and lack of eruption of secondary teeth. The development of coronary artery aneurysms during adulthood and brain abnormalities such as Chiari malformations, lacunar infarctions, and focal white matter hyperintensities on T2-weighted MRI sequences has been described. Lastly, HIES is associated with an increased risk of non-Hodgkin’s lymphomas of B-cell origin. Autosomal recessive HIES (AR-HIES) is a distinct disease entity that shares some features with classic HIES, including highly elevated serum IgE levels, chronic eczematous dermatitis, and recurrent staphylococcal and candidal infections of the skin (including cold abscesses) and respiratory tract.436 However, rather than developing skeletal and dental abnormalities or

439. Borges WG, Hensley T, Carey JC, et al. The face of Job. J Pediatr. 1998;133:303–305.

440

Figure 7.49  Severe eczema of the hand of a patient with hyper-IgE syndrome.

Figure 7.50  Coarse facial features of a patient with hyper-IgE syndrome. The patient had frequent upper respiratory tract and skin infections, severe eczema, and an IgE level of 56 000 IU/mL.

pneumatoceles, patients with AR-HIES are at risk of severe fungal (e.g. Cryptococcus) and viral (e.g. molluscum contagiosum and herpes simplex) infections, autoimmunity, and vasculitis affecting the central nervous system.

LABORATORY FINDINGS HIES patients, by definition, have markedly elevated levels of polyclonal IgE; serum levels of IgG, IgA, and IgM are usually normal. Patients develop especially high levels of

Genodermatoses

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SIGNALING VIA STAT3

FUNCTION OF STAT3 SIGNALING

FINDING IN STAT3 DEFICIENCY/HIES

↑ IL-6

Pyrogen, acute phase response

‘Cold’ abscesses

↑ IL-10

Anti-inflammatory

Destructive inflammation (e.g. in lung)

↑ IL-17

Defense against bacteria and Candida

↑ IL-22

β-defensin production

Bacterial (esp. Staphylococcus aureus) and candidal infections

↓ IL-21

Suppression of IgE production (normally stimulated by IL-21 + IL-4)

Increased IgE production

↓ TNF-α

Regulation of inflammation in response to innate immune agonists (e.g. lipopolysaccharide)

Destructive inflammation

↓ Osteoclast activity

Decreased bone resorption

Osteoporosis

anti-staphylococcal and anti-candidal IgE and tend to have immediate wheal-and-flare reactions upon skin prick testing with a variety of foods, inhaled allergens, and bacterial or fungal antigens. Many patients have eosinophilia of the peripheral blood and sputum. Intermittent abnormalities of neutrophil and monocyte chemotaxis have been observed in some affected individuals. Cell-mediated immunity is often abnormal, as manifested by anergy to skin testing and impaired in vitro lymphoproliferative responses to specific antigens. The histologic features of the neonatal papulopustular eruption of HIES include eosinophilic spongiosis, eosinophilic folliculitis, and a dermal perivascular infiltrate with abundant eosinophils.437,438

PATHOPHYSIOLOGY

HYPERIMMUNOGLOBULIN E SYNDROME

Table 7.18  Consequences of defective STAT3 signaling in hyper-IgE syndrome (HIES)

cytokine responses, increased levels of IgE, and reactivity against S. aureus. In atopic dermatitis patients and normal individuals, IL-4 has a stimulatory effect on IgE secretion. In contrast, production of IgE in patients with HIES is maximally activated and fails to increase further upon administration of IL-4.

DIFFERENTIAL DIAGNOSIS HIES must be differentiated from a number of other disorders characterized by elevated IgE levels and dermatitis. These include atopic dermatitis, Wiskott–Aldrich syndrome, Netherton syndrome, Omenn syndrome, DiGeorge syndrome, IPEX syndrome, prolidase deficiency, and GvHD. Atopic dermatitis and Wiskott– Aldrich syndrome present with eczematous dermatitis and frequent staphylococcal skin infections but not cold abscesses, recurrent pneumonia, or musculoskeletal abnormalities. Platelet defects also help to distinguish patients with Wiskott–Aldrich syndrome. Prolidase deficiency is an autosomal recessive condition due to mutations in the peptidase D (PEPD) gene; it features chronic leg ulcers, facial dysmorphism, and mental retardation as well as increased susceptibility to pyogenic infections and eczematous dermatitis.444 Bacterial and candidal abscesses characterize chronic granulomatous disease and myeloperoxidase deficiency, but patients with these disorders do not have elevated IgE levels.

Heterozygous mutations in the signal transducer and activator of transcription 3 (STAT3) gene cause a subset of autosomal dominant HIES.440,441 Different combinations of receptor-associated Janus kinases (JAKs) and STAT proteins play critical roles in the transduction of various cytokine signals. Upon phosphorylation by JAKs, STAT proteins dimerize, translocate to the nucleus and activate target genes. The infections and inflammatory complications that occur in HIES reflect the underlying disruption of specific cytokine pathways (Table 7.18). In particular, impaired differentiation of IL-17-producing CD4+ T cells contributes to the susceptibility to bacterial infections.442 Interestingly, homozygous mutations in the tyrosine kinase 2 (TYK2) gene, which encodes a member of the JAK family, were identified in a patient with an autosomal recessive condition resembling HIES. This molecular defect led to disruption of additional signaling pathways, including those for IL-12 and IFN-α/β (Table 7.17).443 The eczematous dermatitis of HIES shares several immuno­ pathologic features with atopic dermatitis, including abnormal

The mainstays of therapy for HIES are appropriate use of antiseptics (e.g., dilute sodium hypochlorite baths) and antibiotics together with incision and drainage of abscesses.435 Interferon-γ has been shown to increase neutrophil chemotaxis and potentially help control infections,445 and intravenous immunoglobulin therapy has been reported to improve the dermatitis, prevent infections, and lower the level of IgE.435,446

440. Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med. 2007;357:1608–1619. 441. Minegishi Y, Saito M, Tsuchiya S, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448:1058–1062. 442. Milner JD, Brenchley JM, Laurence A, et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 2008;452:773–776. 443. Minegishi Y, Saito M, Morio T, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25:745–755.

444. Hershkovitz T, Hassoun G, Indelman M, et al. A homozygous missense mutation in PEPD encoding peptidase D causes prolidase deficiency associated with hyper-IgE syndrome. Clin Exp Dermatol. 2006;31:435–440. 445. Jeppson JD, Jaffe HS, Hill HR. Use of recombinant human interferon gamma to enhance neutrophil chemotactic responses in Job syndrome of hyperimmunoglobulinemia E and recurrent infections. J Pediatr. 1991;118:383–387. 446. Kimata H. High-dose intravenous gamma-globulin treatment for hyperimmunoglobulinemia E syndrome. J Allergy Clin Immunol. 1995;95:771–774.

TREATMENT

441

ii

Neonatal and Inherited Disorders

IMMUNOGLOBULIN DEFICIENCIES The pathogenesis and clinical features of immunoglobulin deficiencies, including the selected entities discussed briefly below, are presented in Table 7.19.447–449

IMMUNOGLOBULIN A DEFICIENCY

IPEX SYNDROME

The most common immunoglobulin deficiency is selective IgA deficiency, which is found in 1 in 500 persons with an equal sex distribution. Only 10–15% of affected individuals have clinical manifestations, which include bacterial sinopulmonary infections, Giardia gastroenteritis, and (in one-third of symptomatic patients) autoimmune disorders. Half of patients have circulating anti-IgA antibodies. IVIG and blood products with IgAbearing lymphocytes are therefore contraindicated, and fatal anaphylactic reactions have been reported.

HYPER IGM (HIM) SYNDROMES HIM syndromes are a group of disorders in which defective immunoglobulin class switch recombination results in normal or elevated serum IgM levels but extremely low levels of other immunoglobulin isotypes.450–455 An X-linked recessive inheritance pattern is most common, but autosomal recessive forms can also occur. Affected individuals have recurrent sinopulmonary, GI, and cutaneous infections with pyogenic bacteria and opportunistic organisms. Autoimmune disorders, especially cytopenias, may also develop.456 Additional cutaneous manifestations include severe warts (Fig. 7.51) and oral (Fig. 7.52) or anogenital ulcers.457

PAN-HYPOGAMMAGLOBULINEMIA Pan-hypogammaglobulinemia is found in approximately 1 in 20 000 persons and can be classified into two major subdivisions: agammaglobulinemia (affecting primarily boys) and the

447. Conley ME. Genes required for B cell development. J Clin Invest. 2003;112:1636–1638. 448. Grimbacher B, Schäffer AA, Peter HH. The genetics of hypogammaglobulinemia. Curr Allergy Asthma Reports. 2004;4:349–358. 449. Wood P, Stanworth S, Burton J, et al. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol. 2007;149:410–423. 450. Korthäuser U, Graf D, Mages HW. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993;361:539–540. 451. DiSanto JP, Bonnefoy JY, Gauchat JF, et al. CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM. Nature. 1993;361:541–543. 452. Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AIS) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell. 2000;102:565–575. 453. Durandy A, Peron S, Fischer A. Hyper-IgM syndromes. Curr Opin Rheumatol. 2006;18:369–376. 454. Lougaris V, Badolato R, Ferrari S, et al. Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunol Rev. 2005;203:48–66. 455. Durandy A, Revy P, Imai K, et al. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev. 2005;203:67–79. 456. Jesus AA, Duarte AJ, Oliveira JB. Autoimmunity in hyper-IgM syndrome. J Clin Immunol. 2008;28: S62–S66. 457. Chang MW, Romero R, Scholl PR, et al. Mucocutaneous manifestations of the hyper-IgM immunodeficiency syndrome. J Am Acad Dermatol. 1998;38:191–196.

442

more prevalent common variable immunodeficiency (CVID; no sex predilection). Agammaglobulinemia, which reflects a failure of B-cell differentiation, has an inheritance pattern that is X-linked recessive in 90% of patients and autosomal recessive in the remainder.458,459 CVID represents a heterogeneous group of disorders characterized by decreased levels of immunoglobulins (IgG, IgA, IgM) and variable functional T cell defects, and it may be inherited in an autosomal dominant or autosomal recessive manner.460–462 Approximately 15% of individuals with CVID have family members with selective IgA deficiency. Patients with agammaglobulinemia usually begin to experience recurrent infections during infancy. They sometimes initially present with ecthyma gangrenosum in the setting of Pseudomonas bacteremia.463 CVID has two peaks of onset: the first in children 5–10 years of age and the second in young adults.464 Patients with CVID risk developing recurrent bacterial sinopulmonary infections, non-infectious granulomas of the skin and internal organs, autoimmune cytopenias, and inflammatory bowel disease.465 The treatment of hypogammaglobulinemia includes antibody replacement with IVIG or subcutaneous immunoglobulins and aggressive antibiotic therapy for infections.466 Tumor necrosis factor inhibitors have been successfully used to treat granulomatous disease in patients with CVID. In patients suspected to have X-linked agammaglobulinemia, flow cytometric analysis of lymphocytes can reveal an absence of Bruton tyrosine kinase (the defective protein in this condition) and thereby confirm the diagnosis. Female carriers of X-linked agammaglobulinemia can be detected via examination of B-cell X-inactivation patterns, which show skewing toward cells with a normal X chromosome. DNA-based prenatal diagnosis is possible for the various forms of hypogammaglobulinemia when the genetic defect in affected family members is known.

IPEX SYNDROME The X-linked recessive IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome results from

458. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361:226–233. 459. Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993;72:279–290. 460. Castigli E, Wilson SA, Garibyan L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005;37:829–834. 461. Park MA, Li JT, Hagan JB, et al. Common variable immunodeficiency: a new look at an old disease. Lancet. 2008;372:489–502. 462. Yong PF, Tarzi M, Chua I, et al. Common variable immunodeficiency: an update on etiology and management. Immunol Allergy Clin North Am. 2008;28:367–386. 463. Ng W, Tan CL, Yeow V, et al. Ecthyma gangrenosum in a patient with hypogammaglobulinemia. J Infect. 1998;36:331–335. 464. Glocker E, Ehl S, Grimbacher B. Common variable immunodeficiency in children. Curr Opin Pediatr. 2007;19:685–692. 465. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48. 466. Moore ML, Quinn JM. Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century. Ann Allergy Asthma Immunol. 2008;101(2):114–121.

GENE

PROTEIN (FUNCTION) IG LEVELS

↓↓

B CELLS

  Selective IgM deficiency

?

?

IgM ↓

Nl

Defective class switch recombination (e.g. from IgM to IgG, IgA or IgE) and somatic hypermutationa   Common variable Inducible co-stimulator on IgG,A ↓; ± IgM ↓ Nl or ↓ ICOS immunodeficiency activated T cells (T-cell (CVID)b help for B-cell differentiation) TNFRSF13B (AD or Transmembrane activator AR) and CAML interactor (TACI; B-cell isotype switching) B-cell activating factor TNFRSF13C receptor (BAFFR; B-cell isotype switching) CD19 antigen (B-cell CD19 survival and differentiation) Mismatch repair protein MSH5 (AD) (regulates class switch recombination)   Selective IgA See above section IgA ↓c; anti-IgA Nl TNFRSF13B (AD) 1 deficiency antibodies in ≈ 2 MSH5 (AD)

Block in B-cell differentiation at the pro-B- to pre-B-cell transition   X-linked (Bruton) Bruton tyrosine kinase All ↓ BTK agammaglobulinemia (pre-B-cell receptor [BCR] signaling)   AR µ heavy chain of IgM IGHM agammaglobulinemia (component of pre-BCR) Igα chain, Igβ chain (bind CD79A, CD79B µ heavy chain) λ5 (surrogate light chain IGLL1 of pre-BCR) B-cell linker protein (binds BLNK Bruton tyrosine kinase)   AD Leucine-rich repeatLRRC8A agammaglobulinemia containing 8 family member A

DISORDER

Table 7.19  Primary immunoglobulin deficiency disorders

IPEX SYNDROME

Mucocutaneous candidiasis Eczematous dermatitis Autoimmune conditions such as SLE, vitiligo, and lipodystrophia centrifugalis abdominalis Extensive warts Eczematous dermatitis SLE

Clinical manifestations in only 10–15% Similar to CVID Asthma and allergic rhinoconjunctivitis Recurrent bacterial infections Autoimmune diseases

Continued

Pyodermas and mucocutaneous candidiasis Extensive warts and dermatophyte infections Eczematous dermatitis Non-infectious granulomas Autoimmune conditions such as vitiligo, alopecia areata and vasculitis Clonal CD8+ lymphocytic infiltration of the skin

The skin is the most common site of infection Furuncles and cellulitis Ecthyma gangrenosum Eczematous dermatitis Papular dermatitis due to lymphohistiocytic infiltration Non-infectious granulomas Dermatomyositis-like disorder associated with chronic echoviral meningoencephalitis

CUTANEOUS MANIFESTATIONS

Sinopulmonary infections with encapsulated bacteria Gastroenteritis with Giardia and Campylobacter Autoimmune diseases, esp. thrombocytopenic purpura and hemolytic anemia Enteropathy Non-infectious granulomas/ lymphoproliferation in the lungs, liver, spleen, and GI tract Increased risk of lymphoma and gastric cancer

Recurrent infections with Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, Haemophilus influenzae, Pseudomonas aeruginosa, and Mycoplasma spp. Hepatitis B and enteroviral infections Lymphomas (≈5%)

INFECTIOUS ORGANISMS AND EXTRACUTANEOUS MANIFESTATIONS

Genodermatoses

7

443

444 Activation-induced cytidine deaminase Uracil-DNA glycosylase NF-κB essential modulator IgM ↑; ± IgA ↑; ± (activates NF-κB, which is IgG ↓ involved in CD40 signaling) Inhibitor of κBα (inhibits NF-κb)

AICDA

Nl



Telangiectasias (uncommon) Nevoid hyperpigmentation

Pyodermas Ectodermal dysplasia

Pyodermas

Pyodermas Extensive warts Oral and anogenital ulcers Non-infectious granulomas Autoimmune conditions such as SLE

CUTANEOUS MANIFESTATIONS

Failure to thrive in infancy Recurrent sinopulmonary and GI infections, usually beginning at ≈6 months of age when maternal antibody levels wane

Recurrent pyodermas and abscesses

Recurrent bacterial sinopulmonary Cellulitis and pyodermas infections Extensive verruca vulgaris and Myelokathexis (mature neutrophils fail condyloma acuminata to exit the bone marrow)

Bacterial sinopulmonary and GI infections Abnormal facies, MR

Recurrent sinopulmonary and GI infections with pyogenic bacteria and opportunistic organisms (e.g. Pneumocystis jiroveci) Neutropenia Small lymph nodes Autoimmune diseases, especially cytopenias Increased risk of lymphoma and GI cancer As above, but massive LAN (with germinal centers), HSM and no opportunistic infections Pyogenic bacterial and opportunistic infections Subset of NEMO patients with osteopetrosis and lymphedema

INFECTIOUS ORGANISMS AND EXTRACUTANEOUS MANIFESTATIONS

a

Autosomal recessive (AR) unless otherwise specified. T-cell priming may also defective, particularly in CD40-CD40L disorders (leading some authors to classify the latter as subtypes of severe combined immunodeficiency). b Heterogeneous group of disorders with defects primarily in humoral but also involving cell-mediated immunity; TNFRSF13b is the most common of the underlying genetic defects identified to date, accounting for approximately 10% of CVID. c Symptomatic patients often develop the immunodeficiency pattern of CVID. d Warts, hypogammaglobulinemia, infections, and myelokathexis. AD, autosomal dominant; CAML, calcium-modulating cyclophilin ligand; CNS, central nervous system; GI, gastrointestinal; HSM, hepatosplenomegaly; Ig, immunoglobulin; IKBKG, inhibitor of κ light polypeptide gene enhancer in B-cells, kinase γ; LAN, lymphadenopathy; MR, mental retardation; Nl, normal; SLE, systemic lupus erythematosus. Adapted with permission from Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, ed 2. London: Elsevier; 2007.

IgG,A ↓ (resolves by age 3 years) Nl

CXC chemokine receptor IgG ↓; ± IgA,M ↓ 4 (binds CXCL12; key role in bone marrow homeostasis and lymphocyte trafficking)

Delayed maturation of helper T-cell function   Transient hypo? ? agammaglobulinemia of infancy

Aberrant chemokine signaling   WHIM syndromed CXCR4 (AD, gain-of-function)

Abnormal DNA methylation leading to defective B-cell negative selection and terminal differentiation DNA methyltransferase 3B All ↓ Nl or ↓   Immunodeficiency, DNMT3B centromeric instability, and facial anomalies (ICF) syndrome

UNG   Hypohidrotic IKBKG (NEMO) ectodermal dysplasia (X-linked recessive) with immunodeficiency IKBA (NFKBIA; AD, gain of function)

CD40 (on B cells)

CD40

B CELLS

IgM ↑; Nl isohemagglutinins ↑; IgA,E,G ↓↓

CD40 ligand (on T cells)

CD40LG

  X-linked hyper-IgM syndrome   AR hyper-IgM syndromes

PROTEIN (FUNCTION) IG LEVELS

GENE

DISORDER

IPEX SYNDROME

Table 7.19  Primary immunoglobulin deficiency disorders (continued)

ii Neonatal and Inherited Disorders

Genodermatoses

7

Figure 7.51  Extensive warts, present for years in a patient with hyper-IgM LEUKOCYTE ADHESION DEFICIENCY

disorder.

Figure 7.52  Oral ulceration on the side of the tongue in a patient with hyper-IgM disorder.

FOXP3 gene mutations that lead to abnormal development of regulatory T cells. IPEX patients typically present during infancy with severe diarrhea due to their autoimmune enteropathy and develop various autoimmune endocrinopathies, most often early-onset type 1 diabetes mellitus and thyroiditis, and cytopenias. The majority of patients manifest during the first few months of life with widespread eczematous dermatitis, which is often accompanied by elevated IgE levels and complicated by staphylococcal superinfections and sepsis. Cutaneous manifestations of IPEX can also include psoriasiform dermatitis, cheilitis, nail dystrophy, and autoimmune skin conditions such as alopecia areata, urticaria, and bullous pemphigoid.377 Autoimmune endocrinopathies, enteropathy, and eczematous dermatitis have also been described in a patient with an IL-2 receptor-α-chain (CD25) deficiency (Table 7.11).378

LEINER PHENOTYPE The ‘Leiner phenotype’ is characterized by exfoliative dermatitis, chronic diarrhea, failure to thrive, and recurrent bacterial and candidal infections during infancy. Although originally reported as a condition (‘Leiner’s disease’) caused by defective yeast opsonization in the setting of dysfunctional C5,467 the ‘Leiner phenotype’ has subsequently been described in infants with a variety of immunodeficiency disorders. These include severe combined immunodeficiency (SCID), X-linked agammaglobulinemia, and hyper-IgE syndrome as well as C3 and C5 deficiencies.468

467. Miller ME, Nilsson UR. A familial deficiency of the phagocytosisenhancing activity of serum related to dysfunction of the fifth component of complement. N Engl J Med. 1970;282:354–358. 468. Glover M, Atherton D, Levinsky R, et al. Syndrome of erythroderma, failure to thrive and diarrhea in infancy: a manifestation of immunodeficiency. Pediatrics. 1988;81:66–72. 469. Bunting M, Harris ES, Mclntyre TM, et al. Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving β2 integrins and selectin ligands. Curr Opin Hematol. 2002;9:30–35.

LEUKOCYTE ADHESION DEFICIENCY Leukocyte adhesion deficiency (LAD) is a group of autosomal recessive disorders that affect the ability of neutrophils, monocytes, and T cells to adhere to the vascular endothelium and migrate to sites of infection and tissue injury.411,469,470

CLINICAL PRESENTATION The most frequent clinical manifestation of LAD is gingivitis with periodontitis, which may result in loss of teeth. Patients also have poor wound healing and atrophic scarring. Minor skin wounds may rapidly enlarge to form large, chronic ulcerations (Fig. 7.53) that resemble ‘burnt out’ pyoderma gangrenosum. Patients with LAD experience recurrent skin infections (most often of the face and perianal area), otitis media, and pneumonias caused by pyogenic bacteria. They often develop cellulitis and necrotic abscesses with impaired pus production. Life-threatening bacterial, fungal, or (less often) viral infections may occur. More than three-quarters of patients with severe type I LAD (LAD-I; 90%. However, transplantation of haploidentical parental stem cells, which can be depleted of post-thymic T cells to reduce the risk of GvHD, often requires chemotherapeutic conditioning to facilitate engraftment and results in 50 children with X-linked SCID or ADA deficiency.486,488–490 Follow-up studies on 19 of these patients (4 months to 4 years after treatment) showed that transcriptional start sites and coding regions of active genes were the preferred retroviral integration sites in circulating T cells as well as in preinfusion transduced CD34+ cells; however, in the former cells ~25% of all integrations were clustered at common sites, suggesting in vivo selection of transduced cells with a higher capacity for engraftment, survival and proliferation.491 Although T- and NK-cell function was restored, 2–6 years after treatment at least five patients with X-linked SCID have developed T-cell leukemias related to activation of proto­ oncogenes such as LM02 by the retroviral vector.492 This complication has raised concerns regarding the safety of gene therapy, which has led to protocol modifications and investigation of alternative approaches such as lentiviral vectors and in situ gene transfer. In families with a previously affected sibling, prenatal diagnosis of SCID has been performed by ADA assays and fetal DNA analysis.

7

CLINICAL MANIFESTATIONS Because thrombocytopenia and platelet dysfunction are usually present at birth, the first clinical sign of WAS is often petechiae and ecchymoses of the skin (Fig. 7.54) and oral mucosa. Spontaneous bleeding from the oral cavity, epistaxis, hematemesis, melena, and hematuria are common.

Figure 7.54  Petechiae and ecchymosis in a young boy with the Wiskott– Aldrich syndrome.

489. Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002;296:2410–2413. 490. Gaspar HB, Parsley KL, Howe S, et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004;364:2181–2187. 491. Bushman FD. Retroviral integration and human gene therapy. J Clin Invest. 2007;117:2083–2086. 492. Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;117:3132–3142. 493. Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol. 2008;15:30–36. 494. Ochs HD, Thrasher AJ. The Wiskott–Aldrich syndrome. J Allergy Clin Immunol. 2006;117:725–738. 495. Orange JS, Stone KD, Truvey SE, et al. The Wiskott–Aldrich syndrome. Cell Mol Life Sci. 2004;61:2361–2385.

449

ii

Neonatal and Inherited Disorders

LABORATORY FINDINGS

Figure 7.55  Atopic dermatitis on the feet and lower extremities with serosanguineous drainage in a toddler with Wiskott–Aldrich syndrome.

WISKOTT–ALDRICH SYNDROME

Persistent thrombocytopenia (usually 5000–50 000 platelets/ mm3) and a low mean platelet volume (3.5–5.0 fL) are the most consistent laboratory findings. Lymphopenia and eosinophilia are sometimes observed. Serum levels of IgG2 and IgM are usually low, but levels of IgA, IgE, and IgD tend to be elevated. Antibody responses to polysaccharide antigens are markedly diminished, and skin test anergy and decreased in vitro lymphoproliferative responses to mitogens may develop in older patients.494 Neutrophil and monocyte chemotaxis are also defective. Assessment of WAS protein (WASp) expression in peripheral blood mononuclear cells by flow cytometry-based assays or immunoblot analysis can be performed in suspected cases prior to mutational analysis. Patients with no detectable WASp in circulating cells tend to have a relatively severe phenotype.

PATHOPHYSIOLOGY

450

Dermatitis usually develops during the first few months of life, and it fulfills diagnostic criteria for atopic dermatitis (Fig. 7.55). The face, scalp, and flexural areas are most severely affected, although patients may have widespread involvement with progressive lichenification. Exfoliative erythroderma sometimes develops. Excoriated areas frequently display petechiae as well as serosanguineous crusts. Secondary bacterial infections are common, as are eczema herpeticum and molluscum contagiosum. Recurrent bacterial infections begin during infancy as levels of placentally transmitted maternal antibodies diminish. These infections include otitis externa and media, pneumonia, sinusitis, conjunctivitis, furunculosis, meningitis, and sepsis. The predominant organisms are encapsulated bacteria such as Strep. pneumoniae and H. influenzae. Patients also have increased susceptibility to infections with P. jiroveci and viruses such as herpes simplex.494 The majority of children with WAS develop at least one autoimmune disease, most commonly cutaneous small vessel vasculitis (frequently associated with painful edema), autoimmune cytopenias, arthritis, inflammatory bowel disease, and cerebral vasculitis.496 IgE-mediated conditions such as food allergies and asthma also occur with increased frequency. Additional features of WAS include hepatosplenomegaly and lymphadenopathy. Non-Hodgkin’s lymphoma develops in one-quarter of WAS patients older than 20 years of age, especially those with a history of autoimmune complications. These are typically diffuse large B-cell lymphomas with extranodal and CNS involvement, similar to AIDS-related lymphomas. The median survival for WAS patients is approximately 15 years. Outside the setting of hematopoietic stem cell transplantation, the most common causes of death are infection (40%), bleeding (25%), and malignancy (25%).497

WAS is caused by loss-of-function mutations in the WASP gene, which is constitutively expressed in all hematopoietic lineages. WASp participates in signal transduction from the cell surface to the actin cytoskeleton, thereby activating actin polymerization and facilitating processes such as immune synapse formation, T-cell activation, cell polarization and migration, and phagocytosis.493–495 Recently, WASp has also been found to have important roles in homeostasis of peripheral B cells and activation of regulatory T cells, with the latter helping to explain the autoimmune manifestations of WAS.498 The small, structurally abnormal platelets of WAS have a reduced half-life (due in part to splenic destruction), and some studies have demonstrated premature proplatelet release from the bone marrow due to defective podosome formation. Loss-of-function WASP mutations can also cause isolated X-linked recessive thrombocytopenia, while gain-of-function WASP mutations can lead to X-linked recessive congenital neutropenia (Table 7.17).493

496. Dupuis-Girod S, Medioni J, Haddad E, et al. Autoimmunity in Wiskott–Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. 2003;111:e622–e627. 497. Sullivan KE, Mullen CA, Blaese RM, et al. A multi-institutional survey of Wiskott–Aldrich syndrome. J Pediatr. 1994;125:876–885.

498. Humblet-Baron S, Sather B, Anover S, et al. Wiskott–Aldrich syndrome protein is required for regulatory T cell homeostasis. J Clin Invest. 2007;117:407–418. 499. Conley ME, Saragoussi D, Notarangelo L, et al. An international study examining therapeutic options used in treatment of Wiskott–Aldrich syndrome. Clin Immunol. 2003;109:272–277.

DIFFERENTIAL DIAGNOSIS Although several other immunodeficiency syndromes feature eczematous dermatitis together with susceptibility to infection (Table 7.7), WAS can usually be differentiated by the bleeding tendency and laboratory evidence of microthrombocytopenia.

TREATMENT Supportive therapy for WAS is directed toward treating the recurrent infections and preventing hemorrhage.494 Appropriate prophylactic use of antibiotics and IVIG (which may also improve the dermatitis) can decrease the risk of serious infections.498,499 Topical corticosteroids remain a mainstay for treatment of the eczematous dermatitis. Although splenectomy can

Genodermatoses

PHOTOSENSITIVITY DISORDERS Adrian-Martin Pierini

INTRODUCTION The sun emits electromagnetic radiation energy comprising mainly the ultraviolet, visible, and infrared spectra. About twothirds of this energy reaches the earth’s surface. Ultraviolet radiation is subdivided into UVA (315–400 nm), UVB (280–315 nm) and UVC (100–280 nm), and UVA has been divided into UVAI (340–400 nm) and UVAII (320–340 nm). The precise amount of solar UV radiation is determined by a number of different factors, among them time of the day, season, latitude, composition of the stratospheric ozone layer, cloudiness, pollution, and altitude. The cutaneous photobiologic reaction has been well established, and its several steps and consequences can be summarized as follows503: (1) UVR energy is absorbed by a specific molecule, or chromophore, in the skin; (2) this energy may cause either direct photochemical or indirect oxidative damage to biomolecules, such as DNA and proteins; (3) repair is started immediately and the consequence is the release of cytokines and inflammatory mediators; (4) these mediators modulate the behavior of skin cells, including keratinocytes, Langerhans cells, vascular endothelial cells, fibroblasts, lymphocytes, and melanocytes; (5) the skin pigmentation response to solar UVR com-

500. Litzman J, Jones A, Hann I, et al. Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott–Aldrich syndrome. Arch Dis Child. 1996;75:436. 501. Winkelstein JA, Fearon E. Carrier detection of the X-linked primary immunodeficiency diseases using X-chromosome inactivation analysis. J Allergy Clin Immunol. 1990;85(6):1090–1097. 502. Giliani S, Fiorini M, Mella P, et al. Prenatal molecular diagnosis of Wiskott-Aldrich syndrome by direct mutation analysis. Prenat Diagn. 1999;19(1):36–40. 503. McGregor JM, Hawk JLM. Acute effects of ultraviolet radiation on the skin. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s

prises an immediate pigment darkening and the delayed formation of new melanin; (6) UV-induced pyrimidine dimers in DNA can give rise to tumors through the activation of the N-ras oncogene; and (7) UV radiation-induced damage to T cells leads to immunosuppression that allows for the development of malignancy in other organs. Photosensitivity is an abnormal reaction of the skin to ultraviolet or visible light radiation that usually follows exposure to natural sunlight or some artificial sources, such as tanning beds, medical phototherapy lamps, and unshielded fluorescent and tungsten-halogen lamps.503 Photosensitivity in children is uncommon and encompasses a wide variety of rare diseases, many of which are the result of genetic defects. We must differentiate the skin disorders induced by sun exposure from those aggravated by sun exposure.504–508 STUDY OF THE PATIENT WITH PHOTOSENSITIVITY DISORDERS

reduce bleeding complications in patients with recurrent severe hemorrhage, it increases the risk of infections with encapsulated organisms.500 Platelet transfusions should be administered prior to surgical procedures and in the setting of life-threatening hemorrhage. Hematopoietic stem cell transplantation is the treatment of choice for patients with WAS. Full engraftment results in normal platelet numbers and function, normalization of immunologic status, and clearance of the dermatitis. Young children (age 85% survival rate, compared to approximately 50% for older patients or those with mismatched donors.493 Clinical trials of gene therapy using retrovirally transduced, WASp reconstituted, autologous CD34+ cells are underway.486,493 Genetic counseling is important for the sisters and other female relatives of WAS patients. Female carriers can be detected by the selective inactivation of the abnormal X chromosome in lymphocytes and platelets.501 DNA-based prenatal diagnosis has been successfully performed.502

7

STUDY OF THE PATIENT WITH PHOTOSENSITIVITY DISORDERS The child with a suspected photosensitivity disorder must be carefully evaluated on his or her clinical features, laboratory findings, and phototesting.504,505

CLINICAL FEATURES History is usually the most important issue in diagnosing the photodermatoses. The characteristics of the eruption must be determined, especially duration, distribution over sun-exposed or non-exposed areas, morphology (papules, bullae), seasonal variation, accompanying symptoms (burn, pruritus, pain, and swelling), age at onset, systemic and local medications, family history, and effectiveness of sunscreens in prophylaxis.

LABORATORY FINDINGS All cases of photodermatoses, unless the diagnosis is otherwise certain as in xeroderma pigmentosum, must be evaluated for serum antinuclear factor, anti-SSA (Ro) and anti-SSB (La) antibody titers, and porphyrin concentrations in blood, urine and feces. Skin histology may be helpful but is rarely diagnostic. Direct immunofluorescence can be useful in lupus erythematosus patients. DNA excision repair measurements in UVirradiated cultured fibroblasts are required to diagnose certain genophotodermatoses.

PHOTOTESTING The study of the reaction of unaffected skin to solar simulators may be helpful in the diagnosis of some photosensitivity

504. 505. 506. 507. 508.

dermatology in general medicine. 5th ed. New York: McGraw-Hill; 1999:1555–1561. Roelands R. The diagnosis of photosensitivity. Arch Dermatol. 2000;136:1152–1157. Ramsay CA. Photosensitivity in children. Pediatr Clin North Am. 1983;30:687–699. Bligard CA, Storer JS. Photosensitivity in infants and children. Dermatol Clin. 1986;4:311–319. Kahn G. Photosensitivity and photodermatitis in childhood. Dermatol Clin. 1986;4:107–116. Horkay I, Emri G, Varga V, et al. Photosensitivity skin disorders in childhood. Photodermatol Photoimmunol Photomed. 2008;24:56–60.

451

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disorders such as actinic prurigo, polymorphous light eruption, hydroa vacciniforme, solar urticaria, and drug-induced photosensitivity. The classification of photosensitivity disorders in children shown in Box 7.4 will allow the dermatologist or pediatrician to consider the most probable diagnoses. This section deals with the genetically determined photosensitivity disorders of infants and children. Other photodermatoses will be treated in separate chapters.

A: Idiopathic photodermatoses

THE PORPHYRIAS

>> Hydroa vacciniforme >> Solar urticaria

THE PORPHYRIAS

The porphyrias are a group of rare metabolic disorders in which excessive quantities of porphyrins, or their precursors, are produced. They are due to inherited or acquired abnormalities in the metabolic pathway of heme biosynthesis. Each type of porphyria results from a specific enzyme defect that leads to the accumulation and excretion of porphyrins (Table 7.21). The important advances achieved in the identification of the genes responsible of porphyria allow for the possibility of novel therapeutics of these diseases. A general summary of the clinical and biochemical features of the porphyrias is presented in Table 7.22, and numerous reviews are available.509–515

HISTORICAL ASPECTS The first descriptions of porphyrins were published by the middle of the 19th century, and the first published case of porphyria is credited to Schultz in 1874.516 The first classification of porphyria was proposed by Günther in 1911.517 With the advance of biochemistry, the different types of porphyria were identified in the last 50 years: acute intermittent porphyria (Waldenstrom518 and Goldberg519); hereditary coproporphyria (Berger and Goldberg);520 variegate porphyria (in South Africa);521 erythropoietic protoporphyria (Magnus et al.);522 erythropoietic coproporphyria (Heilmeyer et al.);523 and hepatoerythropoietic porphyria (Piñol Aguadé et al.).524

THE BIOCHEMISTRY OF PORPHYRINS AND HEME Porphyrins are essential biochemical constituents of living beings, controlling oxidation and transporting and exchanging oxygen from the environment to the tissues of the body. The biosynthetic pathway of porphyrins and heme has been almost completely defined (Table 7.21).511,512 Heme, the end product of the pathway, is a tetrapyrrole protoporphyrin chelated with iron.

509. Poh-Fitzpatrick MB. The porphyrias. Dermatol Clin. 1987;5:55–61. 510. Bonnetblanc JM, Bernard P, Fayol J. Porphyries cutanées. Encycl Méd Chir (Paris) Dermatologie. 1989;12440 12A10, 2–1989. 511. Meola T, Lim HW. The porphyrias. Dermatol Clin. 1993;11:583–596. 512. Paslin D. The porphyrias. Clin Dermatol. 1998;16:185–307. 513. Jensen JD, Resnick SD. Porphyria in childhood. Semin Dermatol. 1995;14:33–39. 514. Elder GH. Hepatic porphyrias in children. J Inherit Metab Dis. 1997;20:237–246. 515. Gross U, Hoffmann GF, Doss MO. Erythropoietic and hepatic porphyrias. J Inherit Metab Dis. 2000;23:641–661. 516. Goldberg A. The porphyrias. Historical background. Clin Dermatol. 1998;16:189–193. 517. Günther H. Die Haematoporphyrie. Dtsch Arch Klin Med. 1911;105:89–146.

452

BOX 7.4 CLASSIFICATION OF PHOTOSENSITIVITY DISORDERS IN CHILDREN

>> Polymorphic light eruption (PLE) – Juvenile spring eruption >> Actinic prurigo – Hereditary PMLE of Native Americans

B: DNA repair-defective disorders

>> Xeroderma pigmentosum >> Cockayne’s syndrome >> Trichothiodystrophy >> Bloom’s syndrome >> Rothmund–Thomson and other poikiloderma congenita syndromes

>> Kindler syndrome >> Ataxia telangiectasia

C: Pigmentary deficiencies

>> Albinism >> Phenylketonuria >> Vitiligo

D: Nutritional and metabolic aberrations

>> Pellagra >> Hartnup disease

E: Photosensitization by exogenous drugs or exogenous or endogenous chemicals

>> Porphyrias >> Acute inflammatory reactions (phototoxicity) to drugs or plants >> Eczematous reactions (photoallergy) to drugs or plants F: Dermatoses exacerbated by UV irradiation

>> Lupus erythematosus >> Dermatomyositis >> Lichen planus actinicus >> Pemphigus >> Psoriasis >> Atopic dermatitis >> Acne

518. Waldenstrom J. Studien uber Porphyrie. Acta Med Scand. 1937:92(Suppl):1–254. 519. Goldberg A. Acute intermittent porphyria: A study of 50 cases. Q J Med (Oxford). 1959;28:183–209. 520. Berger H, Goldberg A. Hereditary coproporphyria. BMJ. 1955;2:85–88. 521. Dean G, Barnes AD. The inheritance of porphyria. BMJ. 1955;2:89–91. 522. Magnus IA, Jarret A, Prankerd TAJ, et al. Erythropoietic protoporphyria. A new porphyria syndrome with solar urticaria due to protoporphyrinaemia. Lancet. 1961;2:448–451. 523. Heilmeyer HP, Clotten R, Kerp I, et al. Porphyria erythropoietica congenita Günther bericht uber Familien mit Erfassung Merkmalsträger. Dstch Med Wochenschr. 1963;88:2449. 524. Piñol Aguadé J, Castells A, Indacochea A, et al. A case of biochemically unclassifiable porphyria. Br J Dermatol. 1969;81:270–275.

Genodermatoses

PORPHYRIA

NORMAL METABOLITES

ENZYMES

Glycine + Succinyl-CoA ↓

ALA synthase

Delta-aminolevulinic acid (ALA) ALA dehydratase deficiency



ALA dehydratase

Porphobilinogen (PBG) Acute intermittent porphyria



PBG deaminase

Hydroxymethylbilane Congenital erythropoietic porphyria



Uroporphyrinogen III cosynthase

Uroporphyrinogen III Porphyria cutanea tarda/ HEP



Uroporphyrinogen decarboxylase

Coproporphyrinogen III Hereditary coproporphyria



Coproporphyrinogen oxidase

Protoporphyrinogen IX Variegate porphyria



Protoporphyrinogen oxidase

Protoporphyrin IX Erythropoietic protoporphyria



MECHANISMS OF PORPHYRIN-INDUCED PHOTOSENSITIVITY Porphyrins are excited by visible light with a wavelength between 400 and 410  nm (Soret band) and emit an intense red fluorescence. When irradiated with light of the appropriate wavelength in the presence of oxygen, porphyrins will cause photodynamic effects. The energy released reacts with oxygen to produce free radicals and singlet oxygen that damages molecules, cells and tissues.509,510 Cell damage results from lysosomal and plasma membrane injury and from complement activation. Beta-carotene exerts its protective activity by quenching both free radicals and singlet oxygen.525 Two different phototoxicity patterns can be observed in porphyria patients: (1) the immediate, characterized by erythema, edema, pain, and purpura; and (2) the delayed, which consists of increased fragility of the skin, blistering, and scarring. Photosensitivity of the skin varies considerably according to the type of porphyria. AIP and ALA-dehydratase deficiency do not present with cutaneous photosensitivity. This variation is likely due to the differing aqueous and lipid solubility of the various porphyrins (e.g., the intermediates of the first steps are water soluble, and protoporphyrin is lipid soluble).

CONGENITAL ERYTHROPOIETIC PORPHYRIA

Table 7.21  The porphyrin-heme biosynthetic pathway

7

CLASSIFICATION There is no completely satisfactory classification of porphyria. The current classification has evolved from Günther’s first proposal in 1911,517 and takes into account the porphyrin pattern in the blood, urine and feces, and the clinical features. The classification in Box 7.5, from Poh-Fitzpatrick,509 considers the tissue source of excess porphyrins.

Ferrochelatase

Heme ↓ Hemoglobin myoglobin cytochromes

Heme is central to the structure of a number of metabolic proteins such as hemoglobin, myoglobin, catalases, peroxidases, and cytochromes P450. The starting point of the pathway is the formation of deltaaminolevulinic acid (ALA) from glycine and succinyl-CoA. ALA synthase act as the primary rate-limiting enzyme in the liver, and is regulated by the hepatocellular free heme pool. In bone marrow, ferrochelatase is the rate-limiting step for heme synthesis. In general, the major porphyrin or porphyrin precursor excreted in a given porphyria is the substrate for the defective enzyme. These intermediates, when present in excess amounts, exert toxic effects on the tissues.509,512

525. Mathews-Roth MM. Treatment of the cutaneous porphyrias. Clin Dermatol. 1998;16:295–298.

CONGENITAL ERYTHROPOIETIC PORPHYRIA INTRODUCTION AND HISTORICAL NOTE Also known as Günther disease, congenital porphyria or congenital hematoporphyria, congenital erythropoietic porphyria (CEP) was first recognized by Günther as ‘an inborn error of metabolism’ but the first case was probably published by Shultz.516

EPIDEMIOLOGY Genetics Congenital erythropoietic porphyria (CEP, MIM 263700) is inherited as an autosomal recessive trait. The condition is due to mutations in the uroporphyrinogen III synthetase (UROS) gene, mapped to 10q25.2–26.3.526 At least 17 mutations have been described in the UROS gene, explaining the heterogeneous

526. Astrin KH, Warner CA, Yoo HW, et al. Regional assignment of the human uroporphyrinogen III synthase (UROS) gene to chromosome 10q25.2–q26.3. Hum Genet. 1991;87:18–22.

453

454

AR

AD

?

Sporadic AD Type II-III

AD Homozygous PCT

AD

AD

AD

CEP

EPP

ECP

PCT

HEP

VP

HCP

AIP

11q23.3

3q12

PBG D

Coprogen O

Protogen O

Urogen D

1p34

1q22 and 6p21.3

Urogen D

?

Ferroc

Urogen III S

ENZYME DEFECT

1p34

18q22

10q25.2

GENE LOCATION

SCARRING

+++ Mutilating

+ + ++ Milia

++

++

+



PHOTOSENSITIVITY +++

++ ++ ++

+++

+++

+





+

+

+

+++



±

+

HYPERTRICHOSIS

+

+

+

+

++



+ to +++



LIVER

++

+

+











NEUROLOGIC







Proto



Copro Proto

Proto

Uro Copro Proto

RBC







Uro

Uro Copro

-

Proto

Uro Copro

PLASMA

ALA, PBG Uro Copro

ALA, PBG Copro

ALA, PBG Copro Proto Acute

Uro 7-carboxy

Uro Copro 7-carboxy





Uro Copro

URINE

Jaundice, anemia in newborns (harderoporphyria) No cutaneous signs



Retarded growth

Erythrodontia, anemia, splenomegaly

Associated with diabetes, SLE, hepatitis, hematologic

Only 3 cases published

Cholelithiasis, onycholysis

Erythrodontia, hemolysis, splenomegaly, bone fragility

OTHER

Copro

Proto Copro X-porph

Copro Isocopro

Uro Isocopro Proto Copro



Proto Copro

Uro Copro

FECES

Abbreviations: RBC, red blood cell; CEP, congenital erythropoietic porphyria; EPP, erythropoietic protoporphyria; ECP, congenital erythropoietic coproporphyria; PCT, porphyria cutanea tarda; HEP, hepatoerythropoietic porphyria; VP, variegate porphyria; HCP, hereditary coproporphyria; AIP, acute intermittent porphyria; AR, autosomal recessive; AD, autosomal dominant; Uro, uroporphyrin; Copro, coproporphyrin; Proto, protoporphyrin; 7-carboxy, 7-carboxylate porphyrin; ALA, delta-aminolevulinic acid; PBG, porphobilinogen; Isocopro, isocoproporphyrin; X-porph, X-porphyrin; Urogen III S, Uroporphyrinogen III synthase; Ferroc, ferrochelatase; Urogen D, uroporphyrinogen decarboxylase; Protogen O, protoporphyrinogen oxidase; Coprogen O, coproporphyrinogen oxidase; PBGD, porphobilinogen deaminase (also named hydroxymethylbilane synthase).

INHERITANCE

DISEASE

CONGENITAL ERYTHROPOIETIC PORPHYRIA

Table 7.22  Clinical and biochemical characterization of porphyrias

ii Neonatal and Inherited Disorders

Genodermatoses

7

BOX 7.5 CLASSIFICATION OF PORPHYRIAS

Classification by the tissue source of excess porphyrins509

Figure 7.56  CEP with mild lesions on the cheek and nose of a 1-year-old boy.

CONGENITAL ERYTHROPOIETIC PORPHYRIA

>> Erythropoietic porphyrias – Congenital erythropoietic porphyria (CEP) – Erythropoietic protoporphyria (EPP) – Congenital erythropoietic coproporphyria (ECP) >> Hepatic porphyrias – Acute intermittent porphyria (AIP) – Variegate porphyria (VP) – Hereditary coproporphyria (HCP) – Porphyria cutanea tarda (PCT) – ALA-dehydratase porphyria (ALADP) >> Hepatic/erythropoietic porphyrias – Hepatoerythropoietic porphyria (HEP) – Harderoporphyria Classification by mode of transmission

>> Autosomal dominant – Porphyria cutanea tarda (PCT) – Hereditary coproporphyria (HCP) – Erythropoietic protoporphyria (EPP) – Variegate porphyria (VP) – Acute intermittent porphyria (AIP) – Hepatoerythropoietic porphyria (HEP) >> Autosomal recessive – ALA-dehydratase porphyria (ALADP) – Congenital erythropoietic porphyria (CEP) phenotypes of CEP.527 Patients with severe CEP were noted to be homozygous for a single mutation (C73R).528,529 The approximately 34 kb UROS gene has been isolated and its organization and tissue-specific expression determined. The gene has two promoters, the housekeeping and the erythroid-specific transcripts. The erythroid-specific transcript is present only in erythroid tissues and contains GATA1 and NF-E2 sites. Mutations in these erythroid promoters cause CEP.530 CEP is a rare porphyria with less than 200 cases in both sexes reported to date. In our hospital, we observed two cases in 20 years, from over 100 000 first-visit consultations.531

PRESENTING HISTORY Onset is in infancy or early childhood and has even been reported to be present at birth with the findings of red staining of the diapers from high quantities of porphyrins (uroporphy-

527. Xu W, Astrin KH, Desnick RJ. Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene. Hum Mutat. 1996;7:187–192. 528. Frank J, Wang X, Lam HM, et al. C73R is a hotspot mutation in the uroporphyrinogen III synthase gene in congenital erythropoietic porphyria. Ann Hum Genet. 1998;62:225–230. 529. Freesemann AG, Gross U, Bensidhoum M, et al. Immunological, enzymatic and biochemical studies of uroporphyrinogen III-synthase deficiency in 20 patients with congenital erythropoietic porphyria. Eur J Biochem. 1998;257:149–153.

Figure 7.57  CEP with bullae, crusts, and milia on the hand of the same patient, at age 2.

rinogen I and coproporphyrinogen I) in the urine.532 The clinical presentation is variable due to the heterogeneous nature of the enzyme defect, being most important in the newborn and infant (Figs 7.56, 7.57). Rarely, the onset of symptoms occurs in later childhood or even in adult life.

PHYSICAL EXAMINATION Skin The cutaneous manifestations of CEP are some of the most dramatic of the porphyrias. There is exquisite photosensitivity with painful vesicles and bullae that are filled with red fluorescent fluid containing free porphyrins. Blisters often become

530. Solis C, Aizencang GI, Astrin KH, et al. Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria. J Clin Invest. 2001;107:753–762. 531. Laffargue JA, Pierini AM, Soliani A, et al. Porfirias en la Infancia. Arch Argent Dermatol. 1999;49:49–71. 532. Poh-Fitzpatrick MB. Clinical features of the porphyrias. Clin Dermatol. 1998;16:251–264.

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CONGENITAL ERYTHROPOIETIC PORPHYRIA

Figure 7.58  CEP with severe scars and loss of distal phalanges of the digits. Figure 7.60  CEP with crusts and milia on the hand of the same patient, at age 2 years.

Figure 7.59  CEP with mild lesions on the cheek and nose at the age of 2 years.

Figure 7.61  CEP with erythrodontia at age 9 months.

secondarily infected and progress to mutilating scarring (Figs 7.58, 7.59). The eyelids, nose, ears, and fingers are particularly affected. Most patients develop severe mutilation of the hands and face (Fig. 7.60). Hyperpigmentation and generalized hypertrichosis are seen with the scarring.

Systemic manifestations

Hair, nail, teeth and mucous membranes A striking pathognomonic feature is erythrodontia (Fig. 7.61), a red to dirty brown staining of the teeth secondary to porphyrin deposition in dentine that is thought to be a result of the affinity of porphyrins for calcium phosphate. The teeth show characteristic red fluorescence as well. There may be cicatricial alopecia, onycholysis, koilonychia, and nail pigmentation.

533. Laorr A, Greenspan A. Severe osteopenia in congenital erythropoietic porphyria. Can Ass Radiol J. 1994;45:307–309.

456

Other problems include photophobia, keratoconjunctivitis, ocular ulceration, corneal scarring, ectropion, and cataracts resulting in blindness. There is often intermittent hemolytic anemia, sometimes severe, with associated splenomegaly. Increased bone fragility, due to expansion of the bone marrow or direct toxicity by porphyrins, can lead to fractures and shortened stature.533 Abdominal and neurologic symptoms are absent. In severely affected patients systemic complications can begin in utero, with hydrops fetalis, anemia and hepato­ splenomegaly. In the newborn with severe CEP, blistering over the entire exposed body surface has been brought on by phototherapy.534

534. Huang JL, Zaider E, Roth P, et al. Congenital erythropoietic porphyria: clinical, biochemical, and enzymatic profile of a severely affected infant. J Am Acad Dermatol. 1996;34:924–927.

Genodermatoses

LABORATORY FINDINGS

Topical therapy

Blood, urine and feces determination of porphyrins allows the biochemical diagnosis of CEP, as shown in Table 7.22. Uroporphyrin I and coproporphyrin I are the main metabolites found to be increased in these patients. Uroporphyrinogen III synthase concentration in erythrocytes can be determined by enzymelinked immunosorbent assay thanks to a specific antibody.529 The antenatal diagnosis of CEP is possible by determining increased levels of uroporphyrin I in amniotic fluid and direct detection of the gene mutation in amniotic cells.535

The patient should be instructed to protect from sunlight (the 400  nm wavelength being the most detrimental), using avoidance, coverings, and topical sunscreens that block visible light.

Molecular, biochemical and immunological basis The underlying defect is the deficiency of the enzyme uroporphyrinogen III synthetase, the activity of which is reduced to 3–40% of normal in red blood cells. URO synthase is responsible for conversion of the linear tetrapyrrole, hydroxymethylbilane, to the cyclic tetrapyrrole, uroporphyrinogen III, one of the steps of the heme biosynthetic pathway. Uroporphyrinogen I and coproporphyrinogen I accumulate in the bone marrow, erythrocytes, plasma, bones, and teeth, and their corresponding porphyrins are excreted in the urine and feces. With appropriate UVA light, there is striking red fluorescence of the urine as well.

Histologic findings

Systemic management Beta-carotene may ameliorate some part of the photodamage. Blood transfusion seems to be effective. Splenectomy has been helpful in a few cases with severe hemolytic anemia. Oral superactivated charcoal has given satisfactory results in some patients with CEP, but not in others.525 Bone marrow transplantation is first-line therapy for patients with CEP.536–538 Other promising therapeutic approaches include cord blood stem cell transplantation539 and gene therapy.540,541 Patients succumb by the third or fourth decades without correction of the defective gene (bone marrow transplantation, cord blood stem cell transplantation, and gene therapy).

ERYTHROPOIETIC PROTOPORPHYRIA INTRODUCTION AND HISTORICAL NOTE Erythropoietic protoporphyria (EPP) was first defined in 1961 by Magnus et al.,522 the clinical symptoms having been defined earlier.

Non-specific changes are observed in CEP. Skin lesions are similar to those observed in other forms of porphyria.

EPIDEMIOLOGY

DIFFERENTIAL DIAGNOSIS

Erythropoietic protoporphyria (EPP, MIM 177000) appears to be transmitted as an autosomal dominant trait with variable penetrance. Unlike other dominantly inherited forms of porphyria, enzyme activity levels in EPP are only moderately reduced. The gene for human ferrochelatase (FECH) has been assigned to chromosome 18q22.31.542,543 More than 60 different mutations have been identified in the FECH gene of EPP patients. The carriage of ‘null allele’ mutations seems to be linked with an increased frequency of liver complications.544,545 The unusual inheritance could be explained by co-inheritance of a ‘low expression’ of the normal FECH allele and a mutant allele.546

Mutilating forms of CEP must be distinguished from other severe deforming diseases, as epidermolysis bullosa, and from HEP, by porphyrin determinations. HEP has similar skin manifestations as CEP, but it lacks the erythrodontia, hemolytic anemia and splenomegaly that characterize CEP.

THERAPEUTICS AND PROGNOSIS Therapy is aimed at the cutaneous photosensitivity or at the anemia and its complications.

535. Ged C, Moreau-Gaudry F, Taine L, et al. Prenatal diagnosis in congenital erythropoietic porphyria by metabolic measurement and DNA mutation analysis. Prenat Diagn. 1996;16:83–86. 536. Dupuis-Girod S, Akkari V, Ged C, et al. Successful match-unrelated donor bone marrow transplantation for congenital erythropoietic porphyria (Günther disease). Eur J Pediatr. 2005;164:104–107. 537. Lagarde C, Hamel-Teillac D, De Prost Y, et al. Allogreffe de moelle osseuse dans la porphyrie érythropoiétique congénitale. Maladie de Günther. Ann Dermatol Venereol. 1998;125:114–117. 538. Harada FA, Shwayder TA, Desnick RJ, et al. Treatment of severe congenital erythropoietic porphyria by bone marrow transplantation. J Am Acad Dermatol. 2001;45:279–282. 539. Zix-Kieffer I, Langer B, Eyer D, et al. Successful cord blood stem cell transplantation for congenital erythropoietic porphyria (Gunther’s disease). Bone Marrow Transplant. 1996;18:217–220. 540. Kauppinen R, Glass IA, Aizencang G, et al. Congenital erythropoietic porphyria: prolonged high-level expression and correction of the heme biosynthetic defect by retroviral-mediated gene transfer into porphyric and erythroid cells. Mol Genet Metab. 1998;65:10–17.

ERYTHROPOIETIC PROTOPORPHYRIA

PATHOPHYSIOLOGY AND HISTOGENESIS

7

Genetics

541. de Verneuil H, Robert-Richard E, Ged C, et al. Succès de la thérapie génique d’un modèle murin de porphyrie érythropoïétique congénitale. Med Sci (Paris). 2008;24:615–620. 542. Whitcombe DM, Carter NP, Albertson DG, et al. Assignment of the human ferrochelatase gene (FECH) and a locus for protoporphyria to chromosome 18q22. Genomics. 1991;11:1152–1154. 543. Brenner DA, Didier JM, Frasier F, et al. A molecular defect in human protoporphyria. Am J Hum Genet. 1992;50:1203–1210. 544. Schneider-Yin X, Gouya L, Meier-Weinand A, et al. New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care. Eur J Pediatr. 2000;159:719–725. 545. Norris PG, Nunn AV, Hawk JL, et al. Genetic heterogeneity in erythropoietic protoporphyria: a study of the enzymatic defect in nine affected families. J Invest Dermatol. 1990;95:260–263. 546. Cobbold C, Roberts A, Badminton M. Erythropoietic protoporphyria: a functional analysis of the leader sequence of human ferrochelatase. Mol Genet Metab. 2006;89:227–232.

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Neonatal and Inherited Disorders

ERYTHROPOIETIC PROTOPORPHYRIA

Figure 7.62  EPP in a 5-year-old girl with acute sunburn reaction, and

Figure 7.63  EPP: classic pebbled skin image over the hand of a 7-year-old boy.

superimposed bacterial infection.

Statistics Although this was one of the later porphyrias to be described, it represents one of the most common in childhood and puberty.547,548 Our Dermatology Service followed six cases of EPP between 1987 and 1996, which represents 0.16/1000 of the total first-visit patients.531,548

PRESENTING HISTORY Onset is in infancy and early childhood with all races and both sexes equally involved. There is a wide spectrum of expression of EPP. The presenting history is usually one of photosensitivity. An infant may cry uncomfortably when exposed to even a few minutes of sunlight. Older children complain of burning, stinging, and itching, and then develop erythema with swelling, urticaria-like plaques, and occasional purpura. Rarely, some patients have vesicles or bullae (Fig. 7.62). The frequency of signs and symptoms in a comprehensive study of 32 patients included burning (97%), itching (88%), edema (94%), erythema (69%), scarring (19%), pain (16%), and papulovesicles and petechiae (3%).549

PHYSICAL EXAMINATION Skin Chronically exposed skin shows thickening with a distinctive waxy, pebbly, superficial, scarred appearance (Figs 7.63, 7.64), which has been described as ‘prematurely aged’ or ‘weatherbeaten.’ The bridge of the nose and the knuckles of the hand are most affected. The fine, elliptical, superficial scars of EPP are scattered over the nose, cheeks, chin, or forehead (Fig. 7.65). They are quite different from the mutilating scarring seen in CEP.

547. Horkay I, Emri G, Varga V, et al. Photosensitivity skin disorders in childhood. Photodermatol Photoimmunol Photomed. 2008;24:56–60. 548. Baart de la Faille H. Erythropoietic protoporphyria: a photodermatosis. Microscopical and electron microscopical investigations of irradiated skin and a clinical study. Utrecht: Oosthoek, Scheltema & Holkemal; 1975.

458

Figure 7.64  EPP with mild scars over the nose and cheeks in a 17-year-old boy.

Linear furrowing around the lips is common (Fig. 7.66). Interestingly, some patients do not express cutaneous lesions but complain of pain, burning and severe itching after sun exposure, long before the appearance of typical scars.550

Hair, nail, teeth and mucous membranes In severe exposure, nails may be lost (photo-onycholysis). There is no red staining of the urine or the teeth.

Systemic manifestations Excess protoporphyrins are insoluble in bile, with accumulation leading to cholestasis with increased protoporphyrin deposition in bile canaliculi and hepatocytes, protoporphyrin-containing gallstones, impaired enterohepatic circulation, decreased protoporphyrin excretion and progressive liver dysfunction. In some cases, there is associated liver disease, including acute fatal

549. DeLeo VA, Poh-Fitzpatrick MB, Mathews-Roth M, et al. Erythropoietic protoporphyria. Ten years’ experience. Am J Med. 1976;60:8–22. 550. Lecluse AL, Kuck-Koot VC, van Weelden H, et al. Erythropoietic protoporphyria without skin symptoms – you do not always see what they feel. Eur J Pediatr. 2008;167:703–706.

7

ERYTHROPOIETIC PROTOPORPHYRIA

Genodermatoses

Figure 7.65  EPP with mild scars over the nose in the same patient as Fig. 7.52 at the age of 21 years.

Figure 7.66  EPP with crusts, scars, and linear furrowing of the lips in a 551–553

hepatic failure or severe chronic cirrhosis. Approximately one-third of patients develop microcytic anemic due to impaired erythropoiesis.554,555 Rarely, ophthalmologic complications can be observed.556

LABORATORY FINDINGS Free (not zinc-bound) protoporphyrin is present in massive levels in red blood cells, plasma, and feces. Thus the best test is the free erythrocyte protoporphyrin (FEP) level. However, the more readily available zinc-protoporphyrin assay is usually abnormal as well and, although not reflecting the specific abnormal porphyrin, can be useful if it is elevated. Red blood cells show coral red fluorescence in 5–20% of cells. Liver function tests can be abnormal even in patients without severe hepatic disease. Fluorescence of the hepatic tissue can be positive as the expression of porphyrin deposition. Onset of liver decompensation is acute, rapidly progressive, and an indication for liver transplant. Prior to decompensation, patients may show signs of jaundice, elevated bilirubin, enlarged liver and abdominal pain. There is no reliable method of detecting the patients at risk for liver failure. Autosomal recessive forms may have a higher risk of liver failure than the dominant forms.550–552 Significant levels of vitamin D deficiency and insufficiency have been found in a large cohort of patients with EPP in the UK.557

551. Bloomer JR, Wang Y, Singhal A, et al. Biochemical abnormality in erythropoietic protoporphyria: cause and consequences. J Pediatr Gastroenterol Nutr. 2006;43(Suppl 1):S36–S40. 552. Anstey AV, Hift RJ. Liver disease in erythropoietic protoporphyria: insights and implications for management. Postgrad Med J. 2007;83:739–748. 553. Whatley SD, Mason NG, Khan M, et al. Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease. J Med Genet. 2004;41:e105. 554. Herrero C, To-Figueras J, Badenas C, et al. Clinical, biochemical, and genetic study of 11 patients with erythropoietic protoporphyria including one with homozygous disease. Arch Dermatol. 2007;143:1125–1129.

12-year-old boy.

PATHOPHYSIOLOGY AND HISTOGENESIS Molecular, biochemical and immunological basis The biochemical basis for EPP is a deficiency (10–30% of normal) of ferrochelatase (also known as heme synthetase or heme synthase). This enzyme converts protoporphyrin IX to heme, and is the final enzyme in the heme synthesis pathway. The defect occurs in all erythropoietic tissues. EPP is the only porphyria with absent urinary porphyrins since protoporphyrin is not water soluble. It does have high affinity for the liver and bile. Protoporphyrin IX is activated at 400 nm wavelength of light (Soret band region of 400–410 nm), and generates reactive oxygen species that give rise to photodynamic cell injury. The primary event takes place in the endothelial cells of the skin capillaries, but complement activation and mast cell-derived mediators follow the process.558,559

Histologic findings Histologic examination of the skin shows perivascular and upper dermal accumulations of periodic acid–Schiff positive,

555. Holme SA, Worwood M, Anstey AV, et al. Erythropoiesis and iron metabolism in dominant erythropoietic protoporphyria. Blood. 2007;110:4108–4110. 556. Tsuboi H, Yonemoto K, Katsuoka K. Erythropoietic protoporphyria with eye complications. J Dermatol. 2007;34:790–794. 557. Holme SA, Anstey AV, Badminton MN, et al. Serum 25-hydroxyvitamin D in erythropoietic protoporphyria. Br J Dermatol. 2008;159:211–213. 558. Lim HW. Pathogenesis of photosensitivity in the cutaneous porphyrias. J Invest Dermatol. 2005;124:xvi–xvii. 559. Thunell S, Harper P, Brun A. Porphyrins, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythropoietic protoporphyria – diagnosis, care and monitoring of the patient. Scand J Clin Lab Invest. 2000;60:581–604.

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diastase-resistant amorphous material. Immunofluorescence reveals deposits of IgG. There is also cutaneous deposition of complement, neutral glycoproteins, acid glycosaminoglycans, and lipids. Recent studies show photoactivation of complement in this disorder. In cases with hepatic involvement, huge quantities of protoporphyrin are found in bile and hepatic parenchyma.

DIFFERENTIAL DIAGNOSIS

PORPHYRIA CUTANEA TARDA

EPP can be distinguished from CEP by the less severe photosensitivity, characteristic linear scarring, and absence of mutilation. Urticaria-like eruptions instead of vesicles are the predominant sign. The hematological picture of red cell protoporphyria can also be seen in iron deficiency anemia and lead intoxication, but in these disorders there are normal fecal porphyrin levels. Other sun-sensitive disorders such as polymorphous light eruption, actinic prurigo, and lupus erythematosus should be considered as well.

THERAPEUTICS AND PROGNOSIS Currently there is no cure for EPP and treatment consists of recognition, prevention, symptomatic management and patient education.

Topical therapy Avoidance of sunlight, protective clothing, and sunscreens appropriate for 400 nm wavelength of light are adjunctive measures. Common sunscreens protect from sunburn (290–320 nm) but not from 400 to 410 nm light. In fact, many patients are condemned to a life in darkness.

Systemic management Although only partially successful, beta-carotene, a quencher of reactive oxygen species, (doses of 120–300 mg/day in adults and 25–150 mg/day in children) has been shown to be useful in many cases. Therapy must be given for at least 1–3 months, and blood levels of 600–800 ng/mL must be achieved. The only sideeffect appears to be carotenoderma.560 H1 receptor antagonists may reduce the photosensitivity in some patients.561 Cysteine (500 mg twice a day) has also been proposed because of its photoprotective effect.562 Cholestyramine may be of use (4 g/

560. Mathews-Roth MM. Carotenoids in erythropoietic protoporphyria and other photosensitivity diseases. Ann N Y Acad Sci. 1993;691:127–138. 561. Farr PM, Diffey BL, Mathews JNS. Inhibition of photosensitivity in erythropoietic protoporphyria with terfenadine. Br J Dermatol. 1990;122:809–815. 562. Mathews-Roth MM, Rosner B, Benfell K, et al. A double-blind study of cysteine photoprotection in erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. 1994;10:244–248. 563. Batlle AM, Stella AM, Melito V, et al. S-adenosil-l-metionina, un posible agente terapéutico anticolestático en las porfirias, con particular referencia a la protoporfiria eritropoyética. Resultados preliminares. Arch Argent Dermatol. 1989;39:3–21. 564. Baart de la Faille H, van Hattum J, Rademakers LHPM, et al. Long term effects of chenodeoxycholic acid therapy in erythrohepatic protoporphyria. In: Orfanos CE, Stadler R, Golnik H, eds. Dermatology in five continents. Proceedings of the 17th World Congress of Dermatology. Berlin: Springer Verlag; 1987:455.

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day), as well as S-adenosyl-l-methionine, to prevent the hepatic disease.563 Chenodeoxycholic acid (15 mg/kg per day) has been reported to be useful in some cases.564 Oral calcium and vitamin D supplements may also be indicated in these patients.557 Red blood cell transfusions and intravenous hematin to reduce heme synthesis have been proposed. Plasmapheresis, hemodialysis and extracorporeal exchange transfusions have been used to reduce circulating plasma protoporphyrin levels, mainly in acute hepatic failure cases.552,565 Topical delivery of the defective ferrochelatase enzyme has been used successfully in animals to correct the manifestations of photosensitivity and could open an exciting future in the therapy of these disorders.558,566

PROGNOSIS This is a lifelong disorder and the rare occurrence of acute hepatic disease is the most serious potential threat to life. Liver transplantation has been used in such cases.567,568

CONGENITAL ERYTHROPOIETIC COPROPORPHYRIA Congenital erythropoietic coproporphyria (ECP) is the rarest of all porphyrias, with only three cases published. The clinical picture resembles EPP with photosensitivity presenting in childhood.523,569,570 All three cases presented elevated red blood cells, coproporphyrins, and protoporphyrins. Neither the enzymatic defect nor the responsible gene has been identified.

PORPHYRIA CUTANEA TARDA INTRODUCTION AND HISTORICAL NOTE Porphyria cutanea tarda (PCT) constitutes a heterogeneous group of porphyrias that includes acquired or inherited forms. Type I is a common sporadic disorder that occurs mainly in adults and often is precipitated by ethanol, estrogens, or chemical toxins. Nevertheless, a classic outbreak that occurred in Turkey in 1956, due to contamination of wheat with hexachlorobenzene, affected predominantly children. Type II and Type III PCT (or familial porphyria) are autosomal dominant disorders that have been reported in a few children.

565. McGuire BM, Bloomer JR. Use of extracorporeal albumin dialysis for erythropoietic protoporphyria. Liver Transplant. 2007;13:639–640. 566. Pawliuk R, Tighe R, Wise RJ, et al. Prevention of murine erythropoietic protoporphyria-associated skin photosensitivity and liver disease by dermal and hepatic ferrochelatase. J Invest Dermatol. 2005;124:256–262. 567. Rand EB, Bunin N, Cochran W, et al. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics. 2006;118:e1896–e1899. 568. Zhang F, Lu L, Qian X, et al. Liver transplantation for erythropoietic protoporphyria with hepatic failure: a case report. Transplant Proc. 2008;40:1774–1776. 569. Topi GC, D’Alessandro Gandolfo L, Fazio M, et al. Coproporfiria eritropoyética congénita en 2 hermanos. Med Cutan Ibero Lat Am. 1976;4:229–238. 570. Topi GC, D’Alessandro Gandolfo L, Fazio M, et al. Coproporphyrie érythropoïétique congénitale observée chez un frère et une soeur. Forme nouvelle de coproporphyrie érythropoïétique héréditaire. Ann Dermatol Venereol. 1977;104:68–70.

Genodermatoses

7

EPIDEMIOLOGY The enzyme defect in PCT is cytosolic uroporphyrinogen decarboxylase (also called urogen-decarboxylase, URO-D); its corresponding gene has been identified at chromosome 1p34.571 The enzyme defect has been found in sporadic and familial cases at the same level. Sporadic cases (PCT type I, MIM 176090) are probably heterozygotes for the gene defect, and manifest under special circumstances of hepatocyte damage by agents as alcohol, hepatitis C virus, iron overload, and estrogens.572 Familial cases (PCT type II, MIM 176100) have the deficiency of uroporphyrinogen decarboxylase activity, not only manifesting in their liver, but also in their erythrocytes and other tissues. In these cases it is conceivable that the transmission follows an autosomal dominant pattern. Several mutations have been described.573–576 Rare families exist in which PCT identical to the clinical and biochemical presentation of type I occurs, and they constitute type III. It is suggested that type III PCT could be the result of the involvement of other loci.572 Homozygous cases are known as hepatoerythropoietic porphyria (HEP). An association between PCT and hereditary hemochromatosis has been described, and it is currently accepted that the hemochromatosis gene (HFE) plays a role in the determination of PCT.577–579

PORPHYRIA CUTANEA TARDA

Genetics

Figure 7.67  PCT: scars, hypertrichosis, and hyperpigmentation on the face.

Statistics PCT is the most common porphyria observed in adults and children. In our department, it accounts for more than 50% of all porphyria cases.531 Familial forms of PCT present at any age including the first few years of life, and represent the majority of cases in infancy, but only 20% of cases in adults.

PRESENTING HISTORY PCT presents with photosensitivity of the delayed type.532 Familial forms of PCT appear from early childhood, and sporadic forms usually in middle age. There is a trigger factor in almost all cases of PCT in children, particularly drugs, infections, and malignancies.580

Figure 7.68  PCT: old scars and hyperpigmentation over the hand.

PHYSICAL EXAMINATION Skin Bullae and vesicles, crusts, ulcerations that healed slowly, and atrophic scars with milia, appear on sun-exposed sites such as 571. Dubart A, Mattei MG, Raich N, et al. Assignment of human uroporphyrinogen decarboxylase (URO-D) to the p34 band of chromosome 1. Hum Genet. 1986;73:277–279. 572. Elder GH. Genetic defects in the porphyrias: types and significance. Clin Dermatol. 1998;16:225–233. 573. Jensen JD, Resnick SD. Porphyria in childhood. Semin Dermatol. 1995;14:33–39. 574. Mendez M, Sorkin L, Rossetti MV, et al. Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles. Am J Hum Genet. 1998;63:1363–1375. 575. Santos M, Clevers HC, Marx JJM. Mutations of the hereditary hemochromatosis candidate gene HLA-H in porphyria cutanea tarda. N Engl J Med. 1997;336:1327–1328. 576. Bulaj ZJ, Phillips JD, Ajioka RS, et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood. 2000;95:1565–1571.

the dorsa of the hands, the forearms and the face (Figs 7.67, 7.68). In distinction from other porphyrias of childhood, skin fragility and milia are prominent signs. Pigmentary changes are common, with hyperpigmentation or a mottled pattern of 577. de Villiers JNP, Hillermann R, Loubser L, et al. Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. Hum Mol Genet. 1999;8:1517–1522. 578. Brady JJ, Jackson HA, Roberts AG, et al. Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda. J Invest Dermatol. 2000;115:868–874. 579. Remenyik E, Lecha M, Badenas C, et al. Childhood-onset mild cutaneous porphyria with compound heterozygotic mutations in the uroporphyrinogen decarboxylase gene. Clin Exp Dermatol. 2008;33:602–605. 580. Stella A, Melito V, Parera V, et al. Acerca de 2 nuevos casos de porfiria cutanea tardia infantil en una niña con leucemia y en un niño hemodializado en tratamiento con SAMe. Aspectos bioquímicos. Rev Argent Dermatol. 1988;69:118–124.

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PORPHYRIA CUTANEA TARDA

Figure 7.70  PCT and leukemia: tense hemorrhagic bullae over the hand of the same patient.

Figure 7.69  PCT and leukemia: striking hypertrichosis and melanosis in an 8-year-old girl.

uro- and coproporphyrins. The examination of urine by Wood’s light shows a coral pink fluorescence.

PATHOPHYSIOLOGY AND HISTOGENESIS hypo- and hyperpigmentation over the exposed areas. Sclerodermoid changes and dystrophic calcification are unusual signs in childhood.

Hair, nail, teeth and mucous membranes There may be striking malar hypertrichosis (Fig. 7.69) and erythrodontia with fluorescence of teeth on Wood’s lamp exposure. Scarring alopecia and photo-onycholysis can be observed in adolescents.

Systemic manifestations The photodamage to the conjunctiva leads to higher incidence of pinguecula and pterygium than in controls.581 There may be hepatomegaly and abnormal liver function tests. PCT has been found in association with diabetes mellitus, systemic lupus erythematosus, type B and type C hepatitis,582 hematologic disorders (Fig. 7.70)580 and acquired immune deficiency syndrome (AIDS).583

LABORATORY FINDINGS In PCT there are elevated levels of plasma and urinary uroporphyrins, coproporphyrins, and 7-carboxylate porphyrins. Feces have high levels of iso-coproporphyrinogen, sometimes with

581. Hammer H, Korom I. Photodamage of the conjunctiva in patients with porphyria cutanea tarda. Br J Ophthalmol. 1992;76:592–593. 582. Sampietro M, Fracanzani AL, Corbetta N, et al. High prevalence of hepatitis C virus type 1b in Italian patients with porphyria cutanea tarda. Ital J Gastroenterol Hepatol. 1997;29:543–547. 583. Mansourati FF, Stone VE, Mayer KH. Porphyria cutanea tarda and HIV/ AIDS: a review of pathogenesis, clinical manifestations and management. Int J STD AIDS. 1999;10:51–56.

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Molecular, biochemical and immunological basis Urogen decarboxylase activity is deficient in PCT, accounting for about 50% of that of normal controls. In sporadic type I PCT there is a decreased enzyme activity in the liver. In familial type II PCT the enzyme activity is decreased both in the liver and the erythrocytes; in the other familial type III PCT, erythrocyte enzyme activity is normal. Uroporphyrin has no direct effect on mast cells, thus explaining the different skin manifestations of PCT with respect to EPP.558 Iron overload seems to play an important role in the pathophysiology of PCT, through more than one mechanism.532,584,585

Histologic findings Histologically, all types of PCT show a similar picture of subepidermal bullae with periodic acid–Schiff-positive material in the vessel walls and, less frequently, at the dermoepidermal junction. Immunofluorescence shows these fibrillar deposits to contain IgG and complement. A distinctive elongated structure (‘caterpillar bodies’) has been identified in the roof of the bullae.586

DIFFERENTIAL DIAGNOSIS PCT must be differentiated from epidermolysis bullosa in children, because both entities can present with vesicles, skin

584. Siersema PD, Rademakers LH, Cleton MI, et al. The difference in liver pathology between sporadic and familial forms of porphyria cutanea tarda: the role of iron. J Hepatol. 1995;23:259–267. 585. Méndez M, Rossetti MV, Batlle AM, et al. The role of inherited and acquired factors in the development of porphyria cutanea tarda in the Argentinean population. J Am Acad Dermatol. 2005;52:417–424. 586. Egbert BM, LeBoit PE, McCalmont T, et al. Caterpillar bodies: distinctive, basement membrane-containing structures in blisters of porphyria. Am J Dermatopathol. 1993;15:199–202.

Genodermatoses

fragility and milia. However, epidermolysis bullosa has no photosensitivity or hypertrichosis, and no changes in urine color. Pseudoporphyrias secondary to drug intake or hemodialysis are identified by a careful history. In all cases, porphyrin determination in urine and feces establishes the diagnosis.

7

Genetics VP is an autosomal dominant disease caused by mutation in the gene for protoporphyrinogen oxidase (PPOX) that maps to chromosome 1q22.594 The association with mutations in the gene for hemochromatosis (HFE), mapped to chromosome 6p21.3, has been found in patients with severe forms of variegate porphyria.577

THERAPEUTICS AND PROGNOSIS Restriction of sun exposure is an essential step in topical prevention.

Systemic management Therapeutic measures include diet avoidance of hepatotoxic substances and drugs, phlebotomy (150–200 mL weekly) to remove iron stores and excess porphyrins,587 low-dose hydroxychloroquine (3 mg/kg twice a week),588,589 S-adenosyl-l-methionine (200 mg/day for 3 weeks),580 plasmapheresis, and iron chelating agents (deferoxamine).

Statistics We mentioned above the rarity of VP in children, with just one case observed in our series.593,595–597 VP is common in South Africa, where an estimated 10 000 to 20 000 descendents from a couple from the Netherlands are affected.598 Asymptomatic carriers of the gene defect are usually detected by screening of porphyrins.

VARIEGATE PORPHYRIA

Topical therapy

PRESENTING HISTORY The first clinical features of VP may include either cutaneous photosensitivity indistinguishable from that of PCT, systemic manifestations that mimic those of AIP, or both. Acute attacks are triggered by exacerbating drug intake and other unknown factors.

PROGNOSIS In contrast to CEP and EPP, there may be spontaneous remission with age. However, a high incidence (5–16%) of hepatocellular carcinoma has been reported in cases of PCT with a long symptomatic period before start of therapy and associated chronic active hepatitis.590,591

VARIEGATE PORPHYRIA INTRODUCTION AND HISTORICAL NOTE Variegate porphyria (VP, MIM 176200), also called South African porphyria and mixed porphyria, is a rare autosomal dominant disease.592

PHYSICAL EXAMINATION Skin Clinically, VP resembles PCT with excessive skin fragility, sun sensitivity, vesicles, bullae, crusts, and scarring, particularly over face and hands (Figs 7.71, 7.72). Hyperpigmentation is observed in some cases.

Hair, nail, teeth and mucous membranes Hypertrichosis is uncommon in children with VP, and onycholysis is associated with chronic skin changes of the hands.

Systemic manifestations

Only few cases have been described in children. VP is frequent among the Afrikaner population of South Africa, and in Finland.593

The acute attack is characterized by neurological symptoms and abdominal pain, similar to those reported in acute intermittent porphyria. The attacks are often induced by drug intake, and present with constipation, abdominal pain, tachycardia and hypertension, muscular paralysis, and sensory disturbances.

587. Poh-Fitzpatrick MB, Honig PJ, Kim HC, et al. Childhood-onset familial porphyria cutanea tarda: effects of therapeutic phlebotomy. J Am Acad Dermatol. 1992;27:896–900. 588. Bruce AJ, Ahmed I. Childhood-onset porphyria cutanea tarda: successful therapy with low-dose hydroxychloroquine (Plaquenil). J Am Acad Dermatol. 1998;38:810–814. 589. Cassiman D, Vannoote J, Roelandts R, et al. Porphyria cutanea tarda and liver disease. A retrospective analysis of 17 cases from a single centre and review of the literature. Acta Gastroenterol Belg. 2008;71:237–242. 590. Siersema PD, ten Kate FJ, Mulder PG, et al. Hepatocellular carcinoma in porphyria cutanea tarda: frequency and factors related to its occurrence. Liver. 1992;12:56–61. 591. Lim HW, Mascaro JM. The porphyrias and hepatocellular carcinoma. Dermatol Clin. 1995;13:135–142. 592. Dean G. The porphyrias. A story of inheritance and environment. 2nd ed. Philadelphia: JB Lippincott; 1972.

593. Mustajoki P, Tenhunen R, Niemi KM, et al. Homozygous variegate porphyria: a severe skin disease of infancy. Clin Genet. 1987;32:300–305. 594. Taketani S, Inazawa J, Abe T, et al. The human protoporphyrinogen oxidase gene (PPOX): organization and location to chromosome 1. Genomics. 1995;29:698–703. 595. Rossetti MV, Granata BX, Giudice J, et al. Genetic and biochemical studies in Argentinean patients with variegate porphyria. BMC Med Genet. 2008;9:54. 596. Parera V, Alfonso S, Navone N, et al. Porfiria variegata en una niña de 4 años. Rev Argent Dermatol. 1984;65:68–76. 597. Poblete-Gutiérrez P, Wolff C, Farias R, et al. A Chilean boy with severe photosensitivity and finger shortening: the first case of homozygous variegate porphyria in South America. Br J Dermatol. 2006;154:368–371. 598. Corrigall AV, Hift RJ, Davids LM, et al. Homozygous variegate porphyria in South Africa: genotypic analysis in two cases. Mol Genet Metab. 2000;69:323–330.

EPIDEMIOLOGY

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DIFFERENTIAL DIAGNOSIS Differentiation of VP from PCT is difficult in cases without overt neurologic symptoms, but is essential for the adequate therapeutic approach. Some therapies useful in PCT, such as antimalarials and phlebotomy, are not helpful in VP.509

THERAPEUTICS AND PROGNOSIS Topical therapy and systemic management

HEREDITARY COPROPORPHYRIA/HARDEROPORPHYRIA

Figure 7.71  Variegate porphyria with scars over the cheek of a 14-year-old girl.

Therapy is meant to suppress the acute symptoms by the intravenous infusion of glucose and heme analog.600 Prevention is important, both for the visceral and cutaneous manifestations. Avoidance of precipitating drugs and the sun is imperative, and sunscreens are used. Phlebotomy is ineffective, even though the skin lesions resemble those of PCT. Relatives of patients should be screened to detect the asymptomatic carriers.

Prognosis No cases of spontaneous remission have been reported. Acute attacks must lead to neurological deterioration. Hepatocellular carcinoma is a rare event that has been described in VP.591

HEREDITARY COPROPORPHYRIA/ HARDEROPORPHYRIA Figure 7.72  Variegate porphyria with scars over the hand of the same patient.

Retarded growth has been reported. Seizures, epilepsy, and mental retardation can occur, mainly in homozygous patients. Premature adrenarche has been described in a young girl.599

LABORATORY FINDINGS The enzyme defect in VP is the deficiency of protoporphyrinogen oxidase (PPOX). It leads to the excretion of high amounts of ALA, PBG, coproporphyrinogen and protoporphyrinogen in urine during attacks. Protoporphyrin, and to a lesser extent coproporphyrin as well as X-porphyrins are elevated in feces between attacks and allow the biochemical identification of this porphyria. The plasma has a pathognomonic fluorescence emission pattern at 626 nm.

599. Coakley J, Blake D, Hawkins R, et al. An unusual case of variegate porphyria with possible homozygous inheritance. Aust N Z J Med. 1990;20:587–589. 600. Kalman DR, Bonkovsky HL. Management of acute attacks in the porphyrias. Clin Dermatol. 1998;16:299–306. 601. Cacheux V, Martasek P, Fougerousse F, et al. Localization of the human coproporphyrinogen oxidase gene to chromosome band 3q12. Hum Genet. 1994;94:557–559.

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Hereditary coproporphyria (HCP, MIM 121300), first described by Berger and Goldberg in 1955,520 presents with acute attacks of abdominal pain that resembles AIP but may have photosensitivity (20–30% of cases). It is transmitted by an autosomal dominant gene, located on chromosome 3q12.601,602 It is due to a partial deficiency of coproporphyrinogen oxidase, a mitochondrial enzyme that catalyzes the conversion of coproporphyrinogen III to protoporphyrinogen III. As a result of the enzyme deficiency, high quantities of coproporphyrin III are excreted in urine and predominantly in feces. About half of cases are asymptomatic. It has been described mainly in adults, with hypertrichosis and increased skin pigmentation. The few cases in children have presented as hydroa vacciniforme with vesicles, bullae, burning, and scarring.603 Acute peripheral neuropathy, a common feature of acute intermittent porphyria, has been described.604 Only rare homozygous cases have been reported in the neonatal period with jaundice, hepatosplenomegaly, hemolytic anemia, and photosensitivity. This form, where the activity of coproporphyrinogen oxidase is below 10% of normal levels, is known as

602. Lamoril J, Deybach JC, Puy H, et al. Three novel mutations in the coproporphyrinogen oxidase gene. Hum Mutat. 1997;9:78–80. 603. Jeanmougin M, Pedreiro J, Manciet JR, et al. Eruption à type d’hydroa vacciniforme, révélatrice d’une coproporphyrie héréditaire. Ann Dermatol Venereol. 1988;115:1236–1238. 604. Barohn RJ, Sanchez JA, Anderson KE. Acute peripheral neuropathy due to hereditary coproporphyria. Muscle Nerve. 1994;17:793–799.

Genodermatoses

HEPATOERYTHROPOIETIC PORPHYRIA Hepatoerythropoietic porphyria (HEP, MIM 176100.0002), an extremely rare disorder, has been described with onset in the first year of life.524 Clinically, it mimics CEP, with red teeth, anemia, and hepatosplenic abnormalities. Later on, patients can present with hypertrichosis, skin photosensitivity, and scleroderma-like changes of their hands.609 In HEP there is massively elevated erythrocyte protoporphyrin that is not seen in the childhood onset familial form of PCT. Urinary uroporphyrins and 7-carboxylate porphyrins, and fecal isocoproporphyrins and coproporphyrins are increased. This pathway may be related to the extraordinarily elevated levels of abnormal porphyrins found in HEP that suggest overproduction in both the liver and the bone marrow. The enzyme defect, as in PCT, is hepatic uroporphyrinogen decarboxylase. It is believed that HEP is the homozygous or compound heterozygous form of familial autosomal dominant PCT.610–613 A specific mutation of the gene at chromosome 1p34 has been found in HEP.614 Sun avoidance is essential. Phlebotomy is an ineffective treatment, since plasma iron concentration is normal.

OTHER PORPHYRIAS Acute intermittent porphyria (AIP, MIM 176000) and ALA-dehydratase porphyria (ALADP, MIM 125270) have no cutaneous manifestations since the porphyrin precursors that accumulate are not photosensitizers. They do not usually occur before puberty.532 Diverse atypical forms of porphyria may be observed. The association of two varieties of porphyria in the same patient or family is called dual porphyria.615

605. Nordmann Y, Grandchamp B, de Verneuil H, et al. Harderoporphyria: a variant hereditary coproporphyria. J Clin Invest. 1983;72:1139–1149. 606. Lamoril J, Martasek P, Deybach JC, et al. A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria. Hum Mol Genet. 1995;4:275–278. 607. Lamoril J, Puy H, Gouya L, et al. Neonatal hemolytic anemia due to inherited harderoporphyria: clinical characteristics and molecular basis. Blood. 1998;91:1453–1457. 608. Lamoril J, Puy H, Whatley SD, et al. Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype– phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria. Am J Hum Genet. 2001;68:1130–1138. 609. Fujimoto A, Brazil JL. Hepatoerythropoietic porphyria in a woman with short stature and deformed hands. Am J Med Genet. 1992;44:496–499. 610. de Verneuil H, Grandchamp B, Romeo PH, et al. Molecular analysis of uroporphyrinogen decarboxylase deficiency in a family with two cases of hepatoerythropoietic porphyria. J Clin Invest. 1986;77:431–435. 611. Castaño Suárez E, Zamarro Sanz O, Guerra Tapia A, et al. Hepatoerythropoietic porphyria: relationship with familial porphyria cutanea tarda. Dermatology. 1996;193:332–335. 612. de Verneuil H, Bourgeois F, de Rooij F, et al. Characterization of a new mutation (R292G) and a deletion at the human uroporphyrinogen decarboxylase locus in two patients with hepatoerythropoietic porphyria. Hum Genet. 1992;89:548–552.

Under the name of ‘pseudoporphyria’ are included an array of cutaneous lesions that resemble those of PCT without demonstrable abnormalities of porphyrin metabolism. A PCT-like condition has been described in patients undergoing chronic hemodialysis for renal failure.580,616,617 The mechanism is unclear, but iron overload could play an important role.

DRUG-INDUCED PORPHYRIA It is clear that drugs can cause porphyria in the absence of any identifiable genetic predisposition, producing a clinical and biochemical disorder similar to that of other human porphyria (e.g., hexachlorobenzene and PCT in Turkey). Drugs that have been incriminated in the precipitation of acute attacks of porphyria include anticonvulsants, barbiturates, sex steroid hormones, and griseofulvin (Box 7.6).

XERODERMA PIGMENTOSUM

harderoporphyria.605–608 Marked elevation of coproporphyrins or harderoporphyrins in feces is the main finding.605 The severity of the phenotype does not correlate with the degree of inactivation of the enzyme, which ranges from 1% to 64%.608

7

PHOTOSENSITIVITY DISORDERS OTHER THAN PORPHYRIAS XERODERMA PIGMENTOSUM INTRODUCTION AND HISTORICAL NOTE The term xeroderma pigmentosum was first applied in 1870 by Kaposi618 to describe a patient with pigmentation accompanying skin atrophy. The first American cases were described in 1878.619 De Sanctis–Cacchione syndrome, with neurologic deterioration, was first presented in 1883 by Albert Neisser of Germany.620 Xeroderma pigmentosum (XP) is now known to be a genetically heterogeneous group of degenerative disorders in which sun sensitivity, oculocutaneous pigmentation, and neoplasia are manifestations of abnormal DNA repair. In some cases, progressive neurologic impairment occurs as well.621 Intensive research has been performed on XP patients, primarily because it is a model for sun-induced cancer as well as neurodegenerative disease. Determination of the defective DNA nucleotide excision

613. Moran-Jimenez MJ, Ged C, Romana M, et al. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J Hum Genet. 1996;58:712–721. 614. de Verneuil H, Hansen J, Picat C, et al. Prevalence of the 281 (gly-to-glu) mutation in hepatoerythropoietic porphyria and porphyria cutanea tarda. Hum Genet. 1988;78:101–102. 615. Parera VE, Stella AM, Batlle AM. Porfiria dual: coexistencia de porfiria cutanea tardia y porfiria aguda intermitente en los mismos miembros de una familia. Rev Argent Dermatol. 1988;69:196–198. 616. Harvey E, Bell CH, Paller AS, et al. Pseudoporphyria cutanea tarda: two case reports on children receiving peritoneal dialysis and erythropoietin therapy. J Pediatr. 1992;121:749–752. 617. Green JJ, Manders SM. Pseudoporphyria. J Am Acad Dermatol. 2001;44:100–108. 618. Hebra F, Kaposi M. On diseases of the skin, including exanthemata. London: The New Sydenham Society; 1874;3:252–258. 619. Lambert WC, Kuo HR, Lambert MW. Xeroderma pigmentosum. Dermatol Clin. 1995;13:169–209. 620. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum: cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol. 1987;123:241–250. 621. Moss C, Savin J. Dermatology and the new genetics. Oxford: Blackwell; 1985:113–115.

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BOX 7.6 DRUGS THAT CAN INDUCE ACUTE ATTACK OF PORPHYRIA

XERODERMA PIGMENTOSUM

>> Alcohol >> Amitriptyline >> Amphetamines >> Apronalide >> Barbiturates >> Busulfan >> Carbamazepine >> Chlorambucil >> Chloramphenicol >> Chlordiazepoxide >> Chloroquine >> Chlorpromazine >> Chlorpropamide >> Colistin >> Danazol >> Dapsone >> Diethyl propionate >> Diazepam >> Diclofenac >> Ergot preparations >> Erythromycin >> Estrogens >> Flufenamic acid >> Griseofulvin >> Halothane repair mechanisms in ultraviolet-irradiated skin fibroblasts from XP patients allows the distinction of seven complementation groups (A–G) of the disease.622 A variant type of xeroderma pigmentosum (XP-V), where unscheduled DNA synthesis is normal but post-replication DNA repair is defective, has been described.623

EPIDEMIOLOGY Genetics XP is usually inherited as an autosomal recessive trait. Parental consanguinity is common. Autosomal dominant inheritance has been found in few mild cases of XP-B, mainly associated with Cockayne syndrome. Similar phenotypes may have different gene defects (Table 7.23).622

Statistics The frequency in Europe and the USA (1 to 2 per 1 000 000 births) is much lower than in Japan (1 per 622. Sugasawa K. Xeroderma pigmentosum genes: functions inside and outside DNA repair. Carcinogenesis. 2008;29:455–465. 623. Lehmann AR, Kirk-Bell S, Arlett CF, et al. Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irradiation. Proc Nal Acad Sci USA. 1975;72:219–223.

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>> Hydantoins >> Hydrochlorothiazide >> Imipramine >> Isoniazid >> Mefenamic acid >> Meprobamate >> Methyldopa >> Metoclopramide >> Metronidazole >> Nalidixic acid >> Pyrazolone >> Phenylbutazone >> Phenytoin >> Probenecid >> Progestogens >> Pyrazinamide >> Pyrazolone derivatives >> Rifampicin >> Sulfonamides >> Sulfonylureas >> Tetracycline >> Theophylline >> Valproic acid >> Xylocaine

40 000).624,625 All races, including whites, Asians, blacks, and native Americans could be affected. There is no sex preference for XP.620

PRESENTING HISTORY The following general clinical features are shared to varying degrees by most of patients in different complementation groups. Affected infants present with photophobia and chronic conjunctivitis during the first few months of life. Half of patients with XP have severe sunburn reactions on minimal UV exposure. All patients have some degree of UV reaction on sunexposed areas of skin. Resolving erythema is then replaced with irregular freckling and mottled hyperpigmentation and hypopigmentation, telangiectasias, dryness, atrophy and scarring that justify the name ‘xeroderma pigmentosum.’ The appearance of the skin in children under 2 years of age is similar to that occurring in adults after many years of intense sun exposure, but without dermal elastosis. The tendency to acute sun sensitivity subsides with age.620 624. Takebe H, Nishigori C, Saoth Y. Genetics and skin cancer of xeroderma pigmentosum in Japan. Jpn J Cancer Res. 1987;78:1135–1143. 625. Kleijer WJ, Laugel V, Berneburg M, et al. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair (Amst). 2008;7:744–750.

Genodermatoses

7

GENE

PROTEIN PRODUCT

FUNCTION

XPE/DDB2

UV-DDB (DDB1-DDB2)

GGR

XPC

XPC-RAD23-centrin 2

GGR

XPB/ERCC3

TFIIH complex

GGR and TCR

XPD/ERCC2

XPB-XPD-p62-p52-p44-p34p8-cdk7-cyclin H-MAT1

Transcription

XPG/ERCC5

XPG

GGR and TCR

XPA

XPA

GGR and TCR

XPF/ERCC4

ERCC1-XPF

GGR and TCR

XPV/POLH

Pol η

TLS

UV-DDB, UV-damaged DNA binding protein; GGR, global genomic repair; RAD23, human orthologs of Saccharomyces cerevisiae RAD23p; ERCC3, excision-repair cross complementing group 3; TFIIH complex, transcription factor IIH; TCR, transcription-coupled repair; POLH, polymerase η; TLS, translesion DNA synthesis.

XERODERMA PIGMENTOSUM

Table 7.23  Xeroderma pigmentosum genes

Figure 7.74  Xeroderma pigmentosum. Freckling and a squamous cell carcinoma in a 2-year-old girl (Courtesy Dr A. Lucky).

Figure 7.73  Xeroderma pigmentosum: freckling on the neck of a 2-year-old boy.

Figure 7.75  Xeroderma pigmentosum: multiple carcinomas on the face of a 9-year-old boy.

PHYSICAL EXAMINATION Skin Examination of the skin may reveal erythema along with scaling and hyperpigmented macules (Figs 7.73, 7.74). The facial skin becomes atrophic, with permanent telangiectasias. Blisters, crusts, actinic keratoses, and scars develop at an early age, and with the advent of malignant tumors may cause marked distor-

tion of the nose, eyes, and mouth (Figs 7.75–7.77). The median age of onset of non-melanoma skin cancer is at about 8 years of age. Keratoacanthoma (Fig. 7.78), basal cell carcinoma, squamous cell carcinoma, and malignant melanoma appear, primarily in sun-exposed areas, causing considerable mutilation. Lentigo malignant melanoma of the face is the commonest type of such malignancy, with a median age for development of 17.5 years.626

626. Bernerd F, Asselineau D, Vioux C, et al. Clues to epidermal cancer proneness revealed by reconstruction of DNA repair-deficient xeroderma pigmentosum skin in vitro. Proc Natl Acad Sci USA. 2001;98:7817–7822.

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XERODERMA PIGMENTOSUM

Figure 7.76  Xeroderma pigmentosum: freckling and ulcerated BCC in a 3-year-old boy.

Figure 7.78  Xeroderma pigmentosum: keratoacanthoma in the same patient as in Fig. 7.65.

telangiectasias, leukoplakia and other degenerative changes on the tongue and oral cavity may be caused by ultraviolet radiation.628

Ophthalmologic manifestations

Figure 7.77  Xeroderma pigmentosum: ulcerated basal cell carcinoma in an 18-year-old girl.

Multiple primary cutaneous neoplasms commonly occur.627 It has been estimated that the overall incidence of squamous and basal cell carcinomas is 2500 times greater than that of the general US population, while that of malignant melanoma is 1000 times greater. Less common skin tumors include sarcomas, fibromas, histiocytomas, and angiomas.620,626 Variation in occurrence of malignancies in XP appears to be related to the degree of sun exposure and the genetic heterogeneity.

Hair, nail, teeth and mucous membranes Squamous cell carcinomas of the anterior third of the tongue are common, probably because of sun exposure. XP patients younger than 20 years of age have an estimated 1000 times greater frequency of these tumors than expected for their age. Glossal

627. Fazaa B, Zghal M, Bailly C, et al. Mélanome malin et xeroderma pigmentosum: 12 cas. Ann Dermatol Venereol. 2001;128:503–506. 628. Chidzonga MM, Mahomva L, Makunike-Mutasa R, et al. Xeroderma pigmentosum: a retrospective case series in Zimbabwe. J Oral Maxillofac Surg. 2009;67:22–31.

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The ophthalmic findings are very important in XP, and almost as common as the cutaneous manifestations.620,629 Clinical findings are virtually confined to the anterior portion of the eye, exposed to UV radiation, although choroidal melanomas have been seen. Photophobia is usually present since the first months of life, associated with conjunctival injection. Three-quarters of patients aged 6 months to 3 years demonstrate blepharitis, symblepharon, and crusts on palpebral margins. The lids are often affected with progressive madarosis, scarring, atrophy, entropion or ectropion, trichiasis, lagophthalmos, symblepharon, ankyloblepharon, and even loss of the entire lower lid substance. Basal cell epithelioma, squamous cell carcinoma and melanoma commonly occur on lid margins. Conjunctiva may be involved with hyperemia, xerosis, edema, tenacious mucoid exudates, keratinization, hyperpigmentation, atrophy, pinguecula, pseudopterygia, or malignancy. The corneas are frequently hypervascularized, opacified, and ulcerated or have nodular neoplasms. The irides may be inflamed, atrophic, or abnormally pigmented or may have synechiae.

Systemic manifestations The incidence of internal tumors in XP patients is estimated as 10- to 20-fold increased.630 Reports of brain (medulloblastoma), central nervous system (astrocytoma), lung, gastric, pancreatic, uterine, breast, renal and testicular tumors account for the higher incidence. Many patients die of neoplastic complications before age 20.

629. Kraemer KH, Patronas NJ, Schiffmann R, et al. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotypephenotype relationship. Neuroscience. 2007;145:1388–1396. 630. Mamada A, Miura K, Tsunoda K, et al. Xeroderma pigmentosum variant associated with multiple skin cancers and a lung cancer. Dermatology. 1992;184:177–181.

Genodermatoses

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Table 7.24  Xeroderma pigmentosum complementation groups, genes involved and clinical features MIM

GENE MAP LOCUS

ENZYME ENCODED

FREQUENCY

SKIN DISEASE

SKIN CANCER

NEUROLOGIC SYMPTOMS

XP-A

278700

9q22.3

DDB1

Japan +++ USA, Europe, Middle East, Tunis

+++

+++

+ to +++ subset with no symptoms De Sanctis-Cacchione

XP-B

133510

2q21

ERCC3

Extremely rare USA, Europe (3 cases)

++ to +++

+++

+++

XP-C

278720

3p25

Endonuclease

Commonest worldwide Japan: rare

++ to +++

++ melanoma

rare

XP-D

278730

19q13.2-13.3

ERCC2

Moderate common: 20% of cases

++

+

absent or moderate late onset

XP-E

278740

11p12-p11

DDB2

Rare

+

rare

0 or +

XP-F

278760

16p13.3-p13.13

ERCC4

Moderate rare Japan and Europe

++

few or absent

absent (1 case severe)

XP-G

278780

13q33

Endonuclease

Extremely rare (5 cases)

+++

few or absent

those of CS

XP-V

278750

6p21.1-p12

Polymerase eta

1 3 of all cases

++ to +++

late onset ++

++ few cases

ASSOCIATIONS

Cockayne syndrome TTD (one case)

TTD XP-CS complex

XERODERMA PIGMENTOSUM

GROUP

Cockayne syndrome

ERCC, excision-repair cross-complementing genes; DDB, DNA damage-binding protein; 0, absent; +, mild; ++, moderate; +++, severe; TTD, trichothiodystrophy; CS, Cockayne syndrome; XP-CS complex, xeroderma pigmentosum-Cockayne syndrome.

Neurologic involvement has been observed in 30% of patients with XP, mainly in the XP-A group.629 Mild to severe neurologic abnormalities begin early in infancy or later, up to the second decade (see Xeroderma of De Sanctis and Cacchione, below).631 Deep tendon hyporeflexia, spasticity, seizures, sensorineural deafness, ataxia, and progressive mental retardation have been reported. Skeletal and other developmental abnormalities may occur as well.

LABORATORY FINDINGS Various metabolic and biochemical abnormalities may accompany XP, including renal impairment, aminoaciduria, hypoglycinemia, and adrenal hypofunction. Deficiencies in cellular defenses against oxidative damage, mainly catalase deficiency, have been reported.632 Defective adaptive T-cell-mediated immune responses, deficient NK cell function, depressed induction of interferon gamma activity, and immunodeficiencies have been demonstrated.633 The extent of immune dysfunction may impact the severity of skin neoplasia.

631. De Sanctis C, Cacchione A. L’idiozia xerodermica. Riv Sper Freniatr. 1932;56:269–292. 632. Hoffschir F, Daya-Grosjean L, Petit PX, et al. Low catalase activity in xeroderma pigmentosum fibroblasts and SV40-transformed human cell lines is directly related to decreased intracellular levels of the cofactor, NADPH. Free Radic Biol Med. 1998;24:809–816. 633. Moriwaki S, Kraemer KH. Xeroderma pigmentosum – bridging a gap between clinic and laboratory. Photodermatol Photoimmunol Photomed. 2001;17:47–54.

PATHOPHYSIOLOGY AND HISTOGENESIS Molecular, biochemical and immunological basis At least eight different genetic defects leading to defective DNA nucleotide excision repair are known.622 In each form, there is diminished DNA repair in cells exposed to light in the sunburn range (290–310 nm). These patients have impaired removal of cyclobutane pyrimidine dimer because of deficient enzyme activity; they may be assigned to one of seven XP complementation groups (A, B, C, D, E, F, or G) based on in vitro cell-fusion studies, with DNA repair rates ranging from 0 to 50% of normal. Each complementation group has its own gene defect, as shown in Table 7.24. These genes regulate the appropriate enzymes in the DNA nucleotide excision repair pathway.633–635 Some patients with XP have efficient nucleotide excision repair mechanism but defects in DNA replication after UV irradiation. These patients constitute the so-called variant type of XP (XPV)636,637 and do not fall into any of the complementation groups. Studies on gene function and phenotype show great individual variability. The gene mutations in different XP patients have

634. Hanawalt PC. Controlling the efficiency of excision repair. Mutat Res. 2001;485:3–13. 635. Berneburg M, Lehmann AR. Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription. Adv Genet. 2001;43:71–102. 636. Yuasa M, Masutani C, Eki T, et al. Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene. Oncogene. 2000;19:4721–4728. 637. Inui H, Oh KS, Nadem C, et al. Xeroderma pigmentosum-variant patients from America, Europe, and Asia. J Invest Dermatol. 2008;128:2055–2068.

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been reviewed by Cleaver et al.638 There is a complex relationship between the clinical diseases and the molecular defects in NER.629 These XP genes also possesses additional functions beyond NER or TLS (translesion DNA synthesis), explaining some of the heterogeneity of clinical phenotypes among the different genetic complementation groups.622 Complementation group A is the most common in Japan, and it is also frequently observed in Europe, the USA, and Asia. Complementation group C is the most common worldwide and in particular in Europe and the USA. Complementation groups D and F have intermediate frequency, and the other three (Groups B, E and G) are extremely rare.619,624 The variant form of XP accounts for one-third of XP patients worldwide, and it is especially common in Japan. XERODERMA PIGMENTOSUM

Histologic findings Initially, no specific pathologic findings are present in XP. However, telangiectasias, edema of the papillary dermis with chronic lymphocytic infiltration, epidermal atrophy, and hyperkeratosis may be suggestive in a young person. In the pigmented areas, melanin is markedly increased in granular, malpighian, and basal layers and in the upper dermis. Hyperkeratosis and telangiectasias are pronounced. The atrophic changes resemble chronic radiation dermatitis with epidermal atrophy, absent pigment in areas, collagen degeneration, solar elastosis, and increased vascularity. Malignancies show the same characteristics as seen in patients without XP.619,620

DIFFERENTIAL DIAGNOSIS The early sunburn stage of XP may resemble severe sunburn, drug-induced photosensitivity, erythropoietic protoporphyria, polymorphous light eruption, Cockayne syndrome, Rothmund– Thomson syndrome, Bloom syndrome or Hartnup syndrome. The childhood appearance of basal cell cancers may occur in basal cell nevus syndrome. The pigmentation in XP may mimic radiodermatitis, poikiloderma atrophicans, urticaria pigmentosa, scleroderma, dyskeratosis congenita, arsenic ingestion, or generalized lentigines or ephelides.

638. Cleaver JE, Thompson LH, Richardson AS, et al. A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum Mutat. 1999;14:9–22. 639. Kleijer WJ, van der Sterre ML, Garritsen VH, et al. Prenatal diagnosis of xeroderma pigmentosum and trichothiodystrophy in 76 pregnancies at risk. Prenat Diagn. 2007;27:1133–1137. 640. Halley DJ, Keijzer W, Jaspers NG, et al. Prenatal diagnosis of xeroderma pigmentosum (group C) using assays of unscheduled DNA synthesis and postreplication repair. Clin Genet. 1979;16:137–146. 641. Kore-eda S, Tanaka T, Moriwaki S, et al. A case of xeroderma pigmentosum group A diagnosed with a polymerase chain reaction (PCR) technique. Usefulness of PCR in the detection of point mutation in a patient with a hereditary disease. Arch Dermatol. 1992;128:971–974. 642. Alapetite C, Benoit A, Moustacchi E, et al. The comet assay as a repair test for prenatal diagnosis of xeroderma pigmentosum and trichothiodystrophy. J Invest Dermatol. 1997;108:154–159. 643. Hamouda B, Jamila Z, Najet R, et al. Topical 5-fluorouracil to treat multiple or unresectable facial squamous cell carcinomas in xeroderma pigmentosum. J Am Acad Dermatol. 2001;44:1054. 644. Malhotra AK, Gupta S, Khaitan BK, et al. Multiple basal cell carcinomas in xeroderma pigmentosum treated with imiquimod 5% cream. Pediatr Dermatol. 2008;25:488–491. 645. Zahid S, Brownell I. Repairing DNA damage in xeroderma pigmentosum: T4N5 lotion and gene therapy. J Drugs Dermatol. 2008;7:405–408.

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XP may be diagnosed by studying the DNA repair or postreplication repair abnormalities in skin fibroblasts following UV radiation exposure. Carriers are clinically normal, although some heterozygotes may have a slight degree of defective DNA repair. Similar findings may be seen in lymphocytes and epidermal cells. XP can be diagnosed prenatally by showing a decrease in UV-induced damaged DNA repair in cultured amniotic fluid cells, by DNA analysis of trophoblast cells, polymerase chain reaction (PCR), and alkaline comet assay.639–642

THERAPEUTICS AND PROGNOSIS Topical therapy The treatment of XP should include genetic counseling, and a rigorous program of protection against UV light from infancy with the best sunscreens available, wearing of UV blocking clothing, eyeglasses that block UV radiation, and modification of the patient’s lifestyle to minimize UV exposure. Premalignant skin lesions may be treated with cryosurgery or topical antimitotic agents such as 5-fluorouracil (5-FU), imiquimod and T4N5.643–646 Early removal of neoplasms should be accomplished with excision, chemosurgery, cryosurgery, or intralesional IFN-α. Dental use of UV light-cured resins such as dental restorative materials, occlusal sealants, and orthodontic bracket adhesives should be avoided in XP patients. The external use of a prokaryotic DNA repair enzyme has been reported with some success, related to recovery of catalase activity.647 Different surgical approaches, including resurfacing, dermabrasion, and facial full thickness skin grafts can be useful in some patients with extensive carcinomas.648–651

Systemic management Encouraging results of retrovirus-based genetic correction of XP keratinocytes have been reported and support realistic prospects of gene therapy for the XP patients.652, 653 In selected XP patients, oral isotretinoin (1 mg/kg per day) has been shown to significantly reduce the incidence of skin cancers.654

646. Cafardi JA, Elmets CA. T4 endonuclease V: review and application to dermatology. Expert Opin Biol Ther. 2008;8:829–838. 647. Quilliet X, Chevallier-Lagente O, Zeng L, et al. Retroviral-mediated correction of DNA repair defect in xeroderma pigmentosum cells is associated with recovery of catalase activity. Mutat Res. 1997;385:235–242. 648. Menck CF, Armelini MG, Lima-Bessa KM. On the search for skin gene therapy strategies of xeroderma pigmentosum disease. Curr Gene Ther. 2007;7:163–174. 649. Pyun SH, Shim IS, Ahn GB. Xeroderma pigmentosum treated with advanced phenol-based peeling solution. J Eur Acad Dermatol Venereol. 2008;22:879–880. 650. Agrawal K, Veliath AJ, Mishra S, et al. Xeroderma pigmentosum: resurfacing versus dermabrasion. Br J Plast Surg. 1992;45:311–314. 651. Konig A, Friederich HC, Hoffmann R, et al. Dermabrasion for the treatment of xeroderma pigmentosum. Arch Dermatol. 1992;134:241–242. 652. Magnaldo T, Sarasin A. Xeroderma pigmentosum: from symptoms and genetics to gene-based skin therapy. Cells Tissues Organs. 2004;177:189–198. 653. Menck CF, Armelini MG, Lima-Bessa KM. On the search for skin gene therapy strategies of xeroderma pigmentosum disease. Curr Gene Ther. 2007;7:163–174. 654. DiGiovanna JJ. Retinoid chemoprevention in patients at high risk for skin cancer. Med Pediatr Oncol. 2001;36:564–567.

Genodermatoses

PROGNOSIS Pigmentation and cutaneous neoplasms in XP patients can rarely be prevented, but early protection from UV irradiation should be attempted. Systemic cancer leads to death at 20 years old in the most severely affected patients.

7

the environment for these patients have been unsuccessful in preventing the progressive neurologic sequelae.

COCKAYNE SYNDROME INTRODUCTION AND HISTORICAL NOTE

In 1932, De Sanctis and Cacchione631 described three brothers with XP and microcephaly, delayed motor development, progressive mental deterioration, sensorineural deafness, peripheral neuropathy, dwarfism, and immature sexual development. De Sanctis–Cacchione syndrome is now frequently applied to a subset of patients with xeroderma pigmentosum (20–60% in various series) afflicted with classic cutaneous and ocular manifestations together with a variety of neurologic and developmental abnormalities. According to Lambert et al.619 the term ‘De Sanctis–Cacchione syndrome’ must be reserved for those severely affected patients whose signs and symptoms begin in infancy, and have the full syndrome described by those authors. These may include microcephaly with progressive mental retardation, choreoathetosis, cerebellar ataxia, diminished reflexes, inability to speak, spasticity, sensorineural deafness, epilepsy, shortening of the Achilles tendons with the development of quadriparesis, testicular hypoplasia, and dwarfism. Less severely afflicted patients may not manifest neurologic abnormalities until adolescence. The most extremely affected individuals with De Sanctis– Cacchione syndrome belong to XP complementation group A, the most common form in Japan. A spectrum of neurologic disease may be seen in patients with group D xeroderma pigmentosum. With computed tomography (CT), patients with De Sanctis–Cacchione syndrome demonstrate ventricular dilatation, cerebrocortical atrophy, and a small brain stem. MRI study shows atrophy of the cerebrum and cerebellum with sparing of the white matter.629 Commonly seen EEG patterns are diffuse arrhythmia with a poorly developed rhythm and paroxysmal, burst-like slow-wave discharges. Nerve conduction velocities are normal, while electromyography (EMG) and muscle biopsy reveal neuropathic changes. These findings are consistent with chronic lower motor neuron degeneration with attempted reinnervation by adjacent neurons. The pathologic defect in De Sanctis–Cacchione syndrome is neuronal degeneration predominantly in the cerebral cortex and cerebellum without inflammation or abnormal deposition. Attempts to prevent UV radiation exposure or to otherwise alter

655. Kraemer KH, Patronas NJ, Schiffmann R, et al. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotypephenotype relationship. Neuroscience. 2007;145:1388–1396. 656. Cockayne EA. Inherited abnormalities of the skin and its appendages. London: Oxford University Press; 1933. 657. Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet. 1992;42:68–84. 658. Lehmann AR, Bootsma D, Clarkson SG, et al. Nomenclature of human DNA repair genes. Mutat Res. 1994;315:41–42. 659. Vermeulen W, Jaeken J, Jaspers NGJ, et al. Xeroderma pigmentosum complementation group G associated with Cockayne syndrome. Am J Hum Genet. 1993;53:185–192.

Cockayne syndrome (CS) is a very rare autosomal recessive disorder with defects in DNA nucleotide excision repair (NER), characterized by sensitivity to sunlight, dwarfism, precociously senile appearance, pigmentary retinal degeneration, microcephaly, intracranial calcification, hydrocephalus, deafness, and other somatic abnormalities.655 Cockayne described the syndrome in 1933,656 and Nance and Berry reviewed 140 cases of the literature in 1992.657

COCKAYNE SYNDROME

XERODERMA OF DE SANCTIS AND CACCHIONE

EPIDEMIOLOGY Genetics Cockayne syndrome is inherited as an autosomal recessive trait. Two complementation groups have been identified in Cockayne syndrome.658 CS group A (MIM 216400) gene maps to chromosome 5q12, and has been identified as ERCC8 (excision-repair cross complementing group 8), and CS group B (MIM 133540) gene (ERCC6) maps to 10q11. CS complementation group C (type III) has been described in one patient, but its identity is under discussion. A XP–CS complex has been described659 in some patients with features of both XP and CS. They have been identified with XP complementation groups B, D and G, and the gene (ERCC5) maps to 13q33.

Statistics Cockayne syndrome is a very rare disorder of worldwide distribution. Sexes are equally affected. Complementation group B, or CS type II, is the most common, accounting for 80% of reported cases. XP–CS complex has been described in only 10 patients to present.655

PRESENTING HISTORY Affected infants have a normal appearance at birth, but signs of photosensitivity appear at 6 months or later, concomitantly with failure of growth and developmental deterioration.660,661 Late-onset CS complementation group A manifests in childhood or adolescence, by minor photosensitivity in sun-exposed areas of the skin, and neurologic and growth impairment.662

660. Jaeken J, Klocker H, Schwaiger H, et al. Clinical and biochemical studies in three patients with severe early infantile Cockayne syndrome. Hum Genet. 1989;83:339–346. 661. Patton MA, Giannelli F, Francis AJ, et al. Early onset Cockayne’s syndrome: case reports with neuropathological and fibroblast studies. J Med Genet. 1989;26:154–159. 662. Fryns JP, Bulcke J, Verdu P, et al. Apparent late-onset Cockayne syndrome and interstitial deletion of the long arm of chromosome 10 (del(10) (q11. 23q21. 2)). Am J Med Genet. 1991;40:343–344.

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PHYSICAL EXAMINATION Skin Frequent acute sun-induced, scaly, erythematous eruptions may resolve, leaving hyperpigmentation and scarring. In some patients, the erythema may be limited to the ‘butterfly’ area of the face, while others manifest severe sun burning similar to that observed in xeroderma pigmentosum. An erythematous papular facial eruption may also be seen several hours after sun exposure. Patients who have the XP–CS complex are sensitive to UV light but are not predisposed to develop freckling, precancerous skin lesions as solar keratoses, or skin cancer. Progressive periorbital and subcutaneous fat atrophy causes the characteristic prematurely senile bird-like facies and prominent ‘Mickey Mouse’ ears. Sweating may be absent. COCKAYNE SYNDROME

Hair, nail, teeth and mucous membranes Increased incidence of dental caries has been reported as a good indicator for diagnosis.663

Systemic manifestations CS is a multisystem disorder that can be defined by a triad of UV hypersensitivity, retarded growth, and severe progressive neurologic deterioration. Some patients lack cutaneous manifestations or they appeared very late in their life.664 A typical ‘salt and pepper’ pigmentary retinal degeneration was described by Cockayne.656 Other ophthalmological findings are optic atrophy, cataracts, arteriolar narrowing, pupillary unresponsiveness, strabismus, and nystagmus.665 Retarded growth can be a striking feature, leading to a ‘cachectic dwarfism’ or progeria-like appearance. Microcephaly, prognathism, kyphosis, disproportionately long limbs, large hands and feet, joint contractures, and skeletal muscle atrophy have been reported. Developmental deterioration can be observed as early as the age of 6 months. Mental retardation can be severe, and accompanied by normal-pressure hydrocephalus, sensorineural deafness, progressive upper motor neuron, cerebellar dysfunction, ataxia, intention tremors, incon-

663. Arenas-Sordo M de L, Hernández-Zamora E, Montoya-Pérez LA, et al. Cockayne’s syndrome: a case report. Literature review. Med Oral Patol Oral Cir Bucal. 2006;11:E236–E238. 664. Sonmez FM, Celep F, Ugur SA, et al. Severe form of Cockayne syndrome with varying clinical presentation and no photosensitivity in a family. J Child Neurol. 2006;21:333–337. 665. Traboulsi EI, De Becker I, Maumenee IH. Ocular findings in Cockayne syndrome. Am J Ophthal. 1992;114:579–583. 666. Ozdirim E, Topcu M, Ozon A, et al. Cockayne syndrome: review of 25 cases. Pediatr Neurol. 1996;15:312–316. 667. Sato H, Saito T, Kurosawa K, et al. Renal lesions in Cockayne’s syndrome. Clin Nephrol. 1988;29:206–209. 668. Reiss U, Hofweber K, Herterich R, et al. Nephrotic syndrome, hypertension, and adrenal failure in atypical Cockayne syndrome. Pediatr Nephrol. 1996;10:602–605. 669. Funaki S, Takahashi S, Murakami H, et al. Cockayne syndrome with recurrent acute tubulointerstitial nephritis. Pathol Int. 2006;56:678–682. 670. Park SK, Chang SH, Cho SB, et al. Cockayne syndrome: a case with hyperinsulinemia and growth hormone deficiency. J Korean Med Sci. 1994;9:74–77. 671. Bensman A, Dardenne M, Bach J-F, et al. Decrease of thymic hormone serum level in Cockayne syndrome. Pediat Res. 1982;16:92–94. 672. Adachi M, Kawanami T, Ohshima F, Hosoya T. MR findings of cerebral white matter in Cockayne syndrome. Magn Reson Med Sci. 2006;5:41–45.

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tinence, and hyperreflexive deep tendon reflexes. The neurological manifestations are the consequence of a demyelinating neuropathy.655,666 Accompanying these findings are numerous other defects, including hypertension, nephropathy, adrenal failure, hepatomegaly, hyperinsulinemia and growth hormone deficiency.667–671 Death usually occurs by age 30, but early death has been reported in severe cases.660

LABORATORY FINDINGS Children with CS have an abnormally low or absent thymic hormone level671 reminiscent of premature aging. T-cell function may be normal or diminished. Motor nerve conduction velocities are abnormally slow. Sensorineural deafness and neuropathic electromyogram are frequent.666 Epiphyses close prematurely. By CT and MRI examination characteristic calcifications may be seen in the basal ganglia, lateral ventricles, and frontal lobes; atrophy and dysmyelination of cerebrum and cerebellum, and thickening of the meninges and skull bones are other signs.672 Decreased levels of 5-hydroxyindole acetic acid in cerebrospinal fluid suggest a primary defect of central serotonin metabolism.673 Height and weight are usually below the third percentile for the age. Prenatal diagnosis is possible on the basis of UV light sensitivity of amniotic fluid cells, and by study of RNA synthesis in cultured amniotic cells.674,675

PATHOPHYSIOLOGY AND HISTOGENESIS Molecular, biochemical and immunological basis Skin fibroblasts from CS patients exhibit cellular hypersensitivity to sunlight. In contrast to XP patients, who possess high rates of sunlight-induced cancer, CS patients are not cancer prone. However, CS cells show a deficiency in repair of DNA damage inflicted by light. There is a specific defect in the preferential repair of DNA in active genes, resulting in failure of RNA synthesis to recover, and in pronounced hypersensitivity to sunlight and neurodegeneration, even though the bulk of the DNA is repaired at normal rates.676–679

673. Ellaway CJ, Duggins A, Fung VS, et al. Cockayne syndrome associated with low CSF 5-hydroxyindole acetic acid levels. J Med Genet. 2000;37:553–557. 674. Lehmann AR, Francis AJ, Giannelli F. Prenatal diagnosis of Cockayne’s syndrome. Lancet. 1985;i:486–488. 675. Kleijer WJ, van der Sterre ML, Garritsen VH, et al. Prenatal diagnosis of the Cockayne syndrome: survey of 15 years experience. Prenat Diagn. 2006;26:980–984. 676. Frosina G. Oxidatively damaged DNA repair defect in Cockayne syndrome and its complementation by heterologous repair proteins. Curr Med Chem. 2008;15:940–953. 677. Cleaver JE, Revet I. Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging. Mech Ageing Dev. 2008;129:492–497. 678. Proietti-De-Santis L, Drané P, Egly JM. Cockayne syndrome B protein regulates the transcriptional program after UV irradiation. EMBO J. 2006;25:1915–1923. 679. Laugel V, Dalloz C, Stary A, et al. Deletion of 5’ sequences of the CSB gene provides insight into the pathophysiology of Cockayne syndrome. Eur J Hum Genet. 2008;16:320–327.

Genodermatoses

Histologic findings

TRICHOTHIODYSTROPHY

Neuropathologic examination reveals diffuse, extensive demyelination of the central and peripheral nervous systems, beginning with pericapillary calcification in the cortex and basal ganglia. No inflammation is evident. These findings are consistent with premature aging.

INTRODUCTION AND HISTORICAL NOTE

CS shares several features with XP, including UV photosensitivity, mental retardation and other complex neurologic abnormalities, and cutaneous dyspigmentation. However, CS may be distinguished clinically by the presence of cachectic dwarfism, pigmentary chorioretinitis, and the absence of skin neoplasia. A few patients have manifestations of both XP and CS. The premature aging features of CS may resemble those in progeria, but the latter entity lacks the features of photosensitivity, ocular degeneration, or mental retardation. Telangiectasias and dwarfism may be seen in Rothmund–Thomson syndrome and Bloom syndrome; however, patients with these disorders do not regularly manifest premature aging, deafness, mental retardation, or retinal degeneration. Cerebro-oculofacioskeletal syndrome (COFS, MIM 214150) is caused by a homozygous mutation in the ERCC6 gene, mapped to 10q11, the same gene that causes CS type B. It comprises microcephaly, hypotonia, failure to thrive, arthrogryphosis, eye defects, prominent nose, large ears, overhanging upper lip, micrognathia, widely set nipples, kyphoscoliosis, and osteo­ porosis. Some patients showed photosensitivity and defective DNA repair.680–683

THERAPEUTICS AND PROGNOSIS Topical therapy: Sunscreens and sun-protecting clothing are useful in patients with photosensitivity. Systemic management: No evidence of valuable management measures for systemic manifestations of CS exists at present.

The first cases of trichothiodystrophy (TTD) were reported by Pollitt et al. in 1968.685 They described a family with mental and physical retardation and ‘trichorrhexis nodosa.’ Later on, the term trichothio-dystrophy was coined by Vera Price and colleagues.686 Currently, TTD refers to a heterogeneous group of autosomal recessive disorders that is characterized by brittle hair with abnormally low sulfur content, impaired mental and physical development, ichthyosis, and peculiar facies.687 At least eight different syndromes have been recognized, and a subset of patients presents with photosensitivity. Crovato et al. suggested the acronym PIBIDS (MIM 278730)688 to designate this group, also known as TTD-A. It is characterized by photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature. This section refers to the photosensitivity form of TTD with DNA nucleotide excision repair defect, which represents about half of the cases reported. The TTD syndromes (MIM 601675) have been the subject of extensive reviews.687,689

EPIDEMIOLOGY Genetics TTD is inherited as an autosomal recessive trait. In patients with TTD-A, and those associated with xeroderma pigmentosum group D (TTD/XP-D) and B (TTD/XP-B), deletion of two closely linked loci at chromosome 19q13.2–q13.3 has been proposed.690

Statistics The PIBIDS form of TTD is a rare syndrome, with worldwide incidence. Patients have been reported from Italy, Asia, Latin America, and the USA.

PRESENTING HISTORY

Mental retardation and premature aging are the main findings in CS patients, leading to premature death. However, reports of less severe or incomplete cases with isolated cutaneous photosensitivity suggest that the spectrum of CS is larger than previously considered, and prognosis is variable.684

Collodion baby and other forms of congenital ichthyosis can be observed in newborns.687 Congenital alopecia is a characteristic presenting sign. Some 40–50% of patients with TTD present with severe photosensitivity. The clinical spectrum of associated signs is extremely extensive, including cutaneous, neurologic, ocular, skeletal, cardiovascular, pulmonary, urologic, hematologic, and immunologic features.689

680. Del Bigio MR, Greenberg CR, Rorke LB, et al. Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome. J Neuropath Exp Neurol. 1997;56:1147–1157. 681. Graham JM Jr, Anyane-Yeboa K, Raams A, et al. Cerebro-oculo-facioskeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. Am J Hum Genet. 2001;69:291–300. 682. Jaspers NG, Raams A, Silengo MC, et al. First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. Am J Hum Genet. 2007;80:457–466. 683. Laugel V, Dalloz C, Tobias ES, et al. Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation. J Med Genet. 2008;45:564–571. 684. Miyauchi-Hashimoto H, Akaeda T, Maihara T, et al. Cockayne syndrome without typical clinical manifestations including neurologic abnormalities. J Am Acad Dermatol. 1998;39:565–570.

685. Pollitt RJ, Jenner FA, Davies M. Sibs with mental and physical retardation and trichorrhexis nodosa with abnormal amino acid composition of the hair. Arch Dis Child. 1968;43:211–216. 686. Price VH, Odom RB, Ward WH, et al. Trichothiodystrophy: sulfurdeficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Dermatol. 1980;116:1375–1384. 687. Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol. 2001;44:891–920. 688. Crovato F, Borrone C, Rebora A. Trichothiodystrophy – BIDS, IBIDS and PIBIDS? Br J Dermatol. 1983;108:247. 689. Faghri S, Tamura D, Kraemer KH, et al. Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations. J Med Genet. 2008;45:609–621. 690. Weeda G, Eveno E, Donker I, et al. A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. Am J Hum Genet. 1997;60:320–329.

PROGNOSIS

TRICHOTHIODYSTROPHY

DIFFERENTIAL DIAGNOSIS

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TRICHOTHIODYSTROPHY

Figure 7.80  Slight ichthyosiform changes and reddening of the palms Figure 7.79  Trichothiodystrophy. Photophobia, facial erythema and sparse eyebrows in a 2-year-old girl (Courtesy Dr A. Torrelo).

PHYSICAL EXAMINATION

Systemic manifestations

Skin

Bilateral congenital cataracts, strabismus and myopia,692 short stature, impaired mental development,693,694 recurrent infections, and premature death have been reported.

Non-bullous ichthyosiform erythroderma or mild, ichthyosis vulgaris-like desquamation is observed at birth or during the first months of life.687 Sunburn is a common consequence of the extreme photosensitivity that characterizes PIBIDS. This photosensitivity decreases with age, and lacks freckling, telangiectasias, solar keratoses, and other signs of chronic skin actinic damage (Fig. 7.79). Sun sensitivity in these patients usually does not lead to increased skin cancer incidence.691 Due to lack of sub­ cutaneous fat, the facies has an aged, progeria-like appearance.

Hair, nail, teeth and mucous membranes Diffuse alopecia is a common feature in TTD (Fig. 7.80). The hair is dry and sparse, and the hair shaft breaks easily with trauma.687 Intermittent hair loss, with a cyclic periodicity, has been reported.685 The biochemical defect also affects eyelashes, eyebrows, body and axillary hair, and otic and nasal hair.689 Onychodystrophy accompanies the hair abnormalities: brittle nails, koilonychia, splitting, ridging, onychogryphosis, and yellow discoloration can be present. Dental caries and enamel hypoplasia are observed.

691. Charles CA, Connelly EA, Aber CG, et al. A rare presentation of squamous cell carcinoma in a patient with PIBIDS-type trichothiodystrophy. Pediatr Dermatol. 2008;25:264–267. 692. Vandenberghe K, Casteels I, Vandenbussche E, et al. Bilateral cataract and high myopia in a child with trichothiodystrophy: a case report. Bull Soc Belge Ophtalmol. 2001;282:15–18. 693. Yoon HK, Sargent MA, Prendiville JS, et al. Cerebellar and cerebral atrophy in trichothiodystrophy. Pediatr Radiol. 2005;35:1019–1023. 694. Compe E, Malerba M, Soler L, et al. Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH. Nat Neurosci. 2007;10:1414–1422.

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(Reproduced from Torrelo A, Mediero IG, Baeza J, Zambrano A. Tricotiodistrofia. Presentación de un caso. Actas Dermosifiliogr. 1993;84:183–188).

LABORATORY FINDINGS Prenatal diagnosis is based on DNA repair in trophoblasts or amniotic cells.695 Eyebrow hair study at the end of the first trimester of pregnancy has proven its diagnostic value to detect TTD in utero.696

PATHOPHYSIOLOGY AND HISTOGENESIS Molecular, biochemical and immunological basis Cells from PIBIDS patients show low levels of unscheduled DNA synthesis following exposure to UV radiation. Some of these cells have similar abnormalities to cells from patients with XP complementation groups D697 and B,690 whereas other do not, for at least one independent complementation group referred as TTDA.687,698 Alterations in genes involved in nucleotide excision repair (NER) are associated with three genetic disorders, xeroderma pigmentosum (XP), Cockayne syndrome (CS) and tri-

695. Kleijer WJ, van der Sterre ML, Garritsen VH, et al. Prenatal diagnosis of xeroderma pigmentosum and trichothiodystrophy in 76 pregnancies at risk. Prenat Diagn. 2007;27:1133–1137. 696. Quintero RA, Morales WJ, Gilbert-Barness E, et al. In utero diagnosis of trichothiodystrophy by endoscopically-guided fetal eyebrow biopsy. Fetal Diagn Ther. 2000;15:152–155. 697. Rebora A, Crovato F. PIBI(D)S syndrome – trichothiodystrophy with xeroderma pigmentosum (group D) mutation. J Am Acad Dermatol. 1987;16:940–947. 698. Schärer OD. Hot topics in DNA repair: the molecular basis for different disease states caused by mutations in TFIIH and XPG. DNA Repair (Amst). 2008;7:339–344.

Genodermatoses

Histologic findings Light microscopy reveals transverse fractures of the hair shafts, and irregular cuticle and diameter. Polarizing microscopy shows the typical ‘tiger tail’ pattern,699–701 although this may not be present before 3 months of life. Skin biopsy reveals orthokeratotic hyperkeratosis, thin granular layer, moderate acanthosis and papillomatosis, similar to the image of ichthyosis vulgaris.

DIFFERENTIAL DIAGNOSIS TTD syndromes share a common feature expressed by brittle hair and nails. Extreme photosensitivity is present only in PIBIDS, thus allowing its differentiation from Tay syndrome. XP has striking sun-induced changes and multiple skin cancer of early appearance. CS, another rare DNA nucleotide excision repair deficiency entity, has characteristic neurologic and somatic manifestations.

spontaneous mutation rate in cultured cells may account for the high frequency of internal cancer.

EPIDEMIOLOGY Genetics Inheritance is autosomal recessive (MIM 210900), and the gene locus (BLM) has been identified in chromosome 15q26.1 as a helicase of the RecQ family.706,707

Statistics This rare, life-limiting disease is most commonly seen among Ashkenazi Jews: this represents one-third of reported cases, with males more frequently affected than females.704

PRESENTING HISTORY Beginning in the first few weeks of life, erythema and telangiectasia appear on the butterfly area of the nose and cheeks, resembling lupus erythematosus. Intrauterine growth retardation, with fairly normal proportions, is present in all patients.704 Some patients lack the skin photosensitivity, and have short stature and an enormous predisposition to cancer.

PHYSICAL EXAMINATION

THERAPEUTICS AND PROGNOSIS

Skin

Topical therapy: Sun protection and moisturizers are the main requirements for the skin manifestations of PIBIDS.

BLOOM SYNDROME

Sun exposure accentuates the lupus-like erythema and telangiectasia of the face (Fig. 7.81), the ears, and the dorsal forearms and hands, and bulla, bleeding, and crusting may appear, even on the lips and eyelids.703 The eruption worsens in summer sunlight due to UVB exposure. The intensity of the photosensitivity lesions varies from minimal telangiectasia to severe erythema, but spares the trunk, buttocks, and lower limbs. Besides erythema, patients with Bloom syndrome have numerous café-au-lait spots and areas of hypopigmentation. These lesions locate specially on the trunk. Less frequently axillary acanthosis nigricans is present.

INTRODUCTION AND HISTORICAL NOTE

Hair, nail, teeth and mucous membranes

Bloom reported in 1954 a ‘congenital telangiectatic erythema resembling lupus erythematosus in dwarfs,’702 thus signaling the importance of the dermatologist in the diagnosis of this rare autosomal recessive syndrome. The constellation of photosensitivity, facial telangiectasia, dwarfism, immunodeficiency, and a high incidence of malignancy characterizes Bloom syndrome (BS).703–705 The increased

White hair may be present, but no specific lesions affect the skin appendages.

PROGNOSIS Prognosis is a function of the extent and severity of the neurological, immunological, and ectodermal defects of the disease. Early death by severe infection can occur.

699. Brusasco A, Restano L. The typical ‘tiger tail’ pattern of the hair shaft in trichothiodystrophy may not be evident at birth. Arch Dermatol. 1997;133:249. 700. Liang C, Kraemer KH, Morris A, et al. Characterization of tiger-tail banding and hair shaft abnormalities in trichothiodystrophy. J Am Acad Dermatol. 2005;52:224–232. 701. Liang C, Morris A, Schlücker S, et al. Structural and molecular hair abnormalities in trichothiodystrophy. J Invest Dermatol. 2006;126:2210–2216. 702. Bloom D. Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs. Am J Dis Child. 1954;88:754–758. 703. Kraemer KH. Heritable diseases with increased sensitivity to cellular injury. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick’s

BLOOM SYNDROME

chothiodystrophy (TTD). The transcription and repair factor TFIIH is a central component of NER and mutations of its sub­ units are associated with all three diseases. Accordingly, a more generalized destabilization of TFIIH gives rise to TTD.698 The lack of increased prevalence of skin cancer may be associated with normal catalase levels and NK cell activity.687

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SYSTEMIC MANIFESTATIONS Retardation of growth begins in utero and continues in the face of normal sexual development.708 Patients surviving to

704. 705. 706. 707. 708.

dermatology in general medicine. 5th ed. New York: McGraw-Hill; 1999:1848–1862. German J. Bloom’s syndrome. Dermatol Clin. 1995;13:7–18. German J. Bloom syndrome: a Mendelian prototype of somatic mutational disease. Medicine. 1993;72:393–406. German J, Roe AM, Leppert MF, et al. Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26. 1. Proc Natl Acad Sci USA. 1994;91:6669–6673. Mohaghegh P, Hickson ID. DNA helicase deficiencies associated with cancer predisposition and premature aging disorders. Hum Mol Genet. 2001;10:741–746. Keller C, Keller KR, Shew SB, et al. Growth deficiency and malnutrition in Bloom syndrome. J Pediatr. 1999;134:472–479.

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Bloom syndrome patients develop malignancies, however, their tumors appear exquisitely sensitive to chemotherapy and radiotherapy.704 Recurrent respiratory and gastrointestinal infections seen in patients with Bloom syndrome reflect the myriad of immunologic abnormalities that may occur.712 Chronic lung disease is the second cause of death, after cancer. Men with Bloom syndrome are sterile; women have reduced fertility and a shortened reproductive span.

LABORATORY FINDINGS

BLOOM SYNDROME

Figure 7.81  Bloom syndrome. Facial telangiectasia in a 12-year-old boy.

adulthood are proportionately dwarfed; although mental retardation occasionally occurs, normal intelligence is the rule. The basis for the growth restriction in BS remains to be elucidated.709 The facies in Bloom syndrome is characterized by a narrow, small cranium with malar hypoplasia, nasal prominence, small mandible, and protuberant ears. The voice is high-pitched and of a coarse timbre. Vomiting and diarrhea are frequent in infancy, often leading to dehydration. Intestinal malabsorption has been observed in some patients, but other authors found normal function.709 Glucose metabolism is altered in BS: Impaired glucose tolerance has been diagnosed in 40% of cases, insulin resistance in 50%, and diabetes mellitus in 12% of cases of BS.704,709 The most common ocular finding in Bloom syndrome is the presence of retinal drusen at an early age, similar to that seen in diabetic retinopathy and leukemic retinopathy.710 Persons with Bloom syndrome have a 150- to 300-fold increased frequency of development of a malignancy, which occurs in 20%. Tissues with high mitotic indices – bone marrow, lymphoid tissues, and gastrointestinal mucosa – are most frequently transformed by neoplasia.704 Skin, breast, oral cavity, uterine, lung, and hepatic and renal cancers are also seen, usually at exceptionally early ages.711 Various types of leukemia develop at a mean age of 16 years. Patients who survive beyond this age develop solid tumors at an average age of 30 years. Striking features of the proneness to neoplasia in Bloom syndrome are the great frequency of benign and malignant tumors, the wide variety of tissues affected, the early age of appearance, and the high frequency of multiple tumors in the same patient.704 When

709. Diaz A, Vogiatzi MG, Sanz MM, et al. Evaluation of short stature, carbohydrate metabolism and other endocrinopathies in Bloom’s syndrome. Horm Res. 2006;66:111–117. 710. Bhisitkul RB, Rizen M. Bloom syndrome: multiple retinopathies in a chromosome breakage disorder. Br J Ophthalmol. 2004;88:354–357. 711. Jain D, Hui P, McNamara J, et al. Bloom syndrome in sibs: first reports of hepatocellular carcinoma and Wilms tumor with documented anaplasia and nephrogenic rests. Pediatr Dev Pathol. 2001;4:585–589. 712. Gennery AR, Cant AJ, Jeggo PA. Immunodeficiency associated with DNA repair defects. Clin Exp Immunol. 2000;121:1–7. 713. Kondo N, Motoyoshi F, Mori S, et al. Long-term study of the immunodeficiency of Bloom’s syndrome. Acta Paediatr. 1992;81:86–90. 714. Weemaes CM, Bakkeren JA, Haraldsson A, et al. Immunological studies in Bloom’s syndrome. A follow-up report. Ann Genet. 1991;34:201–205.

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A maturational defect in lymphocytes early in their development may account for the deficiencies of immunoglobulin (IgG, IgM, and/or IgA), together with malfunctioning helper-T cells and delayed hypersensitivity reactions.712–714 Primary hypogonadism affecting the tubular element of the testis leads to azoospermia in men.

PATHOPHYSIOLOGY AND HISTOGENESIS Molecular, biochemical and immunological basis The fundamental derangement in BS stems from abnormalities of DNA repair and chromosomal structure. Among these aberrations are a decreased rate of DNA replication, chromatid and isochromatid gaps, breaks and rearrangements, acentric segments, dicentric and abnormal monocentric chromosomes, and a markedly increased (6- to 12-fold) frequency of sister chromatid exchanges with increased triradial and quadriradial configurations.705,715–718 There is a high spontaneous mutation frequency in both lymphocytes in vivo and in cultured fibroblasts.704 Mutations in the BLM gene cause the features of BS. The RecQ gene family, of which BLM is a member, is a part of the RecF recombination pathway in which mutations abolish the conjugational recombination proficiency and ultraviolet resistance of a mutant strain. RecQL is a human gene isolated from HeLa cells, the product of which possesses DNA-dependent ATPase, DNA helicase, and 3′–5′ single-stranded DNA translocation activities.707,719 Ellis and German716 have suggested that the absence of the BLM gene product destabilizes other enzymes that participate in DNA replication and repair, perhaps through direct interaction and through more general responses to DNA damage. BLM protein resembles two other proteins that are members of the RecQ family of helicases, the gene product encoded by the Werner syndrome gene (WRN) and the product of the yeast gene Sgs1p.715,719

715. Ellis NA, Groden J, Ye T-Z, et al. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell. 1995;83:655–666. 716. Ellis NA, German J. Molecular genetics of Bloom’s syndrome. Hum Mol Genet. 1996;5:1457–1463. 717. Kaneko H, Kondo N. Clinical features of Bloom syndrome and function of the causative gene, BLM helicase. Expert Rev Mol Diagn. 2004;4:393–401. 718. German J, Sanz MM, Ciocci S, et al. Syndrome-causing mutations of the BLM gene in persons in the Bloom’s Syndrome Registry. Hum Mutat. 2007;28:743–753. 719. Killoran MP, Keck JL. Sit down, relax and unwind: structural insights into RecQ helicase mechanisms. Nucleic Acids Res. 2006;34:4098–4105.

Genodermatoses

Histologic findings

ROTHMUND–THOMSON SYNDROME

Histopathologically, Bloom syndrome manifests epidermal flattening and hydropic degeneration of the basal cell layer with pigmentary incontinence; inflammatory infiltrates may be absent, or perivascular mononuclear cells may be present. Because of similarities to lupus erythematosus, a direct immuno­ fluorescence examination of the skin may be needed to distinguish Bloom syndrome, in which no dermal–epidermal junction immunoglobulin deposits are seen.

INTRODUCTION AND HISTORICAL NOTE

The photosensitivity in early childhood can be distinguished from erythropoietic protoporphyria by the absence of red cell protoporphyrins and negative red cell fluorescence. Facial telangiectasias and dwarfism may also be seen in children with Rothmund–Thomson syndrome or CS. Telangiectasias with ataxia-telangiectasia or lupus erythematosus may be distinguished from BS by the accompanying neurologic, rheumatologic, serologic, or other systemic associations. The telangiectasias in hereditary hemorrhagic telangiectasia generally do not appear before the second decade of life.

Rothmund–Thomson syndrome, also known as congenital poikiloderma, is an extremely rare syndrome characterized by infantile-onset poikiloderma associated with cataracts, photosensitivity, short stature, skeletal abnormalities, and hypogonadism. Rothmund, a German ophthalmologist, first described in 1868 the association of juvenile cataracts with a peculiar skin degeneration in three patients drawn from interrelated families living in the Klein-Walserthal valley in Austria. Thomson, a British dermatologist, in 1923 and 1936 emphasized the cuta­ neous findings in naming the same syndrome ‘poikiloderma congenitale.’722

EPIDEMIOLOGY Genetics Autosomal recessive inheritance has been assumed in cases in which marriages were consanguineous. Some cases are caused by mutations in the DNA helicase gene RecQL4, which has been mapped to chromosome 8q.24.3 (MIM 268400).723–725

THERAPEUTICS AND PROGNOSIS

Statistics

Topical therapy

More than 200 cases of Rothmund–Thomson syndrome have been reported worldwide. The disorder has been seen in Indian, Oriental, black, and white children, with a male : female ratio of 2 : 1.726

It is necessary to recommend effective sun protection for affected patients in order to minimize UV damage to the skin and the potential mutagenic stimulation of lymphocytes circulating through the skin.

Systemic management Early detection of malignancies and its surgical or chemotherapeutic approach are essential steps in the management of BS patients.704,720,721 Patients and their families need to be educated about the course of the disease, the preventive measures that must be taken, and the early detection of malignant changes. Efforts to avoid other known environmental mutagens are also advisable.

PROGNOSIS Malignancies of varied cell types and early appearance, as well as recurrent infections, account for death before the age of 50 years in most patients.

720. Thomas ER, Shanley S, Walker L, et al. Surveillance and treatment of malignancy in Bloom syndrome. Clin Oncol (R Coll Radiol). 2008;20:375–379. 721. Holman JD, Dyer JA. Genodermatoses with malignant potential. Curr Opin Pediatr. 2007;19:446–454. 722. Vennos EM, James WD. Rothmund–Thomson syndrome. Dermatol Clin. 1995;13:143–150. 723. McKusick VA. Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University; 2008. www.ncbi.nlm.nih.gov/omim. 724. Kitao S, Shimamoto A, Goto M, et al. Mutations in RECQL4 cause a subset of cases of Rothmund–Thomson syndrome. Nat Genet. 1999;22:82–84.

ROTHMUND–THOMSON SYNDROME

DIFFERENTIAL DIAGNOSIS

7

PRESENTING HISTORY Affected children develop poikiloderma, usually at 3–6 months of age, but varying from birth to 2 years of age. With the knowledge of the gene defect in Rothmund–Thomson syndrome, reexamination of the individuals diagnosed with this disorder showed some patients without poikiloderma.727

PHYSICAL EXAMINATION Skin The original eruption has been described in various cases as diffuse erythema and edema, reticulate erythema, and in two cases as vesicular. Rarely, erythema is absent. The eruption usually involves the face initially, followed by the buttocks and extremities; however, a reverse order of appearance has been noted in several patients. This stage is followed by a chronic

725. Lindor NM, Furuichi Y, Kitao S, et al. Rothmund–Thomson syndrome due to RECQ4 helicase mutations: report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome. Am J Med Genet. 2000;90:223–228. 726. Wang LL, Levy ML, Lewis RA, et al. Clinical manifestations in a cohort of 41 Rothmund–Thomson syndrome patients. Am J Med Genet. 2001;102:11–17. 727. Pujol LA, Erickson RP, Heidenreich RA, et al. Variable presentation of Rothmund–Thomson syndrome. Am J Med Genet. 2000;95:204–207.

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Figure 7.82  Rothmund–Thomson syndrome. Poikiloderma in a 3-year-old girl (Courtesy Dr A. Torrelo).

ROTHMUND–THOMSON SYNDROME

poikilodermatous stage consisting of atrophy, telangiectasia, and patchy or linear hypopigmentation and hyperpigmentation (Fig. 7.82). In most patients, progression of these lesions ceases between 3 and 5 years of age.722 Photosensitivity has been reported in 30% of patients and may produce a bullous eruption. However, blistering in patients has been seen without photosensitivity. After age 2, verrucous hyperkeratoses develop on the hands, feet, knees, and elbows in about one-third of patients. An increased incidence of cutaneous squamous cell carcinoma occurs in adult patients within both hyperkeratotic and atrophic lesions.728 Actinic keratoses and calcinosis cutis have been documented in few cases.729

(Courtesy Dr A. Torrelo).

Juvenile cataracts are present in 50% of the patients. These present bilaterally as either posterior or anterior subcapsular opacities that evolve rapidly to total opacity within weeks. They are usually first detected at 3–7 years of age but have appeared as early as 4 months or as late as 40 years. Other ocular abnormalities have included: keratoconus, colobomata, strabismus, amblyopia with tilted optic discs, microphthalmia with optic

atrophy, aneurysmal dilation of retinal veins, exophthalmos, corneal atrophy, corneal scleralization, congenital glaucoma, chorioretinal atrophy, photophobia, hypertelorism, and blue sclerae.722 Short stature with small stubby hands and feet has been frequently noted. Low birth weight and length with severe growth failure in childhood are characteristic. Skeletal abnormalities have been seen in about 68% of patients, and range from minimally to grossly incapacitating. These include a typical facies with frontal bossing, saddle nose and prognathism, absent or rudimentary thumbs, brachymetacarpophalangy, syndactyly, clinodactyly, and fusion or agenesis of carpal and tarsal bones. The radius and ulna may be hypoplastic, absent or bowed. Fibrous dysplasia, osteogenesis imperfecta and soft tissue contractures may be present. An irregular cortical hyperostosis that mimics rickets or chondrodystrophy, a cup-shaped depression of the radial head, and osteoporosis with pathologic fractures have also been reported.722 Bone age may be lower than chronological age. Hypogonadism has been described in 25% of patients. Mental retardation is rare. Osteosarcoma has been reported in 32% of cases of Rothmund–Thomson syndrome, suggesting either allelic or genetic heterogeneity.726,727,731 Other malignancies reported include squamous cell carcinoma, Bowen’s disease, basal cell carcinoma, fibrosarcoma, Hodgkin lymphoma, gastric carcinoma, and acute myelogenous leukemia. Hematological abnormalities include aplastic anemia and myelodysplastic syndrome.732,733

728. Stinco G, Governatori G, Mattighello P, et al. Multiple cutaneous neoplasms in a patient with Rothmund-Thomson syndrome: case report and published work review. J Dermatol. 2008;35:154–161. 729. Aydemir EH, Onsun N, Ozan S, et al. Rothmund–Thomson syndrome with calcinosis universalis. Int J Dermatol. 1988;27:591–592. 730. Snels DG, Bavinck JN, Muller H, et al. A female patient with the Rothmund–Thomson syndrome associated with anhidrosis and severe infections of the respiratory tract. Dermatology. 1998;196:260–263.

731. Wang LL, Gannavarapu A, Kozinetz CA, et al. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund–Thomson syndrome. J Natl Cancer Inst. 2003;95:669–674. 732. Narayan S, Fleming C, Trainer AH, et al. Rothmund–Thomson syndrome with myelodysplasia. Pediatr Dermatol. 2001;18:210–212. 733. Knoell KA, Sidhu-Malik NK, Malik RK. Aplastic anemia in a patient with Rothmund–Thomson syndrome. J Pediatr Hematol Oncol. 1999;21:444–446.

Hair, nail, teeth and mucous membranes Scalp and body hair tends to be fine or sparse; loss of vellus hair occurs in sites of the poikilodermatous eruption. This may progress to partial or total alopecia. Occasionally there is an absence of eyebrows or eyelashes (Fig. 7.83). Nail dystrophy occurs in 30% and defective dentition in up to 40% of patients. There is increased incidence of dental caries, and microdontia with conical shape. Anhidrosis has been reported in few patients.722,730

SYSTEMIC MANIFESTATIONS

478

Figure 7.83  Rothmund–Thomson syndrome. Loss of eyebrows and lashes

Genodermatoses

While most patients have normal immune function, occasional decreases in the relative and absolute numbers of suppressor T cells or in serum IgG4 levels have been seen.734

PATHOPHYSIOLOGY AND HISTOGENESIS Molecular, biochemical and immunological basis At least a subset of patients show mutations in the DNA helicase gene RecQL4.725 Based on their 11 patients with osteosarcoma in a cohort of 33 RTS patients, Wang et al. suggested that patients who carry truncating mutations in their RECQL4 genes have an increased risk of osteosarcoma.731 It is possible that RECQL4 plays a role in bone differentiation and/or maintenance of genomic stability in osteoblasts. On the contrary, patients with no RECQL4 mutations have no tendency to malignancy. Normal karyotypes are the rule among patients, though isolated chromosomal abnormalities have been detected.

derma have been successfully treated with laser therapy.736 For hyperkeratotic lesions, dermabrasion and keratolytics may be more effective than curettage or topical 5-FU. Cataract extraction may be necessary and can be successfully performed, although other ocular problems may still interfere with vision. Photoprotection with the use of lightweight cotton clothing and sun hats along with judicious use of sunscreen agents is advised. Midday sun exposure, especially in summer, should be avoided to the extent possible.

Systemic management A baseline long bone radiological survey by age 3 is strongly recommended for early detection of osteosarcoma.722,726 Orthopedic bracing and surgery may be necessary for specific deformities. Associated combined immunodeficiency has been corrected by umbilical cord blood transplant in a 7-month old patient.737 Genetic counseling for affected families is mandatory.

KINDLER SYNDROME

LABORATORY FINDINGS

7

PROGNOSIS Histologic findings Poikilodermatous changes are similar in all patients. Direct immunofluorescence studies are usually negative.

DIFFERENTIAL DIAGNOSIS In childhood, Rothmund–Thomson syndrome must be distinguished from Bloom syndrome, XP, ataxia telangiectasia, CS, acrogeria (Gottron syndrome), Kindler syndrome, acrokeratotic poikiloderma, Mendes da Costa syndrome, sclerosing poikiloderma, dyskeratosis congenita, and progeria. In adulthood, it can be distinguished from Werner syndrome by early-onset poikiloderma and cataracts and the absence of muscle atrophy and arteriosclerosis. Mutations of RECQL4 have been reported in patients with RAPADILINO syndrome, a rare autosomal recessive disorder with similar clinical manifestations but absence of the cutaneous features of Rothmund–Thomson syndrome. The acronym stands for specific features: RAdial hypoplasia/aplasia, PAtellar hypoplasia/aplasia, cleft or highly arched PAlate, DIarrhea and DIslocated joints, LIttle size and LImb malformation, and slender NOse and NOrmal intelligence.735

Cancer proneness shortens life expectancy in some patients. However, many of the original reported patients were still living in their sixth, seventh, and eighth decades, and one was in the ninth decade on follow-up interviews.

KINDLER SYNDROME INTRODUCTION AND HISTORICAL NOTE In 1954, Theresa Kindler described a 14-year-old English girl with unusual congenital blistering of her hands and feet.738 Later in childhood, the patient developed reticulate erythema and diffuse cutaneous atrophy, beginning in sun-exposed areas. Her gums bled readily, and the skin of the dorsa on her hands and feet had a thin, wrinkled appearance. She also had webbing between the second and third toes on both feet. By 10 years of age, the blistering and sun sensitivity had resolved, but the skin remained thin and fragile. Other cases have been reported around the world, and probably a number of cases remain unidentified.739

EPIDEMIOLOGY

THERAPEUTICS AND PROGNOSIS

Genetics

Topical therapy

Kindler syndrome trait. The causative ized to 20p12.3. It extracellular-matrix

Treatment consists of avoidance of skin irritants and lubrication in the poikilodermatous state. Facial telangiectasias and poikilo-

734. Kubota M, Yasunaga M, Hashimoto H, et al. IgG4 deficiency with Rothmund–Thomson syndrome: a case report. Eur J Pediatr. 1993;152:406–408. 735. Kellermayer R, Siitonen HA, Hadzsiev K, et al. A patient with Rothmund–Thomson syndrome and all features of RAPADILINO. Arch Dermatol. 2005;141:617–620. 736. Geronemus RG. Treatment of the cutaneous vascular component of the Rothmund–Thomson syndrome. Pediatr Dermatol. 1996;13:175. 737. Broom MA, Wang LL, Otta SK, et al. Successful umbilical cord blood stem cell transplantation in a patient with Rothmund-Thomson syndrome and combined immunodeficiency. Clin Genet. 2006;69:337–343.

is inherited as an autosomal recessive gene, KIND1 or FERMT1, has been localregulates the Kindlin-1 protein, an actin– (ECM) linkage protein.740,741

738. Kindler T. Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy. Br J Dermatol. 1954;66:104–111. 739. Ashton GH. Kindler syndrome. Clin Exp Dermatol. 2004;29:116–121. 740. Siegel DH, Ashton GH, Penagos HG, et al. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome. Am J Hum Genet. 2003;73:174–187. 741. Jobard F, Bouadjar B, Caux F, et al. Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Hum Mol Genet. 2003;12:925–935.

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Statistics Around 100 cases have been reported in the literature, the larger group belonging to a close population of the Ngo be-Bugle tribe Panamian indigens.742 Individual cases were reported in America, Europe, Asia and Africa.743

PRESENTING HISTORY It is characterized in infancy by acral trauma-induced blistering and photosensitivity that improve with age. Later in life, pro­ gressive poikiloderma with diffuse cutaneous atrophy, telan­ giectases, and reticulate pigmentation develop.

KINDLER SYNDROME

PHYSICAL EXAMINATION Skin Blister formation after cutaneous trauma or exposure to sunlight appears since birth or during the first days of life, most frequently on the dorsa of the hands and feet. These bullae diminish in frequency at puberty, but continue to recur in adulthood, and the skin of older patients continues to be fragile and easily injured by mild trauma. Photosensitivity characterized by erythema, burning, and blister formation after sun exposure usually appears at 2 years of age. Generalized poikiloderma in both sun-exposed and non– sun-exposed areas develops from ages 2–3 years, and persists throughout adult life. Some patients have axillary freckling. Diffuse cutaneous atrophy is characterized by thin, wrinkled skin (cigarette paper skin), most pronounced on the dorsa of the hands and feet, but also present on abdomen, thighs, knees, and elbows. Distally located sclerodermoid changes are frequent. The palmar hyperkeratosis often has a glassy appearance. It ends sharply at the volar wrist but extends dorsally on to the hands, wrists, and as far proximally as the distal one third of the forearms. Hyperkeratosis of the palms and soles is not associated with acrokeratotic papules, but patients show loss of fingerprints. Some patients have ridged thickening of the lateral and anterior aspects of the ankles that is reminiscent of epidermolytic hyperkeratosis.739,742,743

Hair, nail, teeth and mucous membranes Mucosal manifestations are common and include hemorrhagic mucositis, hemorrhagic gingivitis, labial leukokeratosis, earlyonset periodontal disease, and premature loss of teeth. Other features may include nail dystrophy, webbing of the fingers and toes. The nail plates are thin with atrophy and oncolysis.

Systemic manifestations

480

elbows is frequent. However, the skin is not hyperextensible. Ectropion formation, esophageal, anal, vaginal, or urethral stenosis, and severe phimosis may require surgical correction.744

LABORATORY FINDINGS Although microcytic anemia has been described in association, it is not thought to be related to Kindler syndrome.

PATHOPHYSIOLOGY AND HISTOGENESIS Molecular, biochemical and immunological basis The highest expression of the KIND1 gene can be found in skin, colon, kidney, and placenta, with lower levels in the heart, skeletal muscle, liver, and small intestine. Kindlin-1 protein is expressed in the epidermis, and in vitro it colocalizes with actin and vinculin in focal contacts. The deficiency of this actin–extracellular-matrix (ECM) linkage protein causes the inherited skin fragility and photosensitivity.

Histologic findings Skin lesions are characterized by epidermal atrophy, focal vacuolization of the basal layer and pigmentary incontinence in addition to a mild lymphocytic infiltrate, consistent with poikiloderma. Electron microscopy shows extensive reduplication and disruption of the lamina densa along the dermoepidermal junction beneath the basal cells, and cleft formation which occurs in the lamina lucida. In immunofluorescence studies, laminin 332 and collagen types IV and VII show a broad, reticular labeling pattern, corresponding to the reduplication of lamina densa observed by electron microscopy. Abnormalities of adhesion molecules linking the lamina densa to the basal cells have been thought to explain these findings.745

DIFFERENTIAL DIAGNOSIS Clinically, Kindler syndrome resembles both inherited blistering skin disorders such as dystrophic epidermolysis bullosa and congenital poikilodermas such as Rothmund–Thomson syndrome. An overlap between KS and hereditary acrokeratotic poikiloderma, an autosomal-dominant disorder described by Weary, has been suggested, and some have adopted the term Weary– Kindler syndrome. Weary and Kindler syndromes have poikiloderma in common, but differ in that bullae and photosensitivity are present in KS but not in Weary syndrome.

THERAPEUTICS AND PROGNOSIS Topical therapy

Phimosis is present in most of male patients. Joint laxity with variable hypermobility of the thumb and fingers, knees, and

Sun protection and moisturizers are the main requirements for the skin manifestations of Kindler syndrome. Bullae and excoriations could require topical antibiotics.

742. Penagos H, Jaen M, Sancho MT, et al. Kindler syndrome in native Americans from Panama: report of 26 cases. Arch Dermatol. 2004;140:939–944. 743. Nofal E, Assaf M, Elmosalamy K. Kindler syndrome: a study of five Egyptian cases with evaluation of severity. Int J Dermatol. 2008;47:658–662.

744. Sadler E, Klausegger A, Muss W, et al. Novel KIND1 gene mutation in Kindler syndrome with severe gastrointestinal tract involvement. Arch Dermatol. 2006;142:1619–1624. 745. Shimizu H, Sato M, Ban M, et al. Immunohistochemical, ultrastructural, and molecular features of Kindler syndrome distinguish it from dystrophic epidermolysis bullosa. Arch Dermatol. 1997;133:1111–1117.

Genodermatoses

The prognosis depends on the gastrointestinal involvement, and the manifestations of chronic photosensitivity and skin fragility.

TUBEROUS SCLEROSIS COMPLEX AND NEUROFIBROMATOSIS Bruce R. Korf

TUBEROUS SCLEROSIS COMPLEX INTRODUCTION Tuberous sclerosis complex is a hereditary disorder, also known as Bourneville’s disease, epiloia, and hereditary multiple system hamartomatosis. It is characterized by hamartomas involving the skin, eye, brain, heart, lungs, kidneys, and bones. The classical description, first proposed by Vogt in 1908, consists of the triad of adenoma sebaceum, epilepsy, and mental retardation; however, at least 50% of affected persons are not retarded.

HISTORY Von Recklinghausen in 1862 first described the association of cerebral sclerotic areas and cardiac tumors in an autopsy report of a newborn infant. Bourneville coined the term ‘sclerose tubéreuse’ to describe the brain tumors and associate them with epilepsy and mental retardation. In 1885, Balzer and Ménétrier described this syndrome’s facial eruption as ‘adenomes sébaces’, without performing histologic studies. Pringle in 1899 correctly classified these facial lesions as angiofibromas. Van der Hoeve in 1920 first reported the presence of retinal lesions, which he termed ‘phakomas’. In 1911, Sherlock introduced the term epiloia, combining the words epilepsy and anoia, meaning ‘minded-less’, for the entire syndrome, in which he included convulsions, mental retardation, adenoma sebaceum, and tumors of the brain and other organs.

BOX 7.7 DIAGNOSTIC CRITERIA FOR TUBEROUS SCLEROSIS COMPLEX

Major features

>> Facial angiofibromas or forehead plaque >> Non-traumatic ungual or periungual fibroma >> Hypomelanotic macules (more than three) >> Shagreen patch (connective tissue nevus) >> Multiple retinal nodular hamartomas >> Cortical tuber >> Subependymal nodule >> Subependymal giant cell astrocytoma >> Cardiac rhabdomyoma, single or multiple >> Lymphangiomyomatosis >> Renal angiomyolipoma Minor features

>> Multiple randomly distributed pits in dental enamel >> Hamartomatous rectal polyps >> Bone cysts >> Cerebral white matter migration lines >> Gingival fibromas >> Non-renal hamartoma >> Retinal achromic patch >> ‘Confetti’ skin lesions >> Multiple renal cysts Definite TSC: Either two major features or one major feature with two minor features Probable TSC: One major feature and one minor feature Possible TSC: Either one major feature or two or more minor features From: www.tsalliance.org.

CLINICAL MANIFESTATIONS

Inheritance is autosomal dominant with variable expressivity. Non-penetrance is uncommon. Birth incidence is estimated at 1 in 6000 and the disorder occurs in all ethnic groups.746 There is a high rate of new mutation, comprising an estimated two-thirds of cases, but careful clinical assessment of the parents of an apparently sporadically affected child is important before concluding that the child represents a new mutation.

Tuberous sclerosis is diagnosed based on clinical features (Box 7.7).747 In infancy and early childhood, presentation is most likely to be prompted by cardiac rhabdomyomas or seizures.748 Cardiac rhabdomyomas are congenital and tend to regress. Developmental delay, mental retardation, autism, and behavioral problems constitute the next most frequent presenting signs. A close correlation has been established between infantile spasms or other generalized seizures and mental retardation; the age of seizure onset and severity of mental retardation are closely related.749,750 The diagnostic workup is aided by a Wood’s light examination of the entire skin surface for hypopigmented macules, present in >95% of affected patients either at birth or soon afterward.751,752

746. Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125–127. 747. Roach ES, Sparagana SP. Diagnosis of tuberous sclerosis complex. J Child Neurol. 2004;19:643. 748. Datta AN, Hahn CD, Sahin M. Clinical presentation and diagnosis of tuberous sclerosis complex in infancy. J Child Neurol. 2008;23:268–273. 749. Osborne J, Webb D. Seizures and intellectual disability associated with tuberous sclerosis. Dev Med Child Neurol. 1993;35:276.

750. Zaroff CM, Barr WB, Carlson C, et al. Mental retardation and relation to seizure and tuber burden in tuberous sclerosis complex. Seizure. 2006;15:558–562. 751. Webb DW, Clarke A, Fryer A, et al. The cutaneous features of tuberous sclerosis: A population study. Br J Dermatol. 1996;135:1. 752. Jozwiak S, Schwartz RA, Janniger CK, et al. Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. Int J Dermatol. 1998;37:911.

EPIDEMIOLOGY

TUBEROUS SCLEROSIS COMPLEX

PROGNOSIS

7

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Figure 7.84  Hypopigmented macules or ‘white spots’ of tuberous sclerosis on the trunk of an affected infant.

TUBEROUS SCLEROSIS COMPLEX

482

Occasionally, a hypopigmented tuft of scalp or eyelash hair may be present. These white macules can be oval or linear, but the most characteristic lesion are lance-ovate (Fig. 7.84), hence the name ash-leaf-spots to describe them. Their size ranges from one millimeter to several centimeters, and the number of lesions varies from a few to more than 75. Histologically, these lesions differ from vitiligo in that they contain hypoactive melanocytes. The lesions are not pathognomonic, but their detection is very helpful in considering the diagnosis of this disease. Cutaneous angiofibromas, the so-called ‘adenoma sebaceum’ lesions, usually appear between 2 and 6 years of age, but their appearance has ranged from birth to the mid-20s. They are only occasionally seen outside tuberous sclerosis, specifically in multiple endocrine neoplasia type I753 and Birt–Hogg– Dube syndrome.754 The cutaneous angiofibromas of TSC occur in 65–90% of reported patients, and consist of 1- to 10-mm pink to red, dome-shaped papules, occurring usually in a symmetric distribution over the nasolabial folds, cheeks (Figs 7.85, 7.86), and chin, and more rarely over the forehead, eyelids, ears, and scalp. Histologic examination of these lesions demonstrates capillary dilatation and dermal fibrosis with atrophy or downward displacement of sebaceous glands and hair follicles. Clinically, these lesions may be obscured by concomitant acne vulgaris, acne rosacea, or seborrheic dermatitis. Large fibrotic plaques or nodules can occur on the forehead (Fig. 7.86), cheeks, and scalp, and may be present at birth. Histologically, they are connective tissue nevi of the collagen type without vascular dilation. Shagreen patches, or peau chagrine lesions, are truncal plaques present in 48% of patients in one series.752 They are usually found in the lumbosacral region (Fig. 7.87) and may be either solitary or multiple. Lesions vary from being palm-sized to 50% of patients758 and are detected by ultrasound, CT, or MRI. Although most lesions are asymptomatic, hemorrhage, hypertension, and renal failure may occur. Embolization can be effective in treatment of angiomyolipomas. Women with tuberous sclerosis are at risk of the potentially fatal complication lymphangiomyomatosis, which typically occurs in those with renal angiomyolipomas.759 Other features include cysts of the liver, pancreas, thyroid, and testes, as well as bony abnormalities visible on hand and skull radiographs.

TUBEROUS SCLEROSIS COMPLEX

Figure 7.87  Shagreen patches, such as this one on the lower back, are

7

PATHOPHYSIOLOGY

Figure 7.88  Multiple periungual fibromas in a child with tuberous sclerosis (Courtesy Dr S. Vañó-Galván).

multinodular lesion described as mulberrylike, frog’s-egglike, or salmon egglike. Both types have been seen in infants and in adults. Other ocular findings include glial hamartomas of the optic disc, occasionally referred to as giant drusen; white pedunculated tumors of the palpebral conjunctiva; yellow–red thickenings of the bulbar conjunctiva; optic atrophy secondary to papilledema caused by intracranial lesions; retinal angiomas;

755. Christophe C, Sekhara T, Rypens F, et al. MRI spectrum of cortical malformations in tuberous sclerosis complex. Brain Dev. 2000;22:487–493. 756. Wong V, Khong PL. Tuberous sclerosis complex: correlation of magnetic resonance imaging (MRI) findings with comorbidities. J Child Neurol. 2006;21:99–105. 757. Torres OA, Roach ES, Delgado MR, et al. Early diagnosis of subependymal giant cell astrocytoma in patients with tuberous sclerosis. J Child Neurol. 1998;13:173. 758. Rakowski SK, Winterkorn EB, Paul E, et al. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int. 2006;70:1777–1782. 759. Chorianopoulos D, Stratakos G. Lymphangioleiomyomatosis and tuberous sclerosis complex. Lung. 2008;186:197–207. 760. Van Slegtenhorst M, De Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997;277:805. 761. The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993;75:1305.

Tuberous sclerosis complex is due to mutations in two different genes, TSC1760 on chromosome 9 and TSC2 on chromosome 16.761 The two gene products, hamartin and tuberin, respectively, interact with one another in the cell, and appear to function in the regulation of GTPase activity of Rheb, which is a negative regulator of mTOR.762 The TSC genes appear to function as tumor suppressors in the pathogenesis of the lesions of TSC.763,764 A wide variety of mutations occurs in both the TSC1 and TSC2 genes; individuals with TSC1 mutations may have a milder clinical course.765 Patients with renal cysts have co-deletion of the TSC2 gene and the PKD1 gene that leads to polycystic kidney disease, on chromosome 16.766 Mosaicism has been seen in individuals with TSC.767

DIFFERENTIAL DIAGNOSIS The angiofibromas can be differentiated from trichoepitheliomas, trichilemmomas, milia, xanthomas, and verrucae. Other disease processes associated with intracranial calcifications include Sturge–Weber syndrome, hyalinosis cutis et mucosae, congenital toxoplasmosis, congenital cytomegalic inclusion disease, and basal cell nevus syndrome.

762. Rosner M, Hanneder M, Siegel N, et al. The mTOR pathway and its role in human genetic diseases. Mutat Res. 2008;659:284–292. 763. Henske EP, Scheithauer BW, Short MP, et al. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet. 1996;59:400. 764. Henske EP, Wessner LL, Golden J, et al. Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am J Pathol. 1997;151:1639–1647. 765. Au KS, Williams AT, Roach ES, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007;9:88–100. 766. Brook-Carter PT, Peral B, Ward CJ, et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease – A contiguous gene syndrome. Nature Genet. 1994;8:328. 767. Verhoef S, Bakker L, Tempelaars AM, et al. High rate of mosaicism in tuberous sclerosis complex. Am J Hum Genet. 1999;64:1632–1637.

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THERAPEUTICS

NEUROFIBROMATOSIS

Prompt treatment of seizures, especially in early life, may enhance subsequent mental development.768 Neurosurgical intervention may be necessary if signs of increased intracranial pressure (e.g., headache, vomiting, visual disturbances, papil­ ledema) develop. Special education may be required. Facial angiofibromas can be treated successfully with dermabrasion or laser treatment but slowly recur. Consensus guidelines for surveillance have been published.769 Elucidation of the role of mTOR signaling in the pathogenesis of tuberous sclerosis has opened the way to clinical trials with targeted therapy. Some success has been reported with the mTOR inhibitor sirolimus (rapamycin) in reducing the size of some lesions.770–773 Affected individuals should be provided genetic counseling regarding the 50% risk of transmission to offspring. Genetic testing, including prenatal diagnosis, is available. Apparently unaffected parents of an affected child should be carefully examined for subtle signs, including skin examination and imaging of the brain and kidneys.

PROGNOSIS The prognosis varies widely, even among members of the same family. Some persons have normal intelligence, no seizures, and a normal life span, whereas others can be severely cognitively impaired.768 Life-threatening complications include pulmonary lymphangiomyomatosis, mostly seen in females, and rare renal cell carcinoma.

NEUROFIBROMATOSIS

HISTORY The first systemic characterization of neurofibromatosis was made by von Recklinghausen in 1882.774 Joseph Merrick, also known as the ‘Elephant Man’, was at one time thought to have had neurofibromatosis; the diagnosis is now believed to be Proteus syndrome.775

EPIDEMIOLOGY NF1 is present in 1 in 3000 persons and shows no ethnic or sexual preponderance.776 The frequency of NF2 is lower, about 1 : 30 000,777 but also occurs in both sexes and in populations around the world. The frequency of schwannomatosis is unknown, but is likely to be similar to that of NF2. NF1 and NF2 are characterized by complete penetrance but variable expressivity and exhibit a high rate of new mutation, approximately 50%. Schwannomatosis displays incomplete penetrance.

INTRODUCTION

CLINICAL MANIFESTATIONS

‘Neurofibromatosis’ is a term that encompasses three distinct disorders, NF1, NF2, and schwannomatosis. All are characterized by the occurrence of multiple tumors of the nerve sheath and are inherited as autosomal dominant traits. Cutaneous manifestations are highly characteristic for NF1, much less prominent in NF2, and non-existent in schwannomatosis. The major distinguishing features are:

Diagnostic criteria for NF1 are the presence of any two of the following778: six or more café-au-lait macules measuring 5 mm or more before puberty or 15 mm or more after puberty; skinfold freckling; two or more neurofibromas or one plexiform neurofibroma; two or more iris Lisch nodules; optic nerve glioma; characteristic skeletal dysplasia (tibial or orbital dysplasia); affected 1st-degree relative. The most common presenting sign is multiple café-au-lait macules (Fig. 7.89A).779 These may be seen at birth, but often do not appear until several weeks to months of life, and may continue to appear or darken over the first 2 years. If the diagnostic criterion of six or more café-au-lait macules is met, there is no significance to the overall number, which does not correlate with

1. NF1: Classic or von Recklinghausen neurofibromatosis, peripheral neurofibromatosis, is characterized by multiple café-au-lait macules, skinfold freckling, numerous neurofibromas, Lisch nodules, learning disabilities, skeletal dysplasia, and risk of malignancy. It accounts for more than 90% of all cases of neurofibromatosis.

768. Winterkorn EB, Pulsifer MB, Thiele EA. Cognitive prognosis of patients with tuberous sclerosis complex. Neurology. 2007;68:62–64. 769. Hyman MH, Whittemore VH. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch Neurol. 2000;57:662–665. 770. Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006;59:490–498. 771. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358:140–151. 772. Crino PB. Rapamycin and tuberous sclerosis complex: from Easter Island to epilepsy. Ann Neurol. 2008;63:415–417. 773. Zeng LH, Xu L, Gutmann DH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008;63:444–453.

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2. NF2: Bilateral acoustic or ‘central’ neurofibromatosis is characterized by an almost 100% incidence of bilateral vestibular schwannomas. Schwannomas may also occur along other cranial, spinal nerves, and peripheral nerves. Café-au-lait spots tend to be few. Posterior subcapsular lens opacities are frequent. Other tumor types include meningiomas, ependymomas, and gliomas. 3. Schwannomatosis: This recently recognized entity is characterized by multiple schwannomas of nerves other than the vestibular nerve. Pain is the usual presenting sign.

774. von Recklinghausen FD. Über die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen. Berlin: Festshrift fur Rudolf Virchow; 1882. 775. Tibbles JA, Cohen MM Jr. The Proteus syndrome: the Elephant Man diagnosed. BMJ (Clin Res Ed). 1986;293:683–685. 776. Friedman JM. Epidemiology of neurofibromatosis type 1. Am J Med Genet. 1999;89:1–6. 777. Evans DG, Moran A, King A, et al. Incidence of vestibular schwannoma and neurofibromatosis 2 in the North West of England over a 10-year period: higher incidence than previously thought. Otol Neurotol. 2005;26:93. 778. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278:51–57. 779. Crowe FW, Schull WJ, Neel JV. A clinical, pathological, and genetic study of multiple neurofibromatosis. Springfield: Charles C. Thomas; 1956.

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NEUROFIBROMATOSIS

Figure 7.90  Dermal neurofibromas may present as reddish papules or deeper, more subtle blue nodular lesions (arrows). These dermal neurofibromas do not tend to first develop until later in childhood and adolescence.

A

B

Figure 7.89  (A) The presence of six or more café-au-lait macules is a major criterion for suspecting the diagnosis in patients with neurofibromatosis, and is usually the only manifestations in children with the disorder. (B) If axillary freckling is present in addition to the multiple café-au-lait macules, the diagnosis of neurofibromatosis may be made with certainty.

the severity of the disorder. Also, the location of café-au-lait macules does not predict the future location of neurofibromas. One exception is that large patches of hyperpigmentation, usually with irregular borders and present at birth, may signal the presence of an underlying plexiform neurofibroma.780 The other major pigmentary feature of NF1, skinfold freckling (Fig.

780. Riccardi VM. Pathophysiology of neurofibromatosis. IV. Dermatologic insights into heterogeneity and pathogenesis. J Am Acad Dermatol. 1980;3:157–166. 781. Crowe FW. Axillary freckling as a diagnostic aid in neurofibromatosis. Ann Intern Med. 1964;61:1142–1143. 782. Korf BR. Diagnostic outcome in children with multiple café au lait spots. Pediatrics. 1992;90:924–927. 783. Carroll SL, Ratner N. How does the Schwann cell lineage form tumors in NF1? Glia. 2008;56:1590–1605.

7.89B), often confirms a suspected diagnosis, and appears between three and five years of age.781,782 This sign is virtually specific to NF1; only individuals with Legius syndrome may also show this finding. Neurofibromas represent growths of the nerve sheath, including Schwann cells, fibroblasts, perineurial cells, and mast cells.783 They may grow along a single site on a nerve (’discrete neurofibromas’) or may extend along the length of a nerve involving multiple fascicles (‘plexiform neurofibromas’). Discrete neurofibromas occur in the skin either on the surface or deeper in the dermis. These tumors are soft in consistency and range in size from a millimeter to several centimeters. Intradermal tumors may have an associated violaceous discoloration and appear as small depressions in the skin (Fig. 7.90). Discrete neurofibromas may occur along peripheral nerves deeper in the body, or along nerve roots near the spine. Those that occur along superficial nerves tend to be firm in consistency. Plexiform neurofibromas can occur superficially, including the dermis, the subdermal layers, or deeper in the body (Fig. 7.91).784 Some are associated with soft tissue and bony overgrowth or bony erosion and can cause local gigantism. Some patients exhibit diffuse growths within the skin that lead to thickening without clearly definable nerve elements. Ocular signs of NF1 include orbital plexiform neurofibroma, Lisch nodules, and optic glioma. The orbital tumors occur in 2–3% of patients, involve the trigeminal nerve, and may cause displacement of the eye and glaucoma.785 Lisch nodules are melanocytic hamartomas of the iris that do not impair vision, but are useful in diagnosis, being present in >95% of adults with NF1 and being highly specific to this disorder.786,787 Optic gliomas may occur along the orbital portion of the optic nerve, unilaterally or bilaterally, or may involve the chiasm, or both. They occur in approximately 15% of children with NF1, but fewer than half exhibit progression and cause signs or symptoms

784. Korf BR. Plexiform neurofibromas. Am J Med Genet. 1999;89:31. 785. Farris SR, Grove AS Jr. Orbital and eyelid manifestations of neurofibromatosis: a clinical study and literature review. Ophthal Plast Reconstr Surg. 1996;12:245–259. 786. Lubs ML, Bauer MS, Formas ME, et al. Lisch nodules in neurofibromatosis type 1. N Engl J Med. 1991;324:1264–1266. 787. Lewis RA, Riccardi VM. Von Recklinghausen neurofibromatosis. Incidence of iris hamartomata. Ophthalmology. 1981;88:348–354.

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Figure 7.91  Extensive plexiform neurofibroma involving the shoulder, neck and scalp of a patient with neurofibromatosis. Note the overlying hyperpigmentation.

of visual impairment or precocious puberty due to hypothalamic involvement.788 Skeletal manifestations include long bone dysplasias, especially tibial dysplasia, and scoliosis.789 Tibial dysplasia presents as anterolateral bowing of the tibia, usually visible within the 1st year of life. There is thickening of the cortex of the bone and narrowing of the medullary canal.790,791 Fracture may occur at the site of dysplasia, leading in some cases to pseudoarthrosis. There also may be non-ossifying cysts in bones which may lead to fracture and generalized osteopenia.792 The scoliosis in NF1 usually occurs in the thoracic region and is associated with dysplastic changes in the vertebral bodies.793 Approximately 50% of children with NF1 exhibit learning disability, including both verbal and non-verbal disabilities as well as attention deficit disorder.794 More severe developmental delay, including ‘mental retardation’, occurs in about

788. Listernick R, Ferner RE, Liu GT, et al. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61:189–198. 789. Crawford AH, Schorry EK. Neurofibromatosis in children: the role of the orthopaedist. J Am Acad Orthop Surg. 1999;7:217–230. 790. Stevenson DA, Birch PH, Friedman JM, et al. Descriptive analysis of tibial pseudarthrosis in patients with neurofibromatosis 1. Am J Med Genet. 1999;84:413. 791. Stevenson DA, Viskochil DH, Schorry EK, et al. The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1. Genet Med. 2007;9:409–412. 792. Stevenson DA, Murray M, Viskochil DH, et al. Bone mineral density in children with neurofibromatosis type 1. J Pediatr Orthop. 2008;28:791; author reply 791–792. 793. Crawford AH, Herrera-Soto J. Scoliosis associated with neurofibromatosis. Orthop Clin North Am. 2007;38:553–562. 794. Hyman SL, Arthur Shores E, North KN. Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Dev Med Child Neurol. 2006;48:973–977.

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5%, and may be associated with a distinct NF1 gene mutation consisting of total deletion of the gene.795 Brain MRI reveals areas of enhanced T2 signal intensity in the internal capsule, brainstem, cerebellum, and basal ganglia. These tend to disappear with age and may represent areas of abnormal myelination. The number of such foci or localization to the thalamus may correlate with the occurrence of learning disabilities.796 Other features of NF1 include macrocephaly, short stature, and hypertension. Macrocephaly is common and usually not associated with hydrocephalus, although aqueductal stenosis may occur rarely. Short stature is usually unexplained, with no evidence of neuroendocrine disturbance.797 Hypertension may be due to renal artery stenosis, or, rarely, pheochromocytoma.798 Some individuals have stenosis of multiple arteries that may cause, in addition to hypertension, strokes or episodes of hemorrhage due to aneurysm.799 NF1 is associated with an increased risk of malignancy. Aside from optic gliomas, noted above, other gliomas may occur in the central nervous system, especially the brainstem.800 These are usually pilocytic astrocytomas, and tend to be slow-growing lesions. Malignant peripheral nerve sheath tumors may occur, often along pre-existing plexiform neurofibromas. These usually present with unexplained pain or sudden growth. The lifetime risk is estimated to be 8–12%.801 Other tumors seen in association with NF1 include leukemia (especially juvenile myelomonocytic leukemia), carcinoid, and pheochromocytoma. The natural history of NF1 includes several epochs of life when particular complications are most likely. Plexiform neurofibromas causing segmental hypertrophy as well as long bone dysplasias tend to be congenital. Very young children may develop juvenile xanthogranulomas, which subsequently regress. Optic gliomas and learning disabilities occur during early childhood. Dermal neurofibromas usually begin to appear in late childhood or adolescence, and may continue to appear or grow throughout life. Women often notice an increase in their neurofibromas during pregnancy. Malignant peripheral nerve sheath tumors usually occur after the first decade, peaking in the second and third decades. Diagnostic criteria of NF2778 require the presence of bilateral vestibular schwannomas, or an affected 1st-degree relative and unilateral vestibular schwannoma or two characteristic findings

795. Kayes LM, Burke W, Riccardi VM, et al. Deletions spanning the neurofibromatosis 1 gene: identification and phenotype of five patients. Am J Hum Genet. 1994;54:424–436. 796. Hyman SL, Gill DS, Shores EA, et al. T2 hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning. J Neurol Neurosurg Psychiatry. 2007;78:1088–1091. 797. Carmi D, Shohat M, Metzker A, et al. Growth, puberty, and endocrine functions in patients with sporadic or familial neurofibromatosis type 1: a longitudinal study. Pediatrics. 1999;103:1257–1262. 798. Fossali E, Signorini E, Intermite RC, et al. Renovascular disease and hypertension in children with neurofibromatosis. Pediatr Nephrol. 2000;14:806. 799. Hamilton SJ, Friedman JM. Insights into the pathogenesis of neurofibromatosis 1 vasculopathy. Clin Genet. 2000;58:341–344. 800. Guillamo JS, Creange A, Kalifa C, et al. Prognostic factors of CNS tumours in neurofibromatosis 1 (NF1): a retrospective study of 104 patients. Brain. 2003;126:152–160. 801. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311.

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802. Evans DG, Ramsden RT, Gokhale C, et al. Should NF2 mutation screening be undertaken in patients with an apparently isolated vestibular schwannoma? Clin Genet. 2007;71:354–358. 803. Kishore A, O’Reilly BF. A clinical study of vestibular schwannomas in type 2 neurofibromatosis. Clin Otolaryngol Allied Sci. 2000;25:561–565. 804. Evans DG, Lye R, Neary W, et al. Probability of bilateral disease in people presenting with a unilateral vestibular schwannoma. J Neurol Neurosurg Psychiatry. 1999;66:764–767. 805. Pearson-Webb MA, Kaiser-Kupfer MI, Eldridge R. Eye findings in bilateral acoustic (central) neurofibromatosis: Association with presenile lens opacities and cataracts but absence of Lisch nodules. N Engl J Med. 1986;315:1553. 806. Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology. 2001;56:1433–1443. 807. Maertens O, De Schepper S, Vandesompele J, et al. Molecular dissection of isolated disease features in mosaic neurofibromatosis Type 1. Am J Hum Genet. 2007;81:243–251. 808. Evans DG, Ramsden RT, Shenton A, et al. Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation-dependent probe amplification. J Med Genet. 2007;44:424–428. 809. MacCollin M, Chiocca EA, Evans DG, et al. Diagnostic criteria for schwannomatosis. Neurology. 2005;64:1838–1845. 810. Cawthon RM, O’Connell P, Buchberg AM, et al. Identification and characterization of transcripts from the neurofibromatosis 1 region: The sequence and genomic structure of EVI2 and mapping of other transcripts. Genomics. 1990;7:555.

tumors or dermal manifestations. The presenting sign in most patients is pain.

PATHOPHYSIOLOGY The genes responsible for all three disorders have been identified. The NF1 gene, on chromosome 17, encodes a protein referred to as ‘neurofibromin’.810–812 The gene responsible for NF2 is located on chromosome 22 and encodes a protein referred to as ‘merlin’ (or, by some, ‘schwannomin’).813,814 Schwannomatosis is due to mutations in a different gene on chromosome 22, referred to as INI1/SMARCB1.815,816 All three genes function as tumor suppressors, in that tumor cells display loss of expression of the relevant gene due to mutation of both alleles. Affected individuals have a high frequency of development of tumors since one allele is mutated in all cells and the second allele is subject to somatic mutation. Schwann cells appear in neurofibromas that display biallelic mutations,807,817 but the bulk of the tumor may be comprised of fibroblasts and perineurial cells stimulated to divide by intercellular signaling.818 Neurofibromas are rich in mast cells, which may be involved in this signaling process. A similar tumor suppressor process appears to be responsible for café-au-lait spots, in which melanocytes display biallelic NF1 mutations.807 The NF1 gene product includes a domain with the properties of a GTPase-activating protein (GAP).819 This domain stimulates the GTPase activity of Ras, causing Ras-GTP to be converted to Ras-GDP, changing this signal transduction molecule from its active to inactive state. It thus appears that the defect in NF1 is related to a failure to regulate Ras, specifically an inability to terminate a signal that may be initiated when the cell is stimulated to divide. It remains unclear whether any of the NF1 phenotype, such as learning disability, may be due to the heterozygous mutation. It is likely that malignant tumors require additional genetic changes besides mutation of both copies of NF1. The spectrum of mutations in the NF1 gene is broad, although the majority of mutations cause premature termination of

811. 812. 813. 814. 815.

816. 817. 818. 819.

NEUROFIBROMATOSIS

(schwannoma, glioma, meningioma, ependymoma, posterior subcapsular cataract). NF2 should also be considered in individuals with unilateral vestibular schwannoma presenting below age 35802 and in those with multiple meningiomas. The cardinal manifestation is the vestibular schwannoma. This presents with tinnitus, hearing loss, and problems with balance.803 Although tumors are almost invariably present bilaterally, onset on one side may precede the other by several years, possibly causing confusion with sporadic unilateral vestibular schwannoma.804 Vestibular tumors may occur during childhood, but usually do not begin until the second decade, well before most sporadic vestibular schwannomas, however. Schwannomas may affect other cranial nerves, especially the Vth nerve, as well as peripheral and spinal nerves. Schwannomas of cutaneous nerves may present as diffuse plaques, often associated with hair growth. Other tumors associated with NF2 include meningiomas, ependymomas, and gliomas. Multiple meningiomas may cause considerable morbidity. As distinct from NF1, malignant tumors are not seen with increased frequency in NF2. Similarly, more than six café-au-lait macules are not seen regularly in NF2, and learning disabilities are not a feature of this disorder. The only non-tumor manifestation of NF2 is cataract, either presenile posterior subcapsular cataract or cortical wedge opacity.805 Both NF1 and NF2 may be associated with mosaic involvement in some individuals. Mosaicism may ameliorate symptoms or cause segmental involvement of manifestations.806–808 These manifestations can include any combination of pigmentary signs (e.g., café-au-lait spots, freckles), neurofibromas, or other lesions (e.g., Lisch nodules, skeletal dysplasia, etc.). Common presentations include patients with café-au-lait spots and skinfold freckles confined to a single region of the body or those with a patch of neurofibromas in a specific region. Sometimes the pigmentary features in patients with mosaicism are located on a region with diffuse hyperpigmentation with clear borders that often stop at the midline. Schwannomatosis presents with multiple schwannomas of nerves other than the vestibular.809 There are no other associated

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Viskochil D, Buchberg AM, Xu G, et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 1990;62:187. Wallace MR, Marchuk DA, Andersen LB, et al. Type 1 neurofibromatosis gene: Identification of a large transcript disrupted in three NF1 patients. Science. 1990;249:181. Trofatter JA, MacCollin MM, Rutter JL, et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell. 1993;72:791. Rouleau GA, Merel P, Lutchman M, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature. 1993;363:515. Patil S, Perry A, Maccollin M, et al. Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathol. 2008;18:517–519. Boyd C, Smith M, Kluwe L, et al. Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis. Clin Genet. 2008;74:358–366. Serra E, Puig S, Otero D, et al. Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. Am J Hum Genet. 1997;61:512–519. Yang FC, Ingram DA, Chen S, et al. Nf1-dependent tumors require a microenvironment containing NF1+/− and c-kit-dependent bone marrow. Cell. 2008;135:437–448. Xu G, Lin B, Tanaka K, et al. The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell. 1990;63:835.

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translation of the gene product.820 Diagnostic testing is now available on a clinical basis, though for the most part mutations do not predict severity or specific complications. Individuals with complete gene deletions display a severe phenotype of developmental delay, large neurofibroma burden, dysmorphic appearance, and increased risk of malignancy.821 One specific mutation, a three base deletion in exon 17, is associated with café-au-lait spots but an absence of neurofibromas.822 Individuals with a variant known as ‘spinal neurofibromatosis’ have a paucity of dermal tumors but a large burden of subdermal and spinal tumors, and tend to have missense and splicing mutations.823,824 The NF2 gene product functions as a cytoskeletal protein and appears to be critical for contact inhibition of cell growth.825 NF2 gene mutations are diverse. Truncating mutations tend to be associated with a more severe phenotype than splicing mutations or amino acid substitutions.826,827 Molecular diagnostic testing is available on a clinical basis. The role of INI1/SMARCB1 in the formation of schwannomas is not well understood. The gene product functions in chromatin remodeling, and tumors display biallelic mutations both in this gene, and in the closely linked NF2 gene. It is also not yet clear that all cases of schwannomatosis are due to INI1/SMARCB1 germline mutation.

DIFFERENTIAL DIAGNOSIS A distinction has to be made from several other syndromes: multiple mucosal neuroma syndrome, LEOPARD syndrome, Noonan syndrome, Proteus syndrome, McCune–Albright syndrome, multiple lipomatosis, and Klippel–Trenaunay–Weber syndrome. Noonan syndrome and LEOPARD syndrome are also due to mutations in genes that encode proteins involved in the ras signaling pathway, probably accounting for their phenotypic similarities. Individuals with multiple café-au-lait macules and skin fold freckles but no other NF1-like features may have mutation in another Ras-pathway gene, SPRED1.828 Specific lesions may occur in isolation, such as optic glioma, tibial dysplasia, café-au-lait macules, neurofibroma, schwannoma; in some cases, this may reflect somatic mosaicism for one of the neurofibromatosis gene mutations.

THERAPEUTICS Management of individuals with NF1 or NF2 consists of surveillance for treatable complications, anticipatory guidance, and

820. Messiaen LM, Callens T, Mortier G, et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15:541. 821. Kayes LM, Riccardi VM, Burke W, et al. Large de novo DNA deletion in a patient with sporadic neurofibromatosis 1, mental retardation, and dysmorphism. J Med Genet. 1992;29:686–690. 822. Upadhyaya M, Huson SM, Davies M, et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in Exon 17 of the NF1 gene (c. 2970–2972 delAAT): Evidence of a clinically significant NF1 genotype–phenotype correlation. Am J Hum Genet. 2007;80:140–151. 823. Messiaen L, Riccardi V, Peltonen J, et al. Independent NF1 mutations in two large families with spinal neurofibromatosis. J Med Genet. 2003;40:122. 824. Korf BR, Henson JW, Stemmer-Rachamimov A. Case records of the Massachusetts General Hospital. Case 13–2005. A 48-year-old man with weakness of the limbs and multiple tumors of spinal nerves. N Engl J Med. 2005;352:1800.

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genetic counseling. Tests such as MRI or X-rays should be done for clinical indications; baseline studies are not recommended. Children should be monitored for learning disabilities and cognitive and educational assessments provided as needed. Regular ophthalmological assessment should be performed during the childhood years to ensure early detection of symptomatic optic glioma. Physical examinations should include measurement of height, weight, head circumference, and blood pressure. There is no treatment available to prevent the growth of neurofibromas. Neurofibromas may be removed by plastic surgical or laser treatments. Plexiform neurofibromas usually cannot be removed entirely, but surgical debulking may be indicated to treat symptoms due to mass effect or to improve cosmesis. Symptomatic and progressive optic gliomas are currently treated with chemotherapy. Radiation therapy increases risk of complications such as vascular dysplasia and malignant tumors.829 Malignant peripheral nerve sheath tumors are currently best treated by early detection and surgery. Monitoring of individuals with NF2 is focused on early detection of vestibular schwannomas. This is best accomplished with MRI, although audiology and auditory brainstem evoked response testing may also be helpful. Treatment of vestibular schwannomas is either by surgery or stereotactic radiation; other schwannomas or meningiomas are treated surgically. Auditory brainstem implants may be helpful in partial restoration of hearing.830 Patients with schwannomatosis are generally offered pain management and judicious surgical removal of symptomatic tumors. Treatments that target the dysfunctional cellular pathways are beginning to be tested in clinical trials. These include Ras pathway inhibitors, anti-angio agents, mTOR inhibitors, and statins. Individuals with neurofibromatosis should be provided genetic counseling regarding the 50% recurrence risk. It is not possible to predict severity in the next generation. Genetic testing to identify an underlying mutation may enable prenatal diagnosis. Parents of an apparently sporadically affected child should be examined for signs of neurofibromatosis. If these are not found, their risk of having another affected child is low, based on the rare occurrence of germline mosaicism.

PROGNOSIS The prognosis of neurofibromatosis is variable, depending on severity of involvement, and development of malignancy. Cosmetic disfigurement from cutaneous and plexiform

825. Curto M, McClatchey AI. NF2/Merlin: a coordinator of receptor signalling and intercellular contact. Br J Cancer. 2008;98:256–262. 826. Parry DM, MacCollin MM, Kaiser-Kupfer MI, et al. Germ-line mutations in the neurofibromatosis 2 gene: Correlations with disease severity and retinal abnormalities. Am J Hum Genet. 1996;59:529. 827. Evans DG, Trueman L, Wallace A, et al. Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J MedGenet. 1998;35:450. 828. Brems H, Chmara M, Sahbatou M, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39:1120–1126. 829. Evans DG, Birch JM, Ramsden RT, et al. Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. J Med Genet. 2006;43:289–294. 830. Grayeli AB, Kalamarides M, Bouccara D, et al. Auditory brainstem implant in neurofibromatosis type 2 and non-neurofibromatosis type 2 patients. Otol Neurotol. 2008;29:1140–1146.

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neurofibromas is progressive. A mild course during childhood and adolescence does not guarantee mild disease in adulthood. Life expectancy in individuals with NF1 is reduced, with mortality accounted for mainly by malignancy and vascular events.831 Intracranial tumors may account for early mortality in NF2 patients.832 Schwannomatosis is rarely lifethreatening, but can cause severe, intractable pain.

TUMOR SYNDROMES Susan J. Bayliss

GARDNER SYNDROME Gardner and Stevens in 1950833 initially described the syndrome that now bears Gardner’s name (OMIM 175100). The main features of Gardner syndrome (GS) are premalignant intestinal polyposis, epidermal cysts, osteomas, and desmoid or fibrous tumors of the skin and other organs.834,835 It is allelic to familial adenomatous polyposis which does not have other organ involvement.836

EPIDEMIOLOGY The incidence of GS is approximately 1 in 8300 to 1 in 16 000 births.837 It is inherited as an autosomal dominant trait with complete penetrance and variable expressivity, equally affecting males and females.838

PRESENTING HISTORY Skin lesions and bone abnormalities are often the presenting complaints in early childhood or infancy836 and frequently occur before polyposis develops (usually around 25–35 years). Malignant transformation of the polyps tends not to occur until 15–20 years later, almost always before age 40 years.837 In adults, diagnosis is commonly made when the patient presents with bleeding secondary to adenomatous polyps. Intussusception, which is common in Peutz–Jeghers syndrome, does not occur in GS.839

831. Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet. 2001;68:1110. 832. Baser ME, Friedman JM, Aeschliman D, et al. Predictors of the risk of mortality in neurofibromatosis 2. Am J Hum Genet. 2002;71:715. 833. Gardner EJ, Stevens F. Cancer of the lower digestive tract in one family group. Am J Hum Genet. 1950;2:41–48. 834. Gorlin RJ, Chaudry AP. Multiple osteomatosis, fibromas, lipomas, fibrosarcomas of the skin and mesentry, epidermoid inclusion cysts of the skin, leiomyomas and multiple intestinal polyposis. N Engl J Med. 1960;263:1141–1158. 835. Parks ET, Caldemeyer KS, Mirowski GW. Gardner syndrome. J Am Acad Dermatol. 2001;45(6):940–942. 836. Ballhausen WG. Genetic testing for familial adenomatous polyposis. Ann NY Acad Sci. 2000;910:36–47. 837. Sanchez MA, Zali MR, Khalil AA, et al. Be aware of Gardner’s syndrome. A review of the literature. Am J Gastroenterol. 1979;71:68–73.

Figure 7.92  Epidermal cyst in Gardner syndrome. GARDNER SYNDROME

INTRODUCTION AND HISTORICAL NOTE

PHYSICAL EXAMINATION Epidermal cysts or multiple pilomatricomas of the skin occur in 35% of cases of GS (Fig. 7.92). These are commonly found on the head and neck, may be present at birth, and tend to increase in size and number and then stabilize. Osteomas occur in 79% of patients840,841 and can appear anywhere on the body but have a predilection for the membranous bones of the face and head, especially the mandible and maxilla. Seen in children as young as 8 years, osteomas may be large enough that they are clinically obvious or they may be picked up only by radiographic survey. Other lesions such as exostoses, endostoses, and cortical thickening of long bones may also be seen. Dental anomalies are seen in 18% of patients with GS840,842 and include supernumerary teeth, odontomas, multiple unerupted teeth, and multiple caries. Desmoid tumors are non-encapsulated, non-metastasizing, locally aggressive benign tumors that occur in 3.5–17.3% of patients with GS, with a marked female preponderance (70– 85%).843 They may occur spontaneously or at incision sites, arising from the musculoaponeurotic soft tissues and commonly develop after colectomy. Although benign, desmoid tumors can be invasive and even cause death. Fibromas may occur in the skin, subcutaneous tissues, mesentery, or retroperitoneal areas.844 Sites of Gardner associated fibroma are most commonly the back and paraspinal region in

838. Naylor EW, Lebenthal E. Gardner’s syndrome. Recent developments in research and management. Dig Dis Sci. 1980;25:945–959. 839. Golitz LE. Heritable cutaneous disorders which affect the gastrointestinal tract. Med Clin North Am. 1980;64:829–846. 840. Järvinen HJ, Peltokallio P, Landtman M, et al. Gardner’s stigmas in patients with familial adenomatosis coli. Br J Surg. 1982;69:718–721. 841. Chacon GE, Ugalde CM, Jabero MF. Genetic disorders and bone affecting the craniofacial skeleton. Oral Maxillofac Surg Clin North Am. 2007;19(4):467–474. 842. Woo VL, Abdelsayed R. Oral manifestations of internal malignancy and paraneoplastic syndromes. Dent Clin North Am. 2008;52(1):203–230. 843. Schlemmer M. Desmoid tumors and deep fibromatoses. Hematol Oncol Clin North Am. 2005;19(3):565–571. 844. Michal M. Non-nuchal-type fibroma associated with Gardner’s syndrome. Pathol Res Pract. 2000;196:857–860.

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61% but other areas can be involved.845 Less commonly seen are lipomas, leiomyomas, trichoepitheliomas, neurofibromas, ovarian cysts846 and lymphoid hyperplasia of the terminal ileum. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is seen in some families with GS and can be a predictive sign of GS.847,848 Because it is present at birth, it is easily picked up by ophthalmologic screening.849 Associated findings that may be found with GS include osteochondromas, papillary carcinoma of the thyroid, hepatoblastoma,850 adrenal adenomas,851 skin pigmentation, brain tumors (craniophyringioma, medulloblastoma, glioma)852 and transitional cell carcinoma of the urinary bladder.853

GASTROINTESTINAL LESIONS GASTROINTESTINAL LESIONS

Premalignant adenomatous polyps occur in the colon in 100% but can also be seen in the small intestines and stomach in >50%.846 Polyps are typically less than a centimeter in diameter.854 Polyps are rarely seen before the age of 10 years; however, they have been recorded as early as age 5 years.838 By age 20 years, 50% of patients with GS have demonstrable polyps. Symptoms of polyposis include bleeding and intestinal obstruction. Unlike Peutz–Jeghers polyps, those in GS are adenomatous and have a very high rate of malignancy.

LABORATORY FINDINGS Skeletal radiographic survey is recommended in patients with GS and their family members. Skull and facial bones, especially the mandible, may show osteomas or abnormalities of dentition and lead to the diagnosis in an otherwise asymptomatic patient.

PATHOPHYSIOLOGY AND HISTOGENESIS The gene for GS has been mapped to the adenomatous polyposis coli (APC) gene on chromosome 5q21–22, which is a tumor suppressor gene. It is allelic to the familial adenomatous polyposis gene855,856 and is part of the ras family of proto-oncogenes which disrupts signal transduction functions, leading to uninhibited growth. 845. Coffin CM, Hornick JL, Zhou H, et al. Gardner fibroma: a clinicopathologic and immunohistochemical analysis of 45 patients with 57 fibromas. Am J Surg Pathol. 2007;31:410–416. 846. Berk T, Friedman LS, Goldstein SD, et al. Relapsing acute pancreatitis as the presenting manifestation of an ampullary neoplasm in a patient with familial polyposis coli. Am J Gastroenterol. 1985;80:627–629. 847. Shields JA, Shields CL, Shah PG, et al. Lack of association among typical congenital hypertrophy of the retinal pigment epithelium, adenomatous polyposis and Gardner syndrome. Ophthalmology. 1992;99:1709–1713. 848. Traboulsi EI, Krush AJ, Gardner EJ, et al. Prevalence and importance of pigmented ocular fundus lesions in Gardner’s syndrome. N Engl J Med. 1987;316:661–667. 849. Traboulsi EI. Ocular manifestations of familial adenomatous polyposis (Gardner syndrome). Ophthalmol Clin North Am. 2005;18(1):163–166. 850. Gruner BA, DeNapoli TS, Andrews W, et al. Hepatocellular carcinoma in children associated with Gardner syndrome or familial adenomatous polyposis. J Pediatr Hematol Oncol. 1998;20:274–278. 851. Chelaïfa K, Bouzaïdi K, Chouaïb S, et al. Adrenal adenoma in a patient with Gardner syndrome: a case report. Acta Radiol. 2003;44(2):158–159. 852. Goodin GS, McCarville MB, Thibodeau SN, et al. Prolactinoma as the first manifestation of Gardner’s syndrome. Pediatr Blood Cancer. 2008;50:409–412. 853. Capps WF, Lewis MI, Gazzsaniga DA. Carcinoma of the colon, ampulla of Vater and urinary bladder associated with familial multiple polyposis: A case report. Dis Colon Rectum. 1968;11:298–305.

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Histologically, intestinal polyps show focal adenomatous hyperplasia in the colonic mucosa857 or adenocarcinoma in advanced cases. Epidermal cysts demonstrate the same microscopic changes as common epidermal cysts, with a typical lining of epithelium, and keratinous debris in the center.858 Multiple pilomatricomas have also been seen in GS.859 Gardner associated fibromas demonstrate an over-expression of beta-catenin and other proteins in the APC and Wnt pathways.845 Environmental factors may play a role in the timing of the development of carcinoma in those people who have the genetic defect.838 High dietary fat intake can affect the fecal microflora and ultimately affect the levels of certain fecal bile acids and neutral sterols.860 These changes, in turn, may affect absorption of carcinogens from the gut and promote tumor formation.854

DIFFERENTIAL DIAGNOSIS GS can be distinguished from familial adenomatous polyposis by the cutaneous findings. In Peutz–Jeghers syndrome one sees hyperpigmented spots on the oral mucosa and periorificial areas. Peutz–Jeghers syndrome polyps in the gastrointestinal tract are hamartomatous and not premalignant. Juvenile polyposis and Cowden syndrome have multiple polyps of the hamartomatous variety.

THERAPEUTICS AND PROGNOSIS The National Comprehensive Cancer Network Guidelines (www. nccn.org) keep up-to-date recommendations for surveillance recommendations. Carcinomatous degeneration occurs in 100% of patients with GS and usually begins between ages 20 and 30 years,850 although diagnosis has been made in a 75-year-old patient.861 Malignant changes have been reported as early as age 9 years.862 The incidence of cancer in pre-adolescents with polyposis is approximately 5.3–6.6%. Because of the inevitable carcinoma of the bowel, early prophylactic colectomy is recommended.863 The treatment of choice is colectomy with mucosal proctectomy,

854. Rustigi AK. Hereditary gastrointestinal polyposis and nonpolyposis syndromes. N Engl J Med. 1994;331:1694–1701. 855. Davies DR, Armstrong JG, Thakker N, et al. Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene. Am J Hum Genet. 1995;57:1151–1158. 856. Entius MM, Westerman AM, van Velthuysen MLF, et al. Molecular and phenotypic markers of hamartomatous polyposis syndromes in the gastrointestinal tract. Hepato-Gastroenterol. 1999;46:661–666. 857. Naylor EW, Lebenthal E. Early detection of adenomatous polyposis coli in the Gardner’s syndrome. Pediatrics. 1979;63:222–227. 858. Narisawa Y, Kohda. Cutaneous cysts of Gardner’s syndrome are similar to follicular stem cells. J Cutan Pathol. 1995;22:115–121. 859. Pujol RM, Casanova JM, Egido R, et al. Multiple familial pilomatricomas: a cutaneous marker for Gardner syndrome? Pediatr Dermatol. 1995;12:331–335. 860. Wynder EL, Reddy BS. Metabolic epidemiology of colorectal cancer. Cancer. 1974;34:801–806. 861. Vaynsthein G, Gurlanik L, Markel A. Gardner syndrome in a 75-year old woman. Intern Med. 2008;47(16):1491–1494. 862. Reed TE, Neel JV. A genetic study of multiple polyposis of the colon (with an appendix deriving a method of estimating relative fitness). Am J Hum Genet. 1955;7:236–263. 863. Hampel H, Peltomaki P. Hereditary colorectal cancer: risk assessment and management. Clin Genet. 2000;58:89–97.

Genodermatoses

864. Soave F. Hirschsprung’s disease: A new surgical technique. Arch Dis Child. 1964;39:116–124. 865. Sugihara K, Muto T, Kamiya J, et al. Gardner’s syndrome associated with periampullary carcinoma, duodenal and gastric adenomatosis. Report of a case. Dis Colon Rectum. 1982;25:766–771. 866. Belliveau P, Graham AM. Mesenteric desmoid tumor in Gardner’s syndrome treated by sulindac. Dis Colon Rectum. 1984;27:53–54. 867. Hughes-Fulford M, Boman B. Growth regulation of Gardner’s syndrome colorectal cancer cells by NSAIDS. Adv Exp Med Biol. 1997;407:433–441. 868. Okai T, Yamaguchi Y, Sakai J, et al. Complete regression of colonic adenomas after treatment with sulindac in Gardner’s syndrome: a 4-year follow-up. J Gastroenterol. 2001;36:778–782. 869. Geurs F, Kok TC. Regression of a great abdominal desmoid tumor by interferon alpha. J Clin Gastroenterol. 1993;16:264–265. 870. Anderson DE, Howell JB. Epithelioma adenoides cysticum: genetic update. Br J Dermatol. 1976;95:225–232.

PEDIATRIC ASPECTS OF THE DISEASE Gardner syndrome is a genodermatosis associated with carcinoma of the bowel. Genetic testing for all family members, including children, should be performed as early as possible to detect those members who have the disorder.

BROOKE–SPIEGLER SYNDROME INTRODUCTION AND HISTORICAL NOTE Synonyms: Brooke syndrome, epithelioma adenoides cysticum. In 1892, Brooke reported an entity that he called epithelioma adenoides cysticum,870 which is now called Brooke tumor or trichoepithelioma. In general, trichoepitheliomas may be solitary or multiple. Brooke–Spiegler syndrome is an autosomal dominant disorder consisting of multiple trichoepitheliomas associated with cylindromas, and spiradenomas (OMIM 605041). Other features of the syndrome that are common but not invariably present are eccrine spiradenomas, milia, organoid nevi, and basal cell carcinomas.871,872 In Brooke–Spiegler syndrome, individuals present with skin appendage tumors such as cylindromas, trichoepitheliomas and spiradenomas, whereas familial cylindromatosis (OMIM 132700) has only cylindromas, and multiple familial trichoepitheliomas (OMIM 601606) only have trichoepitheliomas. These disorders are thought to be on a spectrum of a single entity. There is no genotype–phenotype correlation.873,874

BROOKE–SPIEGLER SYNDROME

followed by ileoanal anastomosis in two stages because of the risk of developing recurrence in the rectum if the rectal mucosa is left after simple colectomy.854,864 Periodic (semiannual) proctoscopic examination or radiologic examination of the colon and upper GI tract or both is also recommended for affected people, with surgical excision of suspicious lesions. Naylor and Lebenthal857 followed four children at risk for GS between the ages of 11 2 and 9 years. The youngest patient showed no polyps, but biopsy of ‘normal’ mucosa revealed early adenomatous hyperplasia. They recommended early mucosal biopsies for at-risk children. Endoscopy that includes a thorough view of the duodenum (periampullary area) is also very important because of the high incidence of duodenal cancer. Carcinoma can arise not only in the intestines but also in the stomach, duodenum, and periampullary areas.865 The average age of development of periampullary carcinoma is 48 years, but a patient as young as 18 years has been reported.853 Other malignant tumors, such as papillary carcinoma of the thyroid and hepatoblastomas, should be suspected in symptomatic patients. Desmoid tumors should be surgically excised; however, there tends to be a high recurrence rate. Tumors can involve the mesentery and thus be difficult to remove. Computed tomographic scan or MRI of the abdomen can demonstrate the origin of the tumors and the extent of involvement of the abdominal structures. Desmoid tumors are so rare in the general population and so common in GS that any patient with a desmoid tumor should have his or her colon examined for polyps. If wide surgical excision fails, radiotherapy or chemotherapy or a combination can be employed and has met with variable success. Drugs which affect prostaglandin metabolism, such as non-steroidal antiinflammatory drugs (NSAID), can reduce the risk of colorectal cancer and desmoids by affecting the enzymatic activity of the cyclo-oxygenases (COX) which are responsible for prostaglandin synthesis.866–868 IFN-α has been reported to cause regression of a large desmoid tumor in one patient.869 Genetic counseling for patients is imperative because of the expected risk that half of the offspring will be affected and develop adenocarcinoma of the bowel. Examination of all family members for extracolonic signs of GS may reveal valuable markers for early detection of asymptomatic family members. Genetic testing can indicate which family members are affected.836 Skin lesions can be excised if they are cosmetically or functionally unacceptable.

7

PRESENTING HISTORY Adolescents or children usually present with 1–5 mm multiple skin-colored papules on the face, particularly along the sides of the nose, although these papules can occur anywhere (Fig. 7.93).

PHYSICAL EXAMINATION Trichoepitheliomas are 1–5  mm, skin-colored or white papules with a smooth and sometimes translucent surface and which resemble basal cell carcinomas.871 Lesions on the face tend to be smaller, while those occurring in other sites, particularly the scalp, can reach 2–5  cm in diameter.875 They tend to form confluent plaques of tiny papules, especially along the nasolabial folds. Cylindromas, sometimes called turban tumors, mainly occur in the scalp and behind the ears, more commonly in adults with this syndrome. They are skin-colored or bluish cysts with a

871. Puig L, Nadal C, Fernandez-Figueras MT, et al. Brooke–Spiegler syndrome variant: segregation of tumor types with mixed differentiation in two generations. Am J Dermatolpathol. 1998;20:56–60. 872. Weyers W, Nilles M, Eckert F, et al. Spiradenomas in Brooke–Spiegler syndrome. Am J Dermatolpathol. 1993;15:156–161. 873. Saggar S, Chernoff KA, Lodha S, et al. CYLD mutations in familial skin appendage tumours. J Med Genet. 2008;45:298–302. 874. Bowen S, Gill M, Lee DA, et al. Mutations in the CYLD gene in Brooke–Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype–phenotype correlation. J Invest Dermatol. 2005;124:919–920. 875. Burrows NP, Russell Jones R, et al. The clinicopathological features of familial cylindromas and trichoepitheliomas (Brooke–Spiegler syndrome): a report of two families. Clin Exp Dermatol. 1992;17:332–336.

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nection to the epidermis.880 The distinction of typical tricho­ epithelioma from basal cell carcinoma is sometimes difficult clinically as well as histologically but can be based on the presence of a fibrotic (not myxoid) stroma, and on the lack of retraction of the tumor stroma from the parenchyma. Mitotic figures are rare in trichoepitheliomas but common in basal cell carcinoma.

DIFFERENTIAL DIAGNOSIS

BROOKE–SPIEGLER SYNDROME

Figure 7.93  Brooke–Spiegler syndrome, multiple trichoepitheliomas.

smooth surface covered by telangiectasias. They slowly enlarge and can become quite disfiguring.876 Although rare, malignancy has been reported.876,877 A congenital plaque with histological features of both trichoepithelioma and cylindroma has been reported in a patient with Brooke syndrome.878

PATHOPHYSIOLOGY AND HISTOGENESIS The gene for Brooke syndrome has been mapped to chromosome 16q12.1. This gene is allelic to cylindromatosis and mutations have been shown in the CYLD gene, a tumor suppressor gene. Mutations in this single gene, CYLD, suggest that these disorders are a phenotypic variation of a single disorder.879 CYLD is critical for various signaling pathways and is a negative regulator of the NF-κB signal transduction pathway. Inhibition of the gene enhances activation of NF-κB, leading to increased resistance to apoptosis.873 Mutations in the genes that regulate proliferation and differentiation of putative stem cells are located in the bulge region of the follicular unit. This could give rise to different adnexal tumors. Trichoepitheliomas are benign adnexal tumors showing pilar differentiation. However, in contrast to trichofolliculoma, formation of hair shafts is generally not a feature of trichoepithelioma. Microscopically, these tumors are composed of aggregates of basaloid cells within the dermis, without con-

876. Pizinger K, Michal M. Malignant cylindroma in Brooke–Spiegler syndrome. Dermatology. 2000;201:255–257. 877. Young A, Kellermayer R, Szigeti R, et al. CYLD mutations underlie Brooke–Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006;70(3):246–249. 878. Schirren CG, Wörle B, Kind P, et al. A nevoid plaque with histological changes of trichoepithelioma and cylindroma in Brooke–Spiegler syndrome. J Cutan Pathol. 1995;22:563–569. 879. Poblete Guitierrez P, Eggerman T, Holler D, et al. Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages. J Invest

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The solitary form of trichoepithelioma can resemble a basal cell carcinoma, and thus a biopsy is indicated. Multiple trichoepitheliomas with the typical appearance and family history is not a diagnostic problem for a child presenting with symptoms. Eruptive syringomas usually occur in a periorbital distribution, not along the nasolabial folds, as in Brooke–Spiegler syndrome. Multiple trichoepitheliomas may also be part of Rombo syndrome which shows vermiculate atrophoderma, milia, hypotrichosis, basal cell carcinomas and peripheral vasodilatation with cyanosis. Bazex syndrome can also have multiple trichoepitheliomas in addition to follicular atrophoderma and basal cell carcinomas. Basal cell nevus syndrome presents with basal cell carcinomas resembling nevi along with jaw cysts, palmar pits and skeletal anomalies.

THERAPEUTICS AND PROGNOSIS Trichoepitheliomas and cylindromas are benign. Most lesions obtain a size no larger than several millimeters. However, some lesions may slowly enlarge to the point of cosmetic disfigurement usually in adulthood. Individual lesions can be treated by any destructive method such as liquid nitrogen or shave excision.875 They may recur if not completely removed, but may be treated by re-excision or electrodesiccation and curettage. Multiple small lesions can be treated by CO2 laser.881,882 Larger lesions will need to be surgically excised. Salicylates or prostaglandin A has been shown to reverse inhibitory effects of CYLD.883

PEDIATRIC ASPECTS OF THE DISEASE Multiple trichoepitheliomas begin in childhood and continue to increase in number into adulthood. Sometimes the lesions remain stable in number and size but occasionally continue to grow in size and number for years. Early detection and removal can potentially aid in cosmesis.882

Dermatol. 2002;119:527–531. 880. Brooke JD, Fitzpatrick JE, Golitz LE. Papillary mesenchymal bodies: a histological finding useful in differentiating trichoepitheliomas from basal cell carcinomas. J Am Acad Dermatol. 1989;21:523–528. 881. Martins C, Bártolo. Brooke–Spiegler syndrome: treatment of cylindromas with CO2 laser. Dermatol Surg. 2000;26:877–882. 882. Retamar RA, Stengel F, Saadi ME, et al. Brook-Spiegler syndrome-report of four families: treatment with CO2 laser. Int J Dermatol. 2007;46(6):583–586. 883. Brummelkamp TR, Nijman SM, Dirac AM, et al. Loss of cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature. 2003;424:797–801.

Genodermatoses

7

PEUTZ–JEGHERS SYNDROME INTRODUCTION AND HISTORICAL NOTE Peutz–Jeghers syndrome (PJS) (OMIM 175200) is characterized by gastrointestinal polyps and periorificial pigmentation.884 There is a very high incidence of both gastrointestinal and other malignancies even though the polyps which arise are hamartomatous (benign) in origin.885,886 In 1896, Hutchinson reported twins with unusual pigmentation of the oral mucosa. One twin died of intussusception, and the other died from carcinoma of the breast. In 1921, Peutz described a family with melanotic spots on the lips and multiple gastrointestinal polyps. Jeghers and colleagues reported the familial pattern and confirmed the association.887

The syndrome is inherited as an autosomal dominant trait, and patients commonly first note the disease in adolescence or adulthood. Males and females are equally affected, and most races and ethnic groups have been affected. Up to 25% of cases are sporadic. The risk of occurrence is approximately 1 in 8300 to 1 in 200 000 live births.

PRESENTING HISTORY The diagnosis of PJS has been made in infancy, although most patients present later.888,889 One-third of patients with PJS begin showing signs during the first decade of life,890 and up to 50– 60% show clinical manifestations before age 20 years. Patients may present with melanosis on the lips or buccal mucosa or with gastrointestinal symptoms. The most common gastrointestinal symptoms in children that lead to the diagnosis are abdominal pain from intussusception (71%), gastrointestinal bleeding (18.5%), anemia (16%), vomiting (6%), and rectal prolapse (7%).891

PHYSICAL EXAMINATION Characteristic pigmentation resembling lentigines is seen in almost all patients, most commonly on the lips (Fig. 7.94), buccal mucosa, and digits, but any mucosal surface can be involved.892 The pigmentation varies widely in size, shape, and color and may fade in adult years. No obvious features distinguish this pigmentation clinically. Lesions are usually 1–12 mm, are regular or irregular in shape, and range in color from brown

884. McGarrity TJ, Kulin HE, Zaino RJ. Peutz–Jeghers syndrome. Am J Gastroenterol. 2000;95:596–604. 885. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology. 2000;119:1447–1453. 886. Giardello FM, Welsh SB, Hamilton ST, et al. Increased risk of cancer in Peutz–Jeghers syndrome. N Engl J Med. 1987;316:1511–1514. 887. Jeghers H, McKusick BA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits. N Engl J Med. 1949;241:993–1005, 1031–1036. 888. Howell J, Pringle K, Kirschner B, et al. Peutz–Jeghers polyps causing colocolic intussusception in infancy. J Pediatr Surg. 1981;16:82–84. 889. Fernandez Seara MJ, Martinez Soto MI, Fernandez Lorenzo JR, et al. Peutz–Jeghers syndrome in a neonate. J Pediatr. 1995;126:965–967. 890. McKitrick JE, Lewis WM, Doane WA, et al. The Peutz–Jeghers syndrome: Report of two cases, one with 30 year follow-up. Arch Surg. 1971;103:57–62.

PEUTZ–JEGHERS SYNDROME

Figure 7.94  Hyperpigmented macules on lips of a child with Peutz–Jeghers

EPIDEMIOLOGY

syndrome. The buccal mucosa, fingerpads and toepads also showed hyperpigmented macules.

to black. Pigmentation can either precede or follow the development of polyps. There is no relationship between either the location and distribution of pigmentation or the severity or location of the polyps. Pigmented oral papillomas have also been described. Gastrointestinal (GI) polyps are characteristically pedunculated, non-neoplastic hamartomas that range from 0.1 to 4  cm. They are typically multiple and are most commonly found in the jejunum (70%) and ileum (36%)891 but have been reported in the stomach (34%), duodenum (27%), and colon (24%). Less commonly, polyps have been found in the nasal passages, bronchi, renal pelvis, ureters,893 bladder, and gallbladder. PJS polyps can give rise to hemorrhage, intussusception, and obstruction early in life.894

LABORATORY FINDINGS Proctoscopic examination, air-contrast barium enema, ultrasound, and radiographs of the GI tract can all be used to demonstrate polyps.895 Upper endoscopy, small bowel follow-through is recommended every 2–3 years starting between ages 10–20 years. From age 25 years, colonoscopy every 2 years is advised. For males, annual testicular examination and ultrasound if clinically suspicious of tumors is advised. For females, every 2 year mammograms starting at age 20 years is recommended plus routine breast examinations.896

891. Tovar JA, Eizaguirre I, Albert A, et al. Peutz–Jeghers in children: Report of two cases and review of the literature. J Pediatr Surg. 1983;18:1–6. 892. Agha FP, Nostrant TT, Cohen AR, et al. Giant hamartoma of the colon: Peutz–Jeghers type. J Clin Gastroenterol. 1985;7:261–265. 893. Sachatello CR, Griffen WO Jr. Hereditary polypoid disease of the gastrointestinal tract: A working classification. Am J Surg. 1975;128:198–203. 894. Mathus-Vliegen EMH, Tytgat GNJ. Peutz–Jeghers syndrome: clinical presentation and new therapeutic strategy. Endoscopy. 1985;17:102–104. 895. Navarro O, Dugougeat F, Kornecki A, et al. The impact of imaging in the management of intussusception owing to pathologic lead points in children. Pediatr Radiol. 2000;30:594–603. 896. Lynch HT, Lynch JF, Lynch PM, et al. Hereditary colorectal cancer syndromes: molecular genetics, genetic counselling, diagnosis and management. Fam Cancer. 2008;7:27–39.

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PATHOPHYSIOLOGY AND HISTOGENESIS

PEUTZ–JEGHERS SYNDROME

PJS is usually caused by mutations in the serine/threonine kinase STK11/LBK1 gene on chromosome 19p13.3 in 52–70% of cases.856,897 STK11 encodes for a multifunctional serine-threonine kinase involved in the transduction of intracellular growth signals and is involved in Wnt signaling. It acts as a tumor suppressor gene and alterations in its activity are involved in tumorigenesis.898 There may be other genetic loci which have similar clinical presentations, as not all families or tumors arising in these patients have this mutation.899,900 Histopathologic examination of the oral pigmentation demonstrates an increase in pigment in the basal cell layer, but not an increase in the numbers of melanocytes. Lesions on the hands, however, demonstrate melanosomes that have accumulated within the dendrites of melanocytes, not within the keratinocytes. This implies a disturbance of melanosome transfer. Giant melanosomes are not seen.901 PJS polyps are hamartomas with mature, non-dividing intestinal epithelial cells organized in arborizing glands surrounded by a delicate, inconspicuous stroma that contains bundles of smooth muscle fibers.856 They are not adenomatous polyps, which commonly give rise to adenocarcinoma.

DIFFERENTIAL DIAGNOSIS It is important to distinguish lentigines seen in PJS from freckles, which are never present at birth, are sun-induced, and never occur on the buccal mucosa.854 LEOPARD syndrome (multiple lentigines syndrome) and Carney complex can be distinguished by other features. Laugier–Hunziker syndrome dermatologically resembles PJS, but even though they may have polyps or gastrointestinal changes, these patients do not have an increased incidence of cancer. Other polyposis syndromes such as Gardner syndrome and Cowden disease are not readily confused with PJS. Juvenile polyposis syndrome demonstrates polyps mainly in the colon and does not have lentigines.

THERAPEUTICS AND PROGNOSIS The National Comprehensive Cancer Network Guidelines (www. nccn.org) keep up-to-date for surveillance recommendations.

897. Nakagawa H, Koyama K, Tanaka T, et al. Localization of the gene responsible for Peutz–Jeghers syndrome within a 6-cM region of chromosomes 19p13. 3. Hum Genet. 1998;102:203–206. 898. Entius MM, Keller JJ, Westerman AM, et al. Molecular genetic alterations in hamartomatous polyps and carcinomas of patients with Peutz–Jeghers syndrome. J Clin Pathol. 2001;54:126–131. 899. Boardman LA, Couch FJ, Burgart LJ, et al. Genetic heterogeneity in Peutz–Jeghers syndrome. Hum Mutat. 2000;16:23–30. 900. Connolly DC, Katabuchi H, Cliby WA, et al. Somatic mutations in the STK11/LKB1 gene are uncommon in rare gynecological tumor types associated with Peutz–Jeghers syndrome. Am J Pathol. 2000;156:339–345. 901. Yamada K, Matsukawa A, Hori Y, et al. Ultrastructural studies on pigmented macules of Peutz–Jeghers syndrome. J Dermatol. 1981;8:367–377. 902. Patterson MJ, Kernen JA. Epithelioid leiomyosarcoma originating in a hamartomatous polyp from a patient with Peutz–Jeghers syndrome. Gastroenterology. 1985;88:1060–1064. 903. Kilic-Okman T, Yardim T, Gucer F, et al. Breast cancer, ovarian gonadoblastoma and cervical cancer in a patient with Peutz–Jeghers syndrome. Arch Gynecol Obstet. 2008;278(1):75–77. 904. Zbuk KM, Eng C. Hamartomatous polyposis syndromes. Nat Clin Prac Gastroenterol Hepatol. 2007;4:492–502.

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PJS is frequently misdiagnosed, leading to major consequences. Repeated surgery can cause intestinal crippling in these patients because of extensive adhesion formation and short-bowel syndrome.894 Endoscopic or surgical removal of large benign lesions may be necessary to prevent hemorrhage and intussusception. It is difficult, however, to differentiate adenomas from hamartomas by either direct visualization or small biopsy specimens. Therefore, complete removal of larger lesions or small-bowel resection may be necessary. Patients with PJS have a 93% chance of developing cancer before age 65 years, especially cancer of the small intestines, stomach, pancreas, esophagus, colon, lung, breast, ovaries, uterus, gallbladder, and bile ducts.885,886,902–904 Adenocarcinoma appears to affect younger individuals (> Basal cell carcinomas >> Palmoplantar pits >> Epithelial cysts >> Milia >> Fibromas >> Lipomas Skeletal

BASAL CELL NEVUS SYNDROME

>> Jaw cysts (mandible, maxilla) >> Sellar bridging >> Vertebral anomalies (scoliosis, spina bifida) >> Rib anomalies (bifid, splayed, synostoses, pectus excavatum) >> Cystic changes (long bones, phalanges) >> Brachymetacarpals >> Frontal bossing >> Defective dentition >> Mandibular prognathism >> Cleft lip or palate >> High arched palate Neurologic

>> Ectopic calcification (falx cerebri, tentorium cerebelli) >> Mental retardation >> Electroencephalographic abnormalities

DIFFERENTIAL DIAGNOSIS Basal cell carcinomas can resemble benign dermal or compound nevi in childhood or even seborrheic keratoses. A high index of suspicion should be raised if other features of the syndrome are present. Biopsy of a lesion would demonstrate a BCC. Although most BCCs in childhood are associated with this or other syndromes such as XP, albinism, Rombo/Bazex syndrome or nevus sebaceus, BCCs have been reported de novo in areas of extensive sunlight exposure.966,967 Multiple epidermal cysts are also seen in Gardner syndrome.

THERAPEUTICS AND PROGNOSIS Genetic counseling is important for BCNS patients and their families because of the autosomal dominant transmission. At-risk family members should have skeletal surveys of the skull,

966. LeSueur BW, Silvis NG, Hansen RC. Basal cell carcinoma in children: report of 3 cases. Arch Dermatol. 2000;136:370–372. 967. Griffin JR, Cohen PR, Tschen JA, et al. Basal cell carcinoma in childhood: case report and literature review. J Am Acad Dermatol. 2007;57(5):S97–S102. 968. Tokar IP, Fraser MC, Bale SJ. Genodermatoses with profound malignant potential. Semin Oncol Nursing. 1992;8:272–280. 969. Mitropoulos P, Norman R. Nevoid basal cell carcinoma syndrome (Gorlin syndrome): updated review of minimally invasive treatments. Cutis. 2008;81(1):53–60.

498

>> Medulloblastoma >> Congenital hydrocephalus >> Agenesis of corpus callosum Ophthalmologic

>> Hypertelorism >> Dystopia canthorum >> Strabismus >> Congenital blindness >> Cataract >> Coloboma >> Microphthalmia Gonads

>> Ovarian fibromas >> Hypogonadism (male) >> Adenocarcinoma of the ovary Miscellaneous

>> Cardiac fibroma >> Fibrosarcoma of the jaw >> Squamous cell carcinoma of the jaw >> Lymphomesenteric cysts >> Enterogenous cysts (bowel)

mandible, maxilla, ribs, vertebrae, or hands, which may be helpful in identifying affected members, particularly children, before typical BCCs are obvious. In general, the life span of a patient with BCNS is the same as in the normal population but depends on the location and invasiveness of BCCs and other tumors. Dental radiographs should be performed yearly starting at age 8 years928,944,968 and cysts should be removed by an experienced surgeon. Neurologic screenings, including magnetic resonance imaging of the head, may be performed if warranted clinically. Patients should use preventive measures such as sun avoidance and sunscreens as well as regular dermatological examinations. Early BCCs should be surgically removed if growing.969 Microscopically controlled surgery is the treatment of choice for larger invasive lesions.970,971 General anesthesia may be necessary to remove numerous lesions at one time, especially in children.

970. Mohs FE, Jones DL, Koranda FC. Microscopically controlled surgery for carcinomas in patients with nevoid basal cell carcinoma syndrome. Arch Dermatol. 1980;116:777–779. 971. Krunic AL, Viehman GE, Madani S, et al. Microscopically controlled surgical excision combined with ultrapulse CO2 vaporization in the management of a patient with the nevoid basal cell carcinoma syndrome. J Dermatol. 1998;25:10–12.

Genodermatoses

PEDIATRIC ASPECTS OF THE DISEASE Basal cell nevus syndrome is a genodermatosis that has a highly variable course. Some family members have minimal disease, whereas others have a highly malignant presentation. It is important to pick up this disease in childhood in order to prevent skin cancers and potentially diagnose medulloblastoma early.

COWDEN SYNDROME (MULTIPLE HAMARTOMA SYNDROME)

breast, thyroid, and gastrointestinal tract.983 They named the disorder ‘Cowden disease’ after their first patient. Cowden syndrome (CS) (OMIM 158350) is a rare genetic disorder caused by a germline mutation in the PTEN gene and consists of multiple hamartomatous tumors of ectodermal, mesodermal, and endodermal origin. Mucocutaneous lesions (trichilemmomas, acral keratoses and oral papillomas) are the most constant and characteristic feature.983,984 Breast lesions including cancer and thyroid abnormalities occur in two-thirds of patients.985 Because the spectrum of abnormalities associated with PTEN mutations is broad, some authors use the term PTEN hamartoma tumor syndrome.986

EPIDEMIOLOGY CS is probably more common than is reported because the clinical findings may be very subtle. It is inherited as an autosomal dominant trait with variable expressivity with a strong predominance of female patients.987 Most of the patients have been Caucasian988 and it affects 1 in 300 000 individuals908 but is likely underdiagnosed.

PRESENTING HISTORY The International Cowden Syndrome Consortium has developed diagnostic criteria (Box 7.9).985 In childhood, macrocephaly is usually the presenting sign.989

PHYSICAL EXAMINATION

Lloyd and Dennis reported in 1963 a multisystem disorder with characteristic mucocutaneous lesions and abnormalities of the

Skin lesions are present in 90% of cases.983 The age of onset of the characteristic mucocutaneous lesions begins in the second to third decades (average 22 years), but can range from 4 to 75 years.983 Frequently presenting before the internal manifestations are the multiple facial trichilemmomas, which are skin-colored or

972. Strange PR, Lang PG Jr. Long-term management of basal cell nevus syndrome with topical tretinoin and 5-fluorouracil. J Am Acad Dermatol. 1992;27:842–845. 973. Tsuji T, Otake N, Nishimura M. Cryosurgery and topical fluorouracil: a treatment method for widespread basal cell epithelioma in basal cell nevus syndrome. J Dermatol. 1993;20:507–513. 974. DiGiovanna JJ. Retinoid chemoprevention in the high-risk patient. J Am Acad Dermatol. 1998;39: S82–S85. 975. Wolf P, Kerl H. Photodynamic therapy with 5-aminolevulinic acid: a promising concept for the treatment of cutaneous tumors. Dermatology. 1995;190:183–185. 976. Karrer S, Szeimies RM, Hohenleutner U, et al. Unilateral localized basaliomatosis: treatment with topical photodynamic therapy after application of 5-aminolevulinic acid. Dermatology. 1995;190:218–222. 977. Tse DT, Kersten RC, Anderson RL. Hematoporphyrin derivative photoradiation therapy in managing nevoid basal-cell carcinoma syndrome: a preliminary report. Arch Ophthalmol. 1984;102:990–994. 978. Kopera D, Cerroni L, Fink-Puches R, et al. Different treatment modalities for the management of a patient with the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol. 1996;34:937–939. 979. Itkin A, Gilchrest BA. Delta-aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome. Dermatol Surg. 2004;30(7):1054–1061.

980. Kagy MK, Amonette R. The use of imiquimod 5% cream for the treatment of superficial basal cell carcinomas in a basal cell nevus syndrome patient. Dermatol Surg. 2000;26:577–578. 981. Ferreres JR, Macaya A, Jucgla A, et al. Hundreds of basal cell carcinomas in a Gorlin–Goltz syndrome patient cured with imiquimod 5% cream. J Eur Acad Dermatol Venereol. 2006;20(7):877–878. 982. Atahan IL, Yildiz F, Özyar E, et al. Basal cell carcinomas developing in a case of medulloblastoma associated with Gorlin’s syndrome. Pediatr Hematol Oncol. 1998;15:187–191. 983. Starink TM. Cowden’s disease: analysis of fourteen new cases. J Am Acad Dermatol. 1984;11:1127–1141. 984. Weary PE, Gorlin RJ, Gentry WC, et al. Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol. 1972;106:682–690. 985. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37:828–830. 986. Vander Velden JJ, Vreeburg M, Smeets EE, et al. Skin abnormalities in individuals with macrocephaly: Cowden disease from a dermatologist’s point of view. Int J Dermatol. 2008;47(Suppl 1):45–48. 987. Starink TM, Van Der Veen JPW, Arwert F, et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet. 1986;29:222–223. 988. Williard W, Borgen P, Bol R, et al. Cowden’s disease, a case report with analyses at the molecular level. Cancer. 1992;69:2969–2974. 989. Hanssen AMN, Fryns JP. Cowden syndrome. J Med Genet. 1995;32:117–119.

INTRODUCTION AND HISTORICAL NOTE

COWDEN SYNDROME (MULTIPLE HAMARTOMA SYNDROME)

Particularly for midface or periorbital BCCS, early detection and treatment are imperative in order to avoid local destruction, metastasis, and even death from invasion of vital structures and hemorrhage. Topical 5-fluorouracil 5% with tretinoin 0.1% cream has been used successfully to treat BCCs,972 but suppression of BCCs requires long-term treatment and BCCs recur within 6 months of stopping treatment. Topical 5-fluorouracil can be combined with cryotherapy for elimination of small lesions.973 Prophylactic isotretinoin may help to prevent early BCCs but pregnancy prevention is imperative in women of childbearing age.974 Photodynamic therapy has been used with some success.975 A photodynamically active dye (5-aminolevulinic) is preferentially retained by malignant tissues and initiates a cytotoxic reaction when exposed to red or blue light.976–979 Imiquimod 5% has been successful in treating superficial BCCs;980,981 however, the degree of inflammatory response may affect the tolerability and compliance of the patient. Children with medulloblastoma and BCNS should not receive radiation as a treatment for the medulloblastoma, as it can predispose to multiple BCCs in the site of irradiation.982

7

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BOX 7.9 INTERNATIONAL COWDEN SYNDROME CONSORTIUM OPERATIONAL CRITERIA, 2000985

Pathognomonic criteria

>> Mucocutaneous lesions >> Trichilemmomas, facial >> Acral keratoses >> Papillomatous lesions >> Mucosal lesions Major criteria

COWDEN SYNDROME (MULTIPLE HAMARTOMA SYNDROME)

>> Breast cancer >> Thyroid cancer (non-medullary) especially follicular type >> Macrocephaly >> Lhermitte–Duclos disease (LDD) >> Endometrial carcinoma Minor criteria

>> Other thyroid lesions (e.g., goiter, adenoma) >> Mental retardation >> GI hamartomas >> Fibrocystic disease of the breast >> Lipomas >> Fibromas >> GU tumors (e.g., uterine fibroids, renal cell carcinoma) or malformation

Operational diagnosis in an individual

>> Mucocutaneous lesions alone if there are: >> ≥6 facial papules, of which ≥3 must be trichilemmoma, or >> cutaneous facial papules and oral mucosal papillomatosis, or >> oral mucosal papillomatosis and acral keratoses, or >> ≥6 palmoplantar keratoses >> Two major criteria but one must include macrocephaly or LDD >> One major and three minor criteria >> Four minor criteria Operational diagnosis in a family where one individual is diagnostic for CS

>> Pathognomonic criteria >> Any one major criterion, six minor criteria >> Two minor criteria

990. Takenoshita Y, Kubo S, Takeuchi T, et al. Oral and facial lesions in Cowden’s disease: report of two cases and a review of the literature. J Oral Maxillofac Surg. 1993;51:682–687. 991. Salem OS, Steck WD. Cowden’s disease (multiple hamartoma and neoplasia syndrome). J Am Acad Dermatol. 1983;8:686–696. 992. Wade TR, Kopf AW. Cowden’s disease: A case report and review of the literature. J Dermatol Surg Oncol. 1978;4:459–464. 993. Metcalf JS, Maize JC, LeBoit PE. Circumscribed storiform collagenoma (sclerosing fibroma). Am J Dermatopathol. 1991;13:122–129. 994. Wheeland RG, McGillis ST. Cowden’s disease – treatment of cutaneous lesions using carbon dioxide laser vaporization: a comparison of conventional and superpulsed techniques. J Dermatol Surg Oncol. 1989;15:1055–1059. 995. Requena L, Guiterrez J, Yus ES. Multiple sclerotic fibromas of the skin, a cutaneous marker of Cowden’s disease. J Cutan Pathol. 1991;19:346–351. 996. Barax CN, Lebwohl M, Phelps RG. Multiple hamartoma syndrome. J Am Acad Dermatol. 1987;17:342–346.

500

yellowish-tan verrucous papules resembling verrucae.990–992 Other non-specific cutaneous papules, commonly seen in CS, show a predilection for the face and distal extremities and may be so numerous that they coalesce around facial orifices and ears. Multiple sclerotic fibromas of the skin have been reported by some authors to be another specific cutaneous marker of this entity.993–995 These are sharply circumscribed dermal papules with a strikingly uniform storiform pattern staining on histology. Palmoplantar lesions, present in more than half of the patients,983 resemble punctate keratoses with central depressions.992 In addition, keratotic skin-colored papules can be seen on the posterior aspect of the heels, the dorsa of the hands and feet, as well as the extensor surfaces of the forearms and lower legs.983 Other cutaneous lesions seen with regularity in CS include lipomas, angiolipomas, hemangiomas,996 and multiple skin tags. Oral lesions are 1–3 mm skin-colored papules. Occasionally, lesions cover extensive areas of the oral cavity, including the tongue,997 and can assume a cobblestone appearance.992 The most frequently reported extracutaneous manifestation is thyroid disease, occurring in approximately two-thirds of patients.983 Patients usually present with an enlarged thyroid. Thyroid disease can manifest as goiter (45%), benign adenomas, fetal adenomas, thyroglossal duct cysts, and follicular adenocarcinoma.983 There is a risk for thyroid carcinoma. Fibrocystic disease of the breast and fibroadenomas occur in 76% of female patients. Ductal papillomas and virginal hypertrophy may also be seen.983 Carcinoma of the breast is the most serious consequence of CS, affecting 25–36% of female patients. The onset of breast cancer occurs at the same age as patients without CS.983,998 Preceding fibrocystic disease or fibroadenomas are often reported in those patients who develop breast carcinoma.999 Breast cancer has also been reported in male patients.1000 Multiple hamartomatous polyps are seen in 60% of patients and may be found anywhere in the gastrointestinal tract including the esophagus, stomach, duodenum, small bowel, colon and anus.1001 They may involve the entire GI tract,1002 but are most common in the colon and usually Dark pigmentation of axillary skin >> Ochronotic discoloration through thin areas of skin overlying pigmented cartilage and tendon

Skeleton

>> Osteoarthritis >> Black ochronotic pigmentation of cartilage Eyes

>> Ochronotic discoloration of sclera, cornea, conjunctiva, tarsus and eyelid skin

Genitourinary tract

>> Cortically pigmented renal stones >> Prostatic calculi >> Renal failure Ears and upper respiratory tract

>> Dark brown-to-black staining of cerumen >> Bluish discoloration of auricular cartilage >> Tinnitus and hearing loss >> Laryngeal and tracheal cartilage ochronosis Other manifestations

>> Cardiovascular involvement >> Dura mater involvement >> Involvement of other organ systems, including breast, lymph nodes, bone marrow, thyroid, nails and teeth

Laboratory

>> Homogentisic acid oxidase deficiency >> Urine turns dark on standing and alkalinization

been found as early as 8–10 years of age and is regularly present in the teenage years. Occasionally, brownish punctiform coloration can be detected in eccrine openings. Pigmentary changes may be confined to sun-exposed areas.1070 A grayish-blue tinge overlying ear cartilage is common in adulthood but is rarely seen before 20 years of age.1071 Ochronotic discoloration of the sclera, cornea, conjunctiva, tarsus and eyelid skin is also rarely seen in childhood but is common in adulthood. Renal disease may increase the risk in affected children.1072 Scleral involvement is noted in most patients. Insidious progression of ochronotic arthropathy, which generally begins in the third and fourth decades, is the most disabling manifestation. Hip, knee and shoulder limitations are early signs, but ochronotic arthropathy

1070. Quaterman MJ, Hall JH, Gourdin FW, et al. Photodistributed hereditary ochronosis. Arch Dermatol. 1992;128:1657–1658. 1071. Gutzmer R, Herbst RA, Kiehl P, et al. Alkaptonuric ochronosis: Report of two affected brothers. J Am Acad Dermatol. 1997;37:305–307. 1072. O’Brien WM, La Du BN, Bunim JJ. Biochemical, pathologic and clinical aspects of alcaptonuria, ochronosis and ochronotic arthropathy. Am J Med. 1963;34:813–838. 1073. Garnica AD, Cerda JJ, Maenard D, et al. Alcaptonuria and sucraseisomaltase deficiency in three offspring of a consanguineous marriage. Acta Vitaminol Enzymol. 1981;3:157–169.

typically involves the spine and larger joints. X-rays show characteristic early calcification of the intervertebral discs and later narrowing of the intervertebral spaces, with eventual disc collapse and progressive loss of height. In three siblings with both alkaptonuria and sucrase–solmatase deficiency, arthralgia was present in childhood.1073 Genitourinary tract complications are more common among men than women, with an increased incidence of renal and prostatic calculi, especially after 50 years but sometimes during teenage years.1074 The high incidence of prostatic calculi is attributed to the more rapid polymerization of homogentisic acid in the presence of alkaline prostatic secretions, with the resultant pigment serving as a nidus for stone formation. Rarely, renal failure occurs in the late stage of disease.1072 Tinnitus, hearing loss and erosion of cartilage have been described, and laryngeal and tracheal cartilage ochronosis may result in hoarseness and dysphagia.1075 Cardiac disease often involves the valves and is associated with calcifications and valvular stenosis.1068 Involvement of other organ systems, including breast, lymph nodes, bone marrow, thyroid and teeth, has been documented by autopsy.1068,1069

ORGANIC ACIDURIAS

BOX 7.10 CLINICAL FEATURES OF OCHRONOSIS

7

Laboratory findings The diagnosis of alkaptonuria is based on the detection of HGA in the urine by gas chromatography-mass spectrometry. The excreted amount of HGA in an affected individual is 1–8 g/24 h.

Pathophysiology and histology Homogentisic acid is an intermediate in the catabolism of the aromatic amino acids phenylalanine and tyrosine. Homogentisic acid oxidase (HGA, homogentisate 1,2-dioxygenase), which cleaves homogentisic acid into its end-product maleylacetocetic acid, normally functions in the liver and kidney; its absence leads to an accumulation of homogentisic acid. As a result, homogentisic acid is excreted in the urine.1076 In patients with alkaptonuria, excess homogentisic acid is oxidized and poly­ merized by homogentisic acid polyphenol oxidase, which catalyzes the oxidation of homogentisic acid into an ochronotic-like pigment; benzoquinoneacetic acid is a known intermediate. The ochronotic pigment accumulates irreversibly within collagen fibers, elastic fibers and macrophages, and may suppress collagen cross-linking.1068 Routine histopathology of affected skin demonstrates ochre or yellow–brown pigment within the dermis. It stains black with methylene blue or cresyl violet.1076 The pigment is seen within elastic fibers and within irregularly shaped degenerated, homogenized and swollen collagen fibers that may display sharp, jagged borders. Fine pigment granules may be seen

1074. Zibolen M, Srsnova K, Srsen S. Increased urolithiasis in patients with alkaptonuria in childhood. Clin Genet. 2000;58:79–80. 1075. Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, et al. The molecular basis of alkaptonuria. Nat Genet. 1996;14:19–24. 1076. Turiansky GW, Levin SW. Bluish patches on the ears and axillae with dark urine: ochronosis and alkaptonuria. Int J Dermatol. 2001;40:333–335.

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within macrophages, free within the dermis, in endothelial cells and in the basement membrane and the secretory cells of eccrine glands. Foreign body giant cells may be seen around the granules.

Differential diagnosis

ORGANIC ACIDURIAS

Other causes of dark urine, such as the porphyrias, hepatobiliary disease, myoglobinuria, hemoglobinuria and hematuria, can be easily eliminated. Many patients with alkaptonuria are unaware that their urine darkens and, unless directly questioned, staining of undergarments is not revealed. Ochronosis due to exogenous agents such as phenol, resorcinol or hydroquinone bleaching creams can be differentiated by the absence of homogentisic acid in the urine.1077

Treatment and prognosis

Websites of interest http://www.

1077. Bory C, Boulieu R, Chantin C, et al. Homogentisic acid determined in biological fluids by HPLC. Clin Chem. 1989;35:321. 1078. Suzuki Y, Oda K, Yoshikawa Y, et al. A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria. J Hum Genet. 1999;44:79–84. 1079. Suwannarat P, O’Brian K, Perry MB, et al. Use of nitisinone in patients with alkaptonuria. Metab Clin Exp. 2005;54:719–728. 1080. Wolff JA, Barshop B, Nyhan WL, et al. Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr Res. 1989;26:140–144. 1081. Lustberg TJ, Schulman JD, Seegmiller JE. Decreased binding of (14) C-homogentisic acid induced by ascorbic acid in connective tissues of rats with experimental alkaptonuria. Nature. 1970;228:770–771. 1082. Mayatepek E, Kallas K, Anninos A, et al. Effects of ascorbic acid and low-protein diet in alkaptonuria. Eur J Pediatr. 1998;157:867–868. 1083. Morava E, Kosztolanyi G, Engelke UF, et al. Reversal of clinical symptoms and radiographic abnormalities with protein restriction and ascorbic acid in alkaptonuria. Ann Clin Biochem. 2003;40:108–111. 1084. Mannoni A, Selvi E, Lorenzini S, et al. Alkaptonuria, ochronosis, and ochronotic arthropathy. Semin Arthritis Rheum. 2004;33:239–248. 1085. Happle R. Acrodermatitis acidaemica – ein kutanes Leitsymptom verschiedener Organoazidämien. Z Hautkr. 2001;76:205. 1086. Happle R. Neurocutaneous diseases. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Dermatology in general medicine. New York: McGraw-Hill; 1999:2131–2148. 1087. Tabanlioglu D, Ersoy-Evans S, Karaduman A. Acrodermatitis enteropathica-like eruption in metabolic disorders: acrodermatitis

508

Introduction and historical note Several metabolic defects, particularly branched-chain aminoacidopathies, may be associated with cutaneous lesions that resemble those of acrodermatitis enteropathica. This resemblance led to the terms acrodermatitis acidemica1085,1086 and acrodermatitis dysametabolica.1087 The branched-chain aminoacidopathies giving rise to acrodermatitis acidemica include methylmalonic acidemia,1088,1089 propionic acidemia, glutaric acidemia, biotinidase deficiency,1090 multiple carboxylase deficiency,1091 and maple syrup urine disease (Table 7.26).1095 In general, patients with acrodermatitis acidemica have severe forms of organic acidemias without enzyme activity.1092 These patients tend to be subjected to severe protein restriction which may exacerbate skin lesions.1093

Epidemiology and genetics

The course of alkaptonuria is slow but irreversible. Life expectancy is normal.1071 Treatment with nitisinone, a blocker of HGA synthesis, is the best option.1078,1079 Protein restriction and administration of large amounts of ascorbic acid (vitamin C) reduce plasma HGA levels and reverse clinical and radiological abnormalities.1080–1083 Antioxidants like vita­ min E or N-acetylcysteine may prevent or delay the accumulation of HGA, but clinical studies are lacking.1084 Management is otherwise supportive, with close observation of development of arthropathy or cardiac and urinary tract involvement. Genetic counseling, pain management with non-steroidal anti-inflammatory agents, and physical therapy to increase the range of motion should accompany regular follow-up visits.1076

http://ghr.nlm.nih.gov/condition=alkaptonuria; alkaptonuria.info/en/home.php.

ACRODERMATITIS ACIDEMICA

Metabolic defects leading to acrodermatitis acidemica are autosomal recessive traits. The frequency of glutaric acidemia may be as high as 1 : 30 000.1096 The incidence of methylmalonic acidemia has been estimated at about 1 : 48 000.1097

Presenting history and clinical manifestation Branched-chain aminoacidopathies are characterized by acral dermatitis, poor feeding, vomiting, hypotonia, lethargy, and dehydration. These disorders may be associated with progressive neurological signs that include dystonic-dyskinetic movements resulting from encephalopathic crises. In methylmalonic acidemia, hyperammonemia and hyperglycinemia are often present. The cutaneous signs of acrodermatitis acidemica develop gradually over several weeks and may be painful and oozing. Clinical features are: (1) superficial scalded skin or superficial desquamation; (2) bilateral and periorificial dermatitis; (3) psoriasiform lesions affecting the trunk and

1088. 1089. 1090. 1091. 1092. 1093. 1094. 1095. 1096. 1097.

dysmetabolica is proposed as a better term. Pediatr Dermatol. 2009;26:150–154. Koopman RJJ, Happle R. Cutaneous manifestations of methylmalonic acidemia. Arch Dermatol Res. 1990;282:272. Howard R, Frieden IJ, Crawford D, et al. Methylmalonic acidemia, cobalamin C type, presenting with cutaneous manifestations. Arch Dermatol. 1997;133:1563. Wastell HJ, Bartlett K, Dale G, Shein A. Biotinidase deficiency: a survey of 10 cases. Arch Dis Child. 1988;63:1244. Williams ML, Packman S, Cowan MJ. Alopecia and periorificial dermatitis in biotin-responsive multiple carboxylase deficiency. J Am Acad Dermatol. 1983;9:97. Bodemer C, De Prost Y, Bachollet B, et al. Cutaneous manifestations of methylmalonic and propionic acidemia: a description based on 38 cases. Br J Dermatol. 1994;131:93. Niiyama S, Koelker S, Hoffmann GF, et al. Acrodermatitis acidemica secondary to malnutrition in glutaric aciduria type 1. Eur J Dermatol. 2001;11:224. Assmann K, Bonsmann G, Werner C, Metze D. Acrodermatitisenteropathica-ähnliche Hautveränderungen bei Ahornsirupkrankheit. Z Hautkr. 2001;76:220. Koch SE, Packman S, Koch TK, Williams MD. Dermatitis in treated maple syrup urine disease. J Am Acad Dermatol. 1993;28:289. Kyllerman M, Steen G. Glutaric aciduria: a common metabolic disorder? Arch Fr Pediatr. 1980;37:279. Coulombe JT, Shih VE, Levy HL. Massachusetts Metabolic Disorders Screening Program: II. Methylmalonic aciduria. Pediatrics. 1981;67:26.

Genodermatoses

7

DISORDER

DEFECTIVE ENZYME

GENE LOCUS

MIM NUMBERS

REFERENCES

Methylmalonic acidemia

Methylmalonyl CoA mutase or its coenzyme adenosylcobalamin

6q21

251000, 251100

Koopman and Happle 19901088

Propionic acidemia

Propionyl CoA carboxylase

3q21–q22, 13q32

232000, 232050, 606054

Bodemer et al. 19941092

Glutaric acidemia I

Glutaryl-CoA dehydrogenase

19p13.2

231670

Niiyama et al. 20011093

Biotinidase deficiency

Biotinidase

3p25

253260

Wastell et al. 19881090

Multiple carboxylase deficiency, biotin responsive

Holocarboxylase synthetase

21q22.1

253270

Williams et al. 19831091

Maple syrup urine disease, types IA and IB

Branched-chain alpha-keto acid dehydrogenase

19q13.1–q13.2, 6p22–p21

248600, 248611

Assmann et al. 2001,1094 Koch et al. 19931095

Maple syrup urine disease, type II

Dihydrolipoamide branched-chain transacylase

1p31

248610

ORGANIC ACIDURIAS

Table 7.26  Metabolic disorders giving rise to acrodermatitis acidemica

Laboratory findings Biotinidase deficiency can routinely be detected by neonatal screening. Acidemias and acidurias can be measured as well.

Pathophysiology and histology

Figure 7.98  Acrodermatitis acidemica in the diaper area.

Histologically, there is pallor of the upper epidermis with para­ keratosis and scattered necrotic keratinocytes. Sometimes subcorneal vesicles surrounded by neutrophils are present above the areas of paleness. A lymphohistiocytic inflammatory infiltrate in the papillary dermis is occasionally present.

Differential diagnosis In addition to acrodermatitis enteropathica, skin lesions may lead to consideration of staphylococcal scalded skin syndrome, chronic mucocutaneous candidiasis, necrolytic migratory erythema and multiple carboxylase deficiency.

Treatment and prognosis

Figure 7.99  Typical facial appearance of acrodermatitis acidemica. (Courtesy of Dr. A. Torrelo.)

the limbs, characterized by sharply demarcated, erythemato­ squamous plaques, sometimes with circinate margins; and (4) alopecia associated with fine, dull and brittle hair.1092 Genotype–phenotype correlations have not been delineated (Figs 7.98, 7.99).

1098. Fenton WA, Gravel RA, Rosenblatt DS. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beandet AL, Sly WS, et al, eds. The Metabolic and molecular basis of inherited disease. 8th ed. New York: McGraw-Hill; 2001:2176.

Methylmalonic acidemia, if responsive, can be treated with vitamin B12. Similarly, biotin-responsive multiple carboxylase deficiency is treated with biotin. In other forms of branchedchain aminoacidopathies, a protein-restricted diet is necessary but difficult to maintain because manifestations of secondary protein deficiency may occur. Metabolic ketoacidosis should be treated by alkali therapy. In propionic acidemia, oral administration of antibiotics may help to reduce propionate production in the gut.1098 In methylmalonic acidemia, tubulointerstitial nephritis with progressive impairment of renal function often occurs, and kidney transplant may be needed in children with end-stage renal disease. Even a low level of enzyme activity in the transplanted kidney may allow normal metabolism of organic acids.1099

1099. Lubrano R, Scoppi P, Barcotti P, et al. Kidney transplantation in a girl with methylmalonic acidemia and end stage renal failure. Pediatr Nephrol. 2001;16:848.

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TRANSPORT DEFECTS: HARTNUP DISORDER Introduction and historical note Hartnup disorder (MIM 234500) is an aminoaciduria which is caused by mutations of the SLC6A19 gene on chromosome 5p15.33, leading to an impairment of the neutral amino acid transport system B0AT1 within the kidneys and small intestine.1100 The disorder was first described in 1956 and is named after that original family.1101

Epidemiology and genetics LYSOSOMAL STORAGE DISEASES

Hartnup disorder is inherited in an autosomal recessive manner and the second most frequent aminoaciduria after phenylketonuria. The overall incidence is 1 in 30 000 newborns in Australia and North America. The disorder occurs in all ethnic groups but most frequently in European Caucasians. Although 18 mutations have been described,1100,1102 the D173N allele is the major disease-causing mutation, present in 42% of all unrelated affected individuals.1103 Cases with the urinary abnormalities and no defect of intestinal transport have been reported.1104

Presenting history and clinical manifestations The characteristic feature is a photosensitive pellagra-like sunburn with blistering, although individuals with Hartnup aminoaciduria are often asymptomatic. Lesions are painful to touch and may cause a burning sensation. A ‘butterfly’ rash on the face is sometimes present. In severe cases, blistering may resemble hydroa vacciniforme. After clearing of the erythema, the skin remains dry, hyperkeratotic and scaly with first a yellowish-brown hyperpigmentation and finally peripheral depigmentation. Neurological features include cerebellar ataxia and emotional instability. Mild to moderate mental retardation or intellectual impairment may likewise be present. Signs tend to cease after childhood with reduced demand of amino acids for protein biosynthesis.

Laboratory findings The diagnosis is established by detecting aminoaciduria of all neutral amino acids but proline. Typically, plasma concentrations of these amino acids are normal, but slightly raised serum levels might correlate with greater severity.

1100. Bröer S. Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology. 2008;23:95–103. 1101. Baron DN, Dent CE, Harris H, et al. Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal aminoaciduria and other bizarre biochemical features. Lancet. 1956;2:421–428. 1102. Azmanov DN, Kowalczuk S, Rodgers H, et al. Further evidence for allelic heterogeneity in Hartnup disorder. Hum Mutat. 2008;29:1217–1221. 1103. Azmanov DN, Rodgers H, Auray-Blais C, et al. Persistence of the common Hartnup disease D173N allele in populations of European origin. Ann Hum Genet. 2007;71:755–761. 1104. Sricantia SG, Venkatachalam PS, Reddy V. Clinical and biochemical features of a case of Hartnup disease. BMJ. 1964;I:228. 1105. Seyhan ME, Selimoglu MA, Ertekin V, et al. Acrodermatitis enteropathicalike eruption in a child with Hartnup disease. Pediatr Dermatol. 2006;3:262–265.

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Pathophysiology and histology Given the wide variety of phenotypes, manifestations may be influenced by dietary intake and intestinal resorption of amino acids, allelic and genetic heterogeneity, and modifier genes. The pellagra-like manifestations result from deficiency of tryptophan, the precursor of niacin. Histopathological findings are non-specific.

Differential diagnosis Given the similarity of clinical symptoms, Hartnup disorder can be misdiagnosed as pellagra (niacin deficiency). Lesions may resemble acrodermatitis enteropathica.1105

Treatment and prognosis Treatment consists of a protein-rich diet and supplementation of nicotinic acid (200–400 mg/day). Oral administration of nicotinamide results in clearing of the rash and sometimes disappearance of the ataxia.

LYSOSOMAL STORAGE DISEASES FABRY DISEASE (ANGIOKERATOMA CORPORIS DIFFUSUM, α-GALACTOSIDASE A DEFICIENCY) Introduction and historical note Fabry disease or Anderson–Fabry disease (MIM 301500) was first described by dermatologists Anderson and Fabry in 1898.1106

Epidemiology and genetics The incidence of Fabry disease is 1 : 117 000 males in Australia and 1 : 42 000 males of the Netherlands.1107,1108 The highest reported incidence is 1 : 3100.1109 This X-linked recessive disorder results from deficient α-galactosidase A (GLA), leading to progressive multi-organ deposition of neutral glycosphingolipids (globotriaosylceramide, GL-3). More than 245 different mutations of the GLA gene, located at Xq21.33–q22, have been identified. Fabry disease may affect both hemizygotes and heterozygotes clinically, although the gene is highly penetrant in the hemizygote.1110 Expressivity in the heterozygote is variable because of random X-inactivation, ranging from totally asymptomatic to the complete expression of the disease. Patients with atypical

1106. Fabry H. An historical overview of Fabry disease. J Inherit Metab Dis. 2001;24(Suppl. 2):3–7. 1107. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–254. 1108. Poorthuis BJHM, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999;105:151–156. 1109. Spada M, Pagliardini S, Yasuda M, et al. High incidence of late-onset Fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79:31–40. 1110. Whybra C, Kampmann C, Willers I, et al. Anderson–Fabry disease: clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis. 2001;24:715–724.

Genodermatoses

Presenting history and clinical manifestations Clinical onset of the disease is variable, usually occurring early in childhood but sometimes delayed until the second or third decade.1113 Symptoms start significantly earlier in males than in females. The first clinical signs are periodic crises of severe pain in the extremities (acroparesthesias), joint pain, fever, appearance of vascular cutaneous lesions (angiokeratomas, typically in a bathing trunk distribution and sometimes on mucosae), scant body hair, hypoacousia, abdominal pain, vomiting, diarrhea, edematous upper eyelids, proteinuria, hypohidrosis and characteristic corneal (cornea verticillata, pathognomonic for the disease) and lenticular opacities. The most common dermatological abnormalities besides angiokeratomas are hypohidrosis, telangiectasias and lymphedema. All cutaneous signs are more often present in men than in the heterozygous women (e. g. only one-third of women will display angiokeratomas). A larger European multicenter Fabry database correlated the presence of angiokeratomas and the severity of systemic manifestations.1114 In adulthood, fever, heat collapse and lymphadenopathy combined with abdominal pain occur. Cardiac or renal involvement with proteinuria can begin in childhood or early adolescence. Life-threatening complications are renal insufficiency, cardiac failure and cerebrovascular events. Lesions can occur singly and may be overlooked, but often occur in groups and cover a large body area. Predilection sites are the thighs, buttocks, groin/genital area and lower abdomen. Telangiectases of the labial, buccal, and/or unattached alveolar mucosa and soft palate are seen in 77% of the cases.1115 Cysts/ pseudocysts of the maxillary sinuses with maxillary prognathism are also common. Angiokeratomas may also occur on the conjunctivae, airways and gastrointestinal and genitourinary tract. Accumulation of glycosphingolipids in eccrine sweat glands leads to hypohidrosis and heat intolerance. The diagnosis of Fabry disease requires a careful history and clinical examination. Confirmation of the diagnosis requires a biochemical test (males) or ultrastructural investigation or genetic analysis (females). Variants without the characteristic skin lesions have been observed.

Pathophysiology and histology The clinical manifestations of Fabry disease mainly result from progressive deposition of neutral glycosphingolipids in the

1111. Altarescu GM, Goldfarb LG, Park KY, et al. Identification of fifteen novel mutations and genotype-phenotype relationship in Fabry disease. Clin Genet. 2001;60:46–51. 1112. Germain D, Biasotto M, Tosi M, et al. Fluorescence-assisted mismatch analysis (FAMA) for exhaustive screening of the alpha-galactosidase A gene and detection of carriers in Fabry disease. Hum Genet. 1996;98:719–726. 1113. Beck M, Ries M. Fabry disease. Clinical manifestations, diagnosis and therapy. OOC Europe Ltd; 2001:1–34.

lysosomes of the vascular endothelium, although perithelial and smooth muscle cells of blood vessels and renal glomerular and tubular epithelial cells, myocardial cells and neurons of the dorsal root ganglia and autonomic nervous system are also directly affected by the storage of glycosphingolipids.1116 Damage to vascular endothelial cells in the skin leads to swelling and focal increases in pressure. After sufficient damage has accumulated, telangiectases, angiomas and angiokeratomas develop. Angiokeratomas histologically show epidermal hyperproliferation overlying dilated capillary vessels in the papillary dermis. Glycosphingolipids can be stained in frozen sections with lipid soluble dyes or modified periodic acid–Schiff (PAS) stain. Electron microscopy shows typical concentric or lamellar inclusions with alternating light- and dark-staining bands. LYSOSOMAL STORAGE DISEASES

Fabry disease have missense mutations, rather than null mutations, that lead to reduction rather than absence of αgalactosidase A activity.1111 Fluorescence-assisted mismatch analysis (FAMA) screens for carriers in Fabry disease.1112 Prenatal assays of α-galactosidase A activity can be performed by chorionic villi biopsy or amniocentesis.

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Differential diagnosis Angiokeratomas may be mistaken for petechiae, melanocytic nevi or malignant melanoma, verrucae vulgaris, hemangiomas, thrombosed capillary aneurysms and in children for Spitz nevi. Angiokeratomas, particularly solitary, may occur in patients without Fabry disease (Fig. 7.98).1117 Angiokeratoma of Fordyce is most often situated on the scrotum of patients beyond the third decade of life. Typically they are multiple and arranged linearly, parallel to the median raphe of the scrotum. Angio­ keratoma circumscriptum naeviforme is typically present from childhood as a large, mostly linear and unilateral hyperkeratotic plaque, composed of confluent keratotic papules. Angio­keratoma of Mibelli typically appears in young women on the dorsa of fingers and toes as multiple dark red papules with a slightly verrucous surface and each measuring about 3–5 mm in diameter. In most cases the lesion is preceded by a long history of recurrent perniosis and acrocyanosis. Angiokeratomas not uncommonly occur in patients with vascular malformation, especially nevus flammeus. Angiokeratomas have also been described in several other metabolic disorders. The autosomal recessively inherited fucosidosis is caused by a deficiency of α-lfucosidase with accumulation of fucose containing glycosphingolipids, oligo- and polysaccharides. The main signs are neurologic abnormalities and development disorders. Angio­ keratomas tend to be generalized, of earlier onset than in Fabry disease, and are more commonly acral. Progression of the disease is variable and death may occur in preschool years or the dis­ order is slowly progressive with long-term survival. Sialidosis is an inherited storage disease with a primary deficiency of α-neuraminidase with or without accompanying deficiency of β-galactosidase, leading to a cellular accumulation of sialylated oligosaccharides. Angiokeratomas develop very early in infancy and usually the disease is accompanied by multiple organ dysfunction and dysplasias, leading to death before the 2nd year of life. Several cases of angiokeratoma corporis diffusum have been

1114. Orteu CH, Jansen T, Lidove O, et al. Fabry disease and the skin: data from FOS, the Fabry outcome survey. Br J Dermatol. 2007;157:331–337. 1115. Baccaglini L, Schiffmann R, Brennan MT, et al. Oral and craniofacial findings in Fabry’s disease: a report of 13 patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;92:415–419. 1116. MacDermot KD, Holmes A, Miners AH. Anderson–Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38:750–760. 1117. Schiller PI, Itin PH. Angiokeratomas: an update. Dermatology. 1996;193:275–282.

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reported without evidence of lysosomal storage disease, and with normal enzyme activities and no relevant family history. Some of these cases are associated with noncutaneous abnormalities, and some occur in completely healthy individuals; no lysosomal inclusions are found in their endothelial cells. An autosomal dominant form of diffuse angiokeratomas with arteriovenous fistulas, but no evidence of a metabolic disorder, has been described.1118

Treatment and prognosis

LYSOSOMAL STORAGE DISEASES

Enzyme-replacement therapy with two preparations of αgalactosidase A: agalsidase-α (Europe) and agalsidase-β (USA) are available, well tolerated and lead to significant clearance of the accumulated glycosphingolipids. Initiation of treatment before fibrosis or other irreversible damage is most beneficial, but up to 80% of patients can develop anti-GLA antibodies.1119 Gabapentin, carbamazepine or phenytoin treat the neuropathic chronic pain, and antihypertensive drugs slow the progressive renal insufficiency. Angiokeratomas of the skin can be treated with laser.1120 Adenovirus-mediated gene therapy for Fabry disease is promising.

II, VI, Gaucher, and Fabry syndrome, enabling the study of disease characteristics and natural course, effects of therapeutic interventions, and guidelines for testing, monitoring and treatment. The characteristic findings usually develop within the first years of life, although diagnosis as late as 44 years of age has been reported.1121 MPS patients share many clinical characteristics including thickened skin and craniofacial abnormalities resulting in a coarse facial appearance. A broad nose, macroglossia, a short neck and macrocephaly are typical features. A pebbly skin pattern with ivory-white to skin-colored papules and nodules especially on the back is a diagnostic clue for MPS I and II. Histology from these lesions shows extracellular mucopolysaccharides within the lower reticular dermis. Staining with Alcian blue, colloidal iron or Giemsa shows metachromatic granules in fibroblasts. Hypertrichosis may also occur. Synophrys is typical for MPS III, Sanfilippo syndrome. Other common clinical manifestations are organomegaly, skeletal abnormalities such as dysostosis multiplex, impaired joint mobility, impaired hearing and vision, and variable degrees of mental retardation (especially severe with MPS I, II, III and VII). All MPS types need to be confirmed by enzymatic testing since urinary measurement of glycosaminoglycans may yield unreliable results.

Website of interest www.ninds.nih.gov/disorders/fabrys/fabrys.htm.

Mucopolysaccharidosis type I: Hurler syndrome Introduction and historical note

MUCOPOLYSACCHARIDOSES General introduction and historical note The mucopolysaccharidoses (MPS) were first described by Hunter in 1917 and labeled as gargoylism in 1936. The mucopolysaccharidoses are a group of heritable disorders caused by deficiency of lysosomal enzymes needed to degrade glycosaminoglycans (Table 7.27). The undegraded or partially degraded glycosaminoglycans are stored in lysosomes of tissues and organs, causing pathology, and/or excreted in urine. There are at least seven biochemically differentiated forms of mucopolysaccharidosis with variable subtypes caused by 11 different known enzyme deficiencies. All forms are autosomal recessive, except Hunter syndrome which is an X-linked recessive trait.

Incidence In the Netherlands, the incidence for mucopolysaccharidoses is 4.5 : 100 000 live births. The global crude cumulative rate for all types of mucopolysaccharidoses is approximately 1 : 25 000. Sanfilippo syndrome (mucopolysaccharidosis III A–D) represents the most common form,1118 whereas other types are quite rare. For example, only 40 cases of Sly syndrome (mucopolysaccharidosis VII) have been described. International registries have been created for rare lysosomal storage disorders such as MPS I,

1118. Calzavara-Pinton P, Colombi M, Carlino A, et al. Angiokeratoma corporis diffusum and arteriovenous fistulas with dominant transmission in the absence of metabolic disorders. Arch Dermatol. 1995;131:57–62. 1119. Zarate YA, Hopkin RJ. Fabry’s disease. Lancet. 2008;372:1427–1435.

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Mucopolysaccharidosis type I (MIM 252800) is a lysosomal storage disorder attributable to a deficiency of the lysosomal enzyme α-L-iduronidase (IDUA) and leading to an inability to degrade dermatan sulfate and heparan sulfate. Historically, MPS I was subdivided into three forms, Hurler (severe), Hurler– Scheie (intermediate) and Scheie (mild) syndromes, but the continuous clinical and biochemical spectrum of severity has terminated the subdivision.

Epidemiology and genetics The incidence of MPS I is reported to be 1 : 100 000 without ethnic or sexual predilection. A total of 50–80% of cases belong to the severe form. MPS I follows an autosomal recessive mode of inheritance. The responsible gene has been located on chromosome 4p16.3 and >100 different disease-causing mutations have been identified.

Presenting history and clinical manifestation MPS I is a progressive multiorgan disorder with accumulation of dermatan sulfate and heparan sulfate in cartilaginous structures such as joints, heart valves and other tissues. If untreated, the neuronopathic variant leads to death within the first ten years. The milder non-neuronopathic forms have a later onset of symptoms, a close to normal or normal mental development and an overall lower risk of complications. The most

1120. Sommer S, Merchant WJ, Sheehan-Dare RA. Severe predominantly acral variant of angiokeratoma of Mibelli: response to long-pulse Nd: YAG (1064 nm) laser treatment. J Am Acad Dermatol. 2001;45:764–766. 1121. Gösele S, Dithmar S, Holz FG, Völcker HE. Spätdiagnose eines Morquio-Syndroms. Klinisch-histopathologische Befunde einer seltenen Mukopolysaccharidose. Klin Mbl Augenheilk. 2000;217:114–117.

Genodermatoses

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NUMBER/SYNDROME

ENZYME/BIOCHEMICAL/ GENE LOCUS

CLINICAL HALLMARKS

MPS I/Hurler syndrome

α-l-iduronidase, dermatan sulfate and heparan sulfate in the urine; chromosome 4p16.3

Severe retardation, corneal clouding, hepatosplenomegaly, chondro-dystrophy, dwarfism, inguinal and umbilical hernia, upper respiratory tract infections, hearing loss, heart disease, hydrocephalus

MPS I/Huler–Scheie syndrome

α-l-iduronidase, dermatan sulfate and heparan sulfate in the urine; chromosome 4p16.3

Joint stiffness, micrognathism, hearing loss, corneal clouding, less marked mental retardation

MPS I/Scheie syndrome

α-l-iduronidase, dermatan sulfate and heparan sulfate in the urine; chromosome 4p16.3

Joint stiffness, hearing loss, corneal clouding, less marked or no mental retardation and short stature, excessive body hair, retinitis pigmentosa

MPS IIA/severe Hunter syndrome

Iduronate sulfatase, dermatan sulfate and heparan sulfate in the urine; chromosome Xq28

Skin papules, hernia, hepatosplenomegaly, short stature, mental retardation, hearing loss, dysostosis multiplex, retinal degeneration, hydrocephalus but no corneal clouding

MPS IIB/mild Hunter syndrome

Iduronate sulfatase, dermatan sulfate and heparan sulfate in the urine; chromosome Xq28

Skin papules, hearing loss, joint stiffness, heart disease and mild corneal clouding and no mental retardation

MPS III/Sanfilippo syndrome A-D

Heparan-N-sulfatase (A), N-acetyl-alfa-dglucosaminidase (B), Acetyl CoA: alfaglucosaminide-N-acetyl transferase (C), N-acetyl-alfa-d-glucosaminide 6-sulfatase (D) Heparan sulfate may be missed due to small amounts; chromosome 17q25.3 (A) 17q21 (B) 14 (C) 12q14 (D)

Mental retardation, sometimes aggressive behavior, mild hepatosplenomegaly, coarse hair, mild dysostosis multiplex, synophrys as a characteristic feature

MPS IV A/B/Morquio syndrome A-B

Galactosamine 6-sulfate sulfatase (A), betagalactosidase (B), keratan sulfate in urine; chromosome 16q24.3 (A)

Normal intelligence, dwarfism, skeletal abnormalities, corneal clouding

MPS VI/Maroteaux– Lamy syndrome

Arylsulfatase B, dermatan sulfate in the urine; chromosome 5q11–q13

Marked impairment of vision by corneal clouding, upper respiratory infections, heart disease, hepatosplenomegaly, hearing impairment, dwarfism, hernia, contractures and osseus abnormalities, normal intellect

MPS VII/Sly syndrome

Beta-glucuronidase, dermatan and heparan sulfate in the urine; chromosome 7q21.11

Hernias, hepatosplenomegaly, orthopedic abnormalities, short stature, upper respiratory infections, mental retardation, hydrocephalus, hearing loss, heart disease, corneal clouding

prominent clinical findings in the first 6–12 months of life are facial dysmorphism (coarse face), thickened lips and enlarged tongue, persistent rhinitis and upper respiratory tract infections, obstructive sleep apnea, organomegaly, recurrent inguinal and umbilical hernias and some degree of thoracolumbar kyphoscoliosis. Short stature, cardiovascular and pulmonary failure, impaired vision with photophobia, corneal clouding and retinal degeneration, hearing impairment, musculoskeletal deficiencies, progressive psychomotor and mental retardation ensue with increasing age. The skin is often thickened, inelastic and hyperpigmented in exposed areas. Hypertrichosis is often prominent and extensive Mongolian spots have been described in Hurler disease,1122 as well as in GM1 gangliosidosis. Gingival hypertrophy and dental abnormalities are common.

1122. Rybojad M, Moraillon I, de Baulny O, et al. Extensive Mongolian spot related to Hurler disease. Ann Dermatol Venereol. 1999;126:35–37. 1123. Muenzer J, Wraith JE, Clarke LA, et al. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123:19–29.

LYSOSOMAL STORAGE DISEASES

Table 7.27  Mucopolysaccharidoses

Laboratory findings Diagnosis of MPS I is confirmed by decreased or absent IDUA enzyme activity in blood leukocytes, fibroblasts or filter paper blood spots and by genetic mutation analysis.

Differential diagnosis Besides symptomatic treatment, there are two recognized effective treatments for MPS I: enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).1123 ERT is commercially available as laronidase, a recombinant form of IDUA, and leads to significant improvement for patients with milder forms of MPS I.1124 The main limitation is failure of the circulating enzyme to cross the blood–brain barrier, limiting its effect on neurologic signs. Only patients started

1124. Clarke LA, Wraith JE, Beck M, et al. Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I. Pediatrics. 2009;123:229–240.

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LYSOSOMAL STORAGE DISEASES

at Pigmentary mosaicism (including formerly called

‘hypomelanosis of Ito’ and phylloid hypomelanosis)

>> Keratinocytic epidermal nevus syndrome (including from FGFR3 mutation)

>> Schimmelpenning syndrome >> Nevus comedonicus syndrome >> McCune–Albright syndrome >> Proteus syndrome >> Maffucci syndrome >> Encephalocraniocutaneous lipomatosis >> Delleman syndrome >> Sturge–Weber–Klippel–Trenaunay syndrome >> Cutis marmorata telangiectatica congenita >> Giant congenital melanocytic nevus

A

Type 1 and type 2 mosaicism of non-lethal autosomal mutations

B

C

GENETIC MECHANISMS GIVING RISE TO MOSAICISM

life.1264 Lethal autosomal recessive mutations may manifest as mosaicism in a healthy heterozygous carrier who develops localized loss of heterozygosity1267 because of a second hit mutation or loss of the normal allele during embryo development. This situation could theoretically explain ‘paradominant’ inheritance, in which a mosaic phenotype that usually occurs sporadically may affect more than one family member.1267,1268 This mechanism has been proposed to explain inheritance of vascular malformation syndromes (Klippel–Trenaunay syndrome, Sturge–Weber syndrome and cutis marmorata telangiectatica congenita) and certain syndromes involving melanocytes (Becker’s nevus and speckled nevus syndromes). Chromosomal mosaicism can be considered a variant of mosaicism of lethal autosomal mutations. In this case, a chromosome fails to divide normally, usually because of nondisjunction, leading to severe chromosomal anomalies such as aneuploidy or trisomy, which can only ‘survive’ by mosaicism. This mechanism underlies many of the hypo- and hyperpigmented forms of mosaicism that are associated with severe CNS and eye anomalies (including the disorder formerly named ‘hypomelanosis of Ito’).1269,1270 Examples of lethal autosomal disorders presumably surviving by mosaicism are shown in Box 7.11. Genetic mosaicism in boys can occasionally involve a gene on the X-chromosome, leading to a milder phenotype. For example, incontinentia pigmenti is generally lethal in affected boys, but mosaicism of the gene mutation may lead to a milder phenotype in a boy, which may show a limited distribution.

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D

Figure 7.106  Two different types of segmental involvement as observed in autosomal dominant skin disorders. (A) healthy embryo; (B) heterozygous embryo; (C) type 1 segmental involvement reflecting heterozygosity; (D) type 2 segmental involvement reflecting loss of heterozygosity in a heterozygous embryo.

Many autosomal dominant generalized skin disorders have been described in a mosaic arrangement affecting one or several patterned areas of the skin, mainly as Blaschko lines or blocks. Two different types of mosaic involvement of non-lethal autosomal dominant mutations have been described (Fig. 7.106).1271 In type 1, as discussed above, a mosaic form of the disease originates from a post-zygotic new mutation. In the case of monogenic dominant diseases, a mosaic disorder may have a generalized counterpart, as was first demonstrated on a molecular level in epidermolytic ichthyosis and its Blaschko linear mosaic counterpart, the epidermolytic form of epidermal nevus.1258 A mosaic manifestation of Apert syndrome has been described as acne in a linear arrangement involving the upper arm, resulting from mutations on fibroblast growth factor receptor 2 (FGFR2).1272 Segmental neurofibromatosis is another example of type 1 mosaicism of an autosomal dominant disorder, and usually presents as blocks of skin with café-au-lait spots and sometimes lentigines and underlying hyperpigmentation; NF-1 gene mutations have been described in the areas of affected

skin, but not in blood.1273 A list of examples of non-lethal autosomal mosaicism is shown in Box 7.12. In mosaic forms of both NF-1 and epidermolytic hyperkeratosis, a parent with segmental (mosaic) manifestations may have one or more offspring with generalized disease if gonadal tissue is affected (gonosomic or gonadosomal mosaicism).1270 Gonadal mosaicism without an expressed somatic component explains the recurrence among siblings of an autosomal dominant disorder from apparently unaffected parents.1270 In type 2 mosaicism, a heterozygous embryo affected by the generalized form of an autosomal dominant disease has a mosaic area of the skin far more severely affected by the disease, superimposed on the ordinary nonsegmental trait. Loss of heterozygosity, resulting in either homozygosity or hemizygosity for the underlying mutation, is the cause of this type 2 mosaicism,

1267. Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol. 1999;41:143. 1268. Happle R, König A. Familial naevus sebaceus may be explained by paradominant transmission. Br J Dermatol. 1999;141:350. 1269. Sybert VP. Hypomelanosis of Ito: a description, not a diagnosis. J Invest Dermatol. 1994;103(5 Suppl):141S–143S. 1270. Siegel DH, Sybert VP. Mosaicism in genetic skin disorders. Pediatr Dermatol. 2006;23:87–92.

1271. Happle R. A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity. Arch Dermatol. 1997;133:1509. 1272. Munro CS, Wilkie AOM. Epidermal mosaicism producing localised acne: somatic mutation in FGFR2. Lancet. 1998;352:704. 1273. Consoli C, Moss C, Green S, et al. Gonosomal mosaicism for a nonsense mutation (R1947X) in the NF1 gene in segmental neurofibromatosis type 1. J Invest Dermatol. 2005;125:463–466.

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BOX 7.12 EXAMPLES OF TYPE 1 MOSAICISM OF AUTOSOMAL DOMINANT SKIN DISORDERS

>> Neurofibromatosis 1 >> Epidermolytic hyperkeratosis of Brocq >> Basal cell nevus syndrome >> Multiple basaloid follicular hamartoma >> Multiple syringoma >> Tuberous sclerosis >> Cutaneous leiomyomatosis >> Classical Ehlers–Danlos syndrome >> Darier disease >> Pachyonychia congenita GENETIC MECHANISMS GIVING RISE TO MOSAICISM

BOX 7.13 EXAMPLES OF TYPE 2 MOSAICISM OF AUTOSOMAL DOMINANT SKIN DISORDERS

Figure 7.107  Linear psoriasis in a young child as a manifestation of mosaicism.

>> Neurofibromatosis 1 >> Tuberous sclerosis >> Cutaneous leiomyomatosis >> Glomangiomatosis >> Buschke–Ollendorff syndrome >> Multiple syringoma >> Multiple trichoepithelioma >> Multiple basaloid follicular hamartoma >> Nonsyndromic hereditary multiple basal cell carcinoma >> Darier disease >> Hailey–Hailey disease >> Epidermolytic ichthyosis >> KID syndrome >> Disseminated superficial actinic porokeratosis >> Autosomal dominant dyskeratosis congenita

which has been genetically demonstrated on a molecular basis in a patient with Hailey–Hailey disease who had a more severely affected Blaschko linear mosaic area, in which loss of heterozygosity resulted from loss of the normal paternal allele (hemizygosity).1274 Other possible examples of type 2 segmental involvement have been found in the literature in at least 15 different autosomal dominant skin disorders (Box 7.13). A strikingly high frequency of this type 2 segmental involvement has been documented in cutaneous leiomyomatosis, glomangiomatosis, and disseminated superficial actinic porokeratosis.1275

1274. Poblete-Gutiérrez P, Wiederholt T, König A, et al. Allelic loss underlies type 2 segmental Hailey–Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest. 2004;114:1467–1474. 1275. Happle R. Segmentale Typ-2-Manifestation autosomal dominanter Hautkrankheiten: Entwicklung eines neuen formalgenetischen Konzeptes. Hautarzt. 2001;52:283.

534

This patient later in life developed generalized psoriasis, implying that linear psoriasis was a superimposed manifestation, with early onset and difficult to treat.

Mosaicism of polygenic inflammatory disorders A number of inflammatory disorders of presumed polygenic inheritance can be seen in a mosaic state of non-lethal mutations. These mosaic disorders primarily tend to show a Blaschko linear distribution.1276 It is supposed that a mutation or loss of heterozygosity during embryonic development in genes which predispose to inflammatory disorders lead to the Blaschkoid mosaic manifestation of disease. Among these are psoriasis, lichen planus, atopic dermatitis, lupus erythematosus, vitiligo, morphea and atrophoderma, and lichen nitidus. Patients with polygenic inflammatory disorders may show patchy areas in a mosaic distribution that are more severely affected and difficult to treat, perhaps owing to a homologous basis such as type 2 mosaicism in monogenic disorders.1277 Some examples are psoriasis vulgaris, lichen planus, systemic lupus erythematosus, pemphigus vulgaris, and vitiligo (Fig. 7.107).

EPIGENETIC MOSAICISM In epigenetic mosaicism, changes in the phenotype or gene expression occur because of modifications (activation or silencing) of certain genes, but not changes in the structure or sequence of the DNA. Epigenetic changes are critical for cellular differentiation, development, evolution and also in many diseases. Transposable elements, particles of retroviral origin that are interspersed in large amounts (as much as 40%) in the human genome, have been hypothesized to play a role in epigenetic mosaicism.1278

1276. Grosshans EM. Acquired Blaschko linear dermatoses. Am J Med Genet. 1999;85:334–337, 22. 1277. Happle R. Superimposed segmental manifestation of polygenic skin disorders. J Am Acad Dermatol. 2007;57:690–699. 1278. Whitelaw E, Martin DIK. Retro transposons as epigenetic mediators of phenotypic variation in mammals. Nat Genet. 2001;27:361.

Genodermatoses

In females, the random inactivation of one of the X-chromosomes during the first weeks of gestation results in the so-called functional mosaicism. Mutations underlying functional mosaicism may be dominant or recessive. If a female XX zygote carries a dominant X-linked mutation, the cells in which the affected allele is inactivated will show no phenotypic anomaly, but cells in which the normal allele is inactivated will show a mosaic pattern of the disease. Male XY zygotes carrying the affected X gene will most probably be severely affected, and perhaps not viable. Thus, in dominant X-linked disorders, largely females are affected and the mutation ‘survives’ by mosaicism; males are very seldom affected, usually in association with a 47XXY genotype or from true mosaicism. The skin lesions resulting from functional X-chromosome mosaicism may follow the lines of Blaschko, but other patterns have also been described, such as the block-like pattern in X-linked hypertrichosis1279 or a lateralization pattern in CHILD syndrome.1280 If a female XX zygote carries a recessive non-lethal X-linked mutation, only the cells in which the normal allele is inactivated will show evidence of disease, with a variable extent based on random inactivation, in contrast to the generalized, more complete phenotypic manifestation in the male XY embryo. A prototypic example is mutations in ectodysplasin in hypohidrotic ectodermal dysplasia. There are certain recessive non-lethal skin disorders, such as X-linked ichthyosis and Wiskott–Aldrich syndrome, in which female carriers show no evidence of disease. With respect to X-linked ichthyosis, the steroid sulfatase gene is localized to a small region of the X-chromosome that escapes random inactivation.1281 In Wiskott–Aldrich syndrome, expression of the mutant allele is selectively disadvantageous to the affected hematopoietic cell, resulting in seemingly non-random inactivation of the mutant allele owing to the growth advantage to cells with activation of the normal allele. Mosaicism resulting from functional inactivation of the X-chromosome is heritable, and requires appropriate genetic counseling. Box 7.14 summarizes the disorders in which functional X-linked mosaicism is operative.

Autosomal epigenetic mosaicism In mice and dogs, transposable elements may give rise to a variegated coat pattern reminiscent of the lines of Blaschko. It is conceivable that these particles may cause similar heritable mosaic lesions in human skin, as has been proposed in the cases of some families with inflammatory linear verrucous epidermal nevus and hypermelanotic or hypomelanotic Blaschko linear mosaicism.1266 So far, a genetic proof of transmittable autosomal epigenetic mosaicism in humans has not been demonstrated.

1279. Happle R. X-chromosome inactivation: role in skin disease expression. Acta Paediatr Suppl. 2006;95:16–23. 1280. Hebert AA, Esterly NB, Holbrook KA, et al. The CHILD syndrome. Arch Dermatol. 1987;123:503–509. 1281. Li XM, Alperin ES, Salido E, et al. Characterization of the promoter region of human steroid sulfatase: a gene which escapes X inactivation. Somat Cell Mol Genet. 1996;22:105–117. 1282. Jonkman MF, Scheffer H, Stulp R, et al. Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell. 1997;88:543. 1283. Darling TN, Yee C, Hintner H, et al. Revertant mosaicism: partial correction of a germ-line mosaicism in COL17A1 by a frame-restoring mutation. J Clin Invest. 1999;103:1371–1377.

BOX 7.14 EXAMPLES OF SKIN DISORDERS OF FUNCTIONAL X-CHROMOSOME MOSAICISM

Male: lethal phenotypes

>> Incontinentia pigmenti >> Focal dermal hypoplasia >> Microphthalmia with linear skin defects (MLS or MIDAS syndrome)

>> Conradi–Hünermann–Happle syndrome >> Oral–facial–digital syndrome, type 1 >> CHILD syndrome Non-lethal phenotypes

>> Hypohidrotic ectodermal dysplasia of Christ–Siemens–Touraine >> Hypohidrotic ectodermal dysplasia with immunodeficiency >> Menkes disease >> Dyskeratosis congenita, X-linked type >> Ichthyosis follicularis with alopecia and photophobia (IFAP)

GENETIC MECHANISMS GIVING RISE TO MOSAICISM

Functional X-chromosome mosaicism

7

syndrome

>> X-linked reticulate pigmentary disorder (Partington syndrome) >> X-linked hypertrichosis

PECULIAR MANIFESTATIONS OF MOSAICISM IN HUMAN SKIN Revertant mosaicism In patients with different autosomal recessive types of epidermolysis bullosa, patches of normal looking skin can be seen. At a molecular level, this ‘natural gene therapy’ is due to a revertant mutation giving rise to a mosaic clone of heterozygous cells that has regained its normal function. This has been the case in patients with generalized atrophic benign epidermolysis bullosa as well as with non-Herlitz junctional EB from LAMB3 mutations.1282–1284 A more recent case involved a patient with recessive epidermolysis bullosa simplex with gene reversion in one allele.1285 In this case, however, the clinical phenotype continued to show blistering because the revertant protein did not function. A variety of molecular genetic mechanisms have been reported to underlie revertant mosaicism, such as true reverse point mutation, second downstream mutations compensating for the frameshift, non-disjunction, crossing-over, gene deletion, gene conversion, and even the action of retrotransposons.1286,1287 In a case of dominant EB simplex Dowling–Meara type, a second mutation upstream of the original causative one led to a premature termination codon, thus eliminating the dominant-negative

1284. Pasmooij AM, Pas HH, Bolling MC, et al. Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3. J Clin Invest. 2007;117:1240–1248. 1285. Schuilenga-Hut PHL, Scheffer H, Pas HH, et al. Partial revertant mosaicism of keratin 14 in a patient with recessive epidermolysis bullosa simplex. J Invest Dermatol. 2002;118:626–630. 1286. Bittar M, Happle R. Revertant mosaicism and retro transposons: another explanation of ‘natural gene therapy’. Am J Med Genet A. 2005;137:222. 1287. Frank J, Happle R. Cutaneous mosaicism: right before our eyes. J Clin Invest. 2007;117:1216–1219.

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Figure 7.109  Type 2 segmental involvement with concomitant segment of absent involvement in the form of allelic didymosis, as observed in autosomal dominant skin disorders.

GENETIC MECHANISMS GIVING RISE TO MOSAICISM

Figure 7.108  Cutis tricolor as allelic twin-spots. See the paired hypo- and hyperpigmented macules against a background of normal pigmentation.

effect of the originally abnormal keratin K14.1288 Second mutations in affected EB genes are very common and revertant mosaicism may occur more often than expected. Revertant mosaicism is well established for several other disorders, among them Fanconi’s anemia and Wiskott–Aldrich syndrome.1289,1290

Twin spotting (didymosis) Twin spots are patches of mutant tissue that differ from each other and from the background tissue; these patches may appear in close apposition (paired), intermingled or in contralateral corresponding areas. Nevoid lesions that are distant from each other should not be considered twin spots.1291 The term didymosis (Greek didymos = twin) was proposed by Happle for the mechanism of twin spotting.1292 Two types of twin spots have been described. In allelic twin spotting, areas of excess and insufficiency of various skin characteristics are paired. Paired macules of hyper- and hypopigmentation are called cutis tricolor (Fig. 7.108), and a neurocutaneous syndrome with many paired macules has been called cutis tricolor parvimaculata.1293 In Proteus syndrome, segmental areas of hypertrophy and hypotrophy may be present.1294,1295 Finally, it is not uncommon to observe areas of hypovascularization intermingled within tel-

1288. Smith FJ, Morley SM, McLean WH. Novel mechanism of revertant mosaicism in Dowling–Meara epidermolysis bullosa simplex. J Invest Dermatol. 2004;122:73–77. 1289. Gross M, Hanenberg H, Lobitz S, et al. Reverse mosaicism in Fanconi anemia: natural gene therapy via molecular self-correction. Cytogenet Genome Res. 2002;98:126–135. 1290. Wada T, Schurman SH, Jagadeesh GJ, et al. Multiple patients with revertant mosaicism in a single Wiskott–Aldrich syndrome family. Blood. 2004;104:1270–1272. 1291. Torrelo A. Non-allelic twin spotting under attack. Eur J Dermatol. 2004;14:75. 1292. Happle R, König A. Didymosis aplasticosebacea: coexistence of aplasia cutis congenita and nevus sebaceus may be explained as a twin spot phenomenon. Dermatology. 2001;202:246.

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angiectatic nevi. Remarkably, in autosomal dominant skin disorders such as Darier disease or epidermolytic hyperkeratosis of Brocq, a type 2 segmental manifestation may occur with a concomitant segment of completely healthy skin in the form of allelic didymosis (Fig. 7.109).1296,1297 Non-allelic twin spotting refers to the presence of two paired patches of mutant tissue with different cellular components. In fact, almost any combination of nevi or nevoid conditions is possible, and there are many examples in the literature of possible non-allelic twin spotting, summarized in Box 7.15. Two paradigmatic examples of nonallelic didymosis are the so-called phacomatosis pigmentovascularis and phacomatosis pigmentokeratotica. Phacomatosis pigmentovascularis (PPV). The combination of vascular anomalies and pigmentary disorders in the form of twin spotting has been termed PPV.1298 In fact, three distinct PPV syndromes have recently been renamed more descriptively phacomatosis cesio-flammea (combination of extensive Mongolian spots and nevus flammeus) (Fig. 7.110), phacomatosis spilorosea (combination of extensive nevus spilus with pale pink telangiectatic nevus) and phacomatosis cesio-marmorata (combination of extensive or intermingled dermal melanocytosis with cutis marmorata telangiectatica congenita).1299 All these syndromes may also have extracutaneous (mainly CNS and ocular) manifestations. Since these syndromes have nothing to do with each other besides the fact that they share a twin spotting phenomenon, and because every combination of nevoid conditions is possible, a distinct common denomination of PPV is of no pathogenetic or clinical significance, and thus the term PPV should be avoided.

1293. Larralde M, Happle R. Cutis tricolor parvimaculata: a distinct neurocutaneous syndrome? Dermatology. 2005;211:149–151. 1294. Happle R, Steijlen PM, Theile U, et al. Patchy dermal hypoplasia as a characteristic feature of Proteus syndrome. Arch Dermatol. 1997;133:77. 1295. Happle R. Lipomatosis and partial lipohypoplasia in Proteus syndrome: a clinical clue for twin spotting? Am J Med Genet. 1995;56:332. 1296. Happle R, König A. Dominant traits may give rise to paired patches of either excessive or absent involvement. Am J Med Genet. 1999;84:176. 1297. Itin PH, Happle R. Darier disease with paired segmental manifestation of either excessive or absent involvement: A further step in the concept of twin spotting. Dermatology. 2002;205:344. 1298. Fernández-Guarino M, Boixeda P, de Las Heras E, et al. Phakomatosis pigmentovascularis: Clinical findings in 15 patients and review of the literature. J Am Acad Dermatol. 2008;58:88–93. 1299. Happle R. Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol. 2005;141:385–388.

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7

BOX 7.15 EXAMPLES OF POSSIBLE TWIN SPOTTING (DIDYMOSIS)

Allelic didymosis

>> Vascular twin nevi >> Cutis tricolor >> Hyperplastic and hypoplastic lesions in Proteus syndrome >> Paired segments of either excessive or absent involvement in epidermolytic ichthyosis

>> Paired segments of either excessive or absent involvement in Darier disease

Non-allelic didymosis

>> Mongolian spot with nevus flammeus (didymosis GENETIC MECHANISMS GIVING RISE TO MOSAICISM

cesio-flammea)

>> Speckled nevus with nevus roseus (didymosis spilo-rosea) >> Mongolian spot with cutis marmorata telangiectatica congenita (didymosis cesio-marmorata)

>> Phacomatosis pigmentokeratotica >> Unilateral nevoid telangiectasia associated with Becker nevus >> Aplasia cutis congenita with sebaceous nevus (didymosis

Figure 7.110  Didymosis cesio-flammea (formerly called phacomatosis pigmentovascularis type II). An ‘aberrant’ Mongolian spot intermingled with extensive blocks of nevus flammeus.

aplasticosebacea)

>> Aplasia cutis congenita with nevus psiloliparus (didymosis aplasticopsilolipara)

>> Melorrheostosis with sebaceous nevus (didymosis melorrheosebacea)

>> Becker nevus with nevus depigmentosus >> Nevoid hypertrichosis and hypomelanosis >> Congenital linear punctate keratoderma and nevus depigmentosus with lentigines

>> Speckled lentiginous nevus with giant congenital melanocytic nevus

>> Segmental lentiginosis with nevus depigmentosus >> Other combinations of nevi

Phacomatosis pigmentokeratotica (PPK). The cutaneous hallmark of PPK is a concurrence of sebaceous nevus and speckled lentiginous nevus (Fig. 7.111).1300 Although it was initially thought that PPK was a distinct phenotype within epidermal nevus syndromes (see below),1301,1302 it is now proposed that PPK is a form of didymosis with a combination of Schimmelpenning epidermal nevus syndrome and the recently described speckled nevus (SN) syndrome.1303,1304 Extracutaneous manifestations in PPK are in fact a combination of the extracutaneous manifestations of both Schimmelpenning and SN syndrome, and include mental retardation, seizures, deafness, ptosis or strabismus (appearing in Schimmelpenning syndrome), and hemiatrophy with muscular 1300. Happle R, Hoffmann R, Restano L, et al. Phacomatosis pigmentokeratotica a melanocytic-epidermal twin nevus syndrome. Am J Med Genet. 1996;65:363. 1301. Tadini G, Restano L, Gonzáles-Pérez R, et al. Phacomatosis pigmentokeratotica: report of new cases and further delineation of the syndrome. Arch Dermatol. 1998;134:333. 1302. Boente C, Pizzi de Parra N, Larralde de Luna M, et al. Phacomatosis pigmentoleratotica: another epidermal nevus syndrome and a distinctive type of twin spotting. Eur J Dermatol. 2000;10:190. 1303. Happle R. Speckled lentiginous nevus syndrome: delineation of a new distinct neurocutaneous phenotype. Eur J Dermatol. 2002;12:133–135.

Figure 7.111  Phacomatosis pigmentokeratotica. Paired extensive Blaschko linear sebaceous nevus and speckled nevus in a block-like pattern. This patient developed several basal cell carcinomas from sebaceous nevus on the trunk.

weakness, segmental dysesthesia, and segmental hyperhidrosis (corresponding to NS syndrome). A remarkable fact in PPK is the increased risk of transformation to malignancy of both the sebaceous and the melanocytic components,1305,1306 in comparison to isolated sebaceous or melanocytic nevi. 1304. Boente Mdel C, Asial RA, Happle R. Phacomatosis pigmentokeratotica: a follow-up report documenting additional cutaneous and extracutaneous anomalies. Pediatr Dermatol. 2008;25:76–80. 1305. Martínez-Menchón T, Mahiques Santos L, Vilata Corell JJ, et al. Phacomatosis pigmentokeratotica: a 20-year follow-up with malignant degeneration of both nevus components. Pediatr Dermatol. 2005;22:44–47. 1306. Tévar E, Torrelo A, Contreras F, et al. Multiple basal cell carcinomas on phacomatosis pigmentokeratotica. Actas Dermosifiliogr. 2006;97:518–521.

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As an explanation for twin spotting, an embryo may be doubly heterozygous in a way that two different mutations involve either of a pair of homologous chromosomes. At an early developmental stage, mitotic recombination may give rise to two daughter cells that are homozygous for either mutation, and these would be the stem cells of two different homozygous skin areas that tend to be arranged in close proximity to each other.1267 Nevertheless, this proposed molecular mechanism has not been confirmed genetically. In addition, this proposed mechanism does not explain all cases of non-allelic twin spotting, because if every combination of nevi is possible, then all genes responsible for these mutations should be closely packed together in the same chromosome, which is not very likely.1291 Thus, other mechanisms of recombination of non-homologous chromosomes, including transposable elements, must exist. KERATINOCYTIC NEVI

EPIDERMAL NEVI The word nevus, from Latin naevus, means literally ‘birthmark’. The word that usually accompanies this term denotes the type of cells that compose the hamartomatous growth within the nevus. A hamartoma (from Greek hamartia, ‘to err’) is an abnormal accumulation of usual components of a tissue. Therefore, literally, an epidermal nevus would be a birthmark due to an accumulation of any of the components of the epidermis. However, in clinical settings, only nevi derived from keratino­ cytes, hair follicles, and sebaceous and sweat glands fall under the ‘umbrella term’ of epidermal nevus. Thus, although melanocytes are natural components of the epidermis, melanocytic nevi are not regarded as epidermal nevi. The term nevus is widely used by dermatologists worldwide. Although a molecular confirmation has not been achieved for every type of nevus, it is most likely that all nevi reflect mosaicism, usually in the form of somatic mutation during embryo development leading to an abnormal cell clone.1307 Gene mutation or loss of heterozygosity probably underlies the appearance of nevi during postnatal and even adult life. Since mosaic conditions follow regular and repeated clinical patterns (see above), it is expected that nevi also do so. In fact, epidermal nevi are the paradigm of Blaschko lines, which are strongly suspected to be the lines of embryologic development of the epidermis. As will be discussed later, demonstration of mosaicism at a molecular level has been achieved for at least some types of epidermal nevi.

KERATINOCYTIC NEVI PATHOGENESIS

From a histopathological point of view, epidermal nevi can be classified according to the cell type giving rise to the hamartomatous growth. Hence, epidermal nevi could be classified as keratinocytic, sebaceous, hair follicle, apocrine, and eccrine nevi, as well as other types of mixed components. It was long ago observed that many epidermal nevi were not histologically ‘pure’, but showed different cell components within the nevi; that was the situation in many predominantly sebaceous nevi which also had nevoid growth of keratinocytes, absorptive hair follicles, and apocrine glands. The term ‘organid nevus’ was

Most probably, all epidermal nevi are due to genetic mosaicism, usually developed from somatic mutations during embryo development, leading to an abnormal clone of cells which continues its embryologic development along a precise pattern of epidermal development, the so called lines of Blaschko. The genetic mosaic abnormality leads to a specific clinical manifestation, and thus keratinocytic nevus is not a single disease, but a hyperkeratotic linear manifestation of different mutations, leading to subtle clinical differences than can often be recognized. A somatic lethal mutation surviving in the form of mosaicism is the cause of a number of typical velvety non-organoid keratinocytic nevi. A specific activating FGFR3 single-base mutation at codon 248 (R248C) has been detected in the skin in 11/33 (33%) patients in one series of non-organoid non-epidermolytic epidermal nevi, whereas no mutation was detected in normal skin or in germ line, a demonstration of cutaneous mosaicism.1264 Whereas achondroplasia and other growth disorders are due to FGFR3 mutation, the specific R248C activating mutation leading to epidermal nevi leads to a disease called thanatophoric dysplasia when affects the germ line, and this disease is incompatible with postnatal life. One patient with keratinocytic nevus had a double FGFR3 mutation G372C/G382R, the former

1307. Happle R. What is a nevus? A proposed definition of a common medical term. Dermatology. 1995;191:1–5.

1308. Mehregan AH, Pinkus H. Life history of organoid nevi. Special reference to nevus sebaceus of Jadassohn. Arch Dermatol. 1965;91:574–588.

CLASSIFICATION OF EPIDERMAL NEVI

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coined by dermatopathologists, to describe the mixed and uneven organization within the epidermal hamartoma, containing a mixture of keratinocytic, sebaceous, hair follicle and gland components.1308 Although most organoid nevi are composed of a mixture of cell types, there is usually a predominant one, which is usually the one which is used for a denomination. For example, virtually every sebaceous nevus has at least a minor keratinocytic and hair follicle component, but as sebaceous glands overly predominate, the term ‘sebaceous nevus’ is appropriate; the same holds true for hair follicle, apocrine and eccrine nevi. In contrast, the ‘purely’ keratinocyte nevi, showing only a hamartomatous growth of a single component of the epidermis, mainly keratinocytes, were referred to as non-organoid epidermal nevi. Although this morphologic classification of epidermal nevi is useful, it has become apparent that every type of cell in the epidermis may give rise to different types of epidermal nevi, due to different post-zygotic mutations in different genes, giving rise to different clinical manifestations. It is now clear that there is not a single ‘keratinocytic nevus’, but different mutations, each giving rise to different hamartomatous growths (i.e., different types of nevi) derived from a single cell, the keratinocyte. This can be also apparent on clinical grounds under careful observation. However, until a complete genetic demonstration of all types of epidermal nevi is achieved, it is still useful to classify epidermal nevi based on clinico-pathological grounds, as shown in Box 7.16. We will discuss, however, the underlying genetic mechanisms in every type of epidermal nevi, when known.

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7

BOX 7.16 CLASSIFICATION OF EPIDERMAL NEVI

>> Common, non-organoid keratinocytic nevus >> Acanthosis nigricans-like keratinocytic nevus >> Hypopigmented keratinocytic nevus >> Epidermolytic keratinocytic nevus >> Inflammatory linear verrucous epidermal nevus (ILVEN) >> CHILD nevus >> Cowden nevus >> PENS nevus >> Acantholytic and dyskeratotic epidermal nevi >> Other nevoid conditions Sebaceous nevus

>> Sebaceous nevus >> Large, papillomatous, pedunculated sebaceous nevus >> Cerebriform sebaceous nevus >> Nevus marginatus Follicular nevi

>> Hair follicle nevus >> Nevus comedonicus and Munro nevus >> ‘Acne-free’ nevus

>> Basaloid follicular hamartoma >> Dilated pore nevus >> Hairy malformation of the palms and soles >> Trichilemmal cyst nevus Apocrine nevi

>> Apocrine nevus >> Syringocystadenoma papilliferum Eccrine nevi

>> Eccrine nevus >> Mucinous eccrine nevus >> Eccrine angiomatous hamartoma >> Mucinous eccrine angiomatous hamartoma >> Eccrine angiokeratomatous hamartoma >> Sudoriparous angioma >> Angiomyxoid eccrine nevus >> Porokeratotic adnexal ostial nevus (including porokeratotic

KERATINOCYTIC NEVI

Keratinocytic nevi

eccrine ostial and dermal duct nevus and porokeratotic eccrine and hair follicle nevus)

Becker’s nevus

>> (see Ch. 10)

being associated with thanatophoric dysplasia and the latter with achondroplasia.1264 Interestingly, a patient with an extensive keratinocytic nevus and facial dysmorphic features had the R248C on the skin affected by the epidermal nevus.1309 Furthermore, a skin mosaic mutation in the phosphatidylinositol 3-kinase gene (PIK3CA) was detected in the skin affected by non-organoid keratinocytic nevi in nine of 33 patients, but not in normal skin or germ line.1265 The mutation is a single-base substitution in codon 545 leading to a Glu>Gly amino acid substitution (E545G). It is interesting that these two mutations leading to non-organoid keratinocytic nevi also appear in the skin affected by seborrheic keratoses, thus indicating that seborrheic keratoses are in fact acquired keratinocytic nevi, that mutation in postnatal life also explains the appearance of nevi, and that lesional skin patterning is dependent on the timing of the mutational event leading to mosaicism. Different types of mutations in both genes, FGFR3 and PIK3CA, are also involved in certain types of cancer, such as bladder, ovarian, breast, liver cancer, and others.1310 Regarding PIK3CA, the three most common cancer-associated mutations are E542K, E545K, and H1047R, which are not present in keratinocytic nevi; for FGFR3, cancer mutations include a wide spectrum, such as the R248C,

S249C, G372C, S373C, Y375C, A393E, K652M, and K652E substitutions.1265 Some patients with epidermal nevi and urothelial cancer have been reported,1311 but mutations in FGFR were not detected in two of those patients neither in the skin nor in the bladder cancer.1310 It has been hypothesized that effect of the tumor repressor gene PTEN on cell death is mediated through the PIK3CA/AKT1 pathway;1312 interestingly, a mosaic PTEN mutation has been demonstrated to occur in a patient with extensive keratinocytic nevi (see below). Other types of lethal mutation surviving in the form of mosaicism can also give rise to epidermal nevi. A patient with extensive Blaschkolinear epidermal nevus due to mosaic trisomy 6 in fibroblasts cultivated from the nevus has been reported.1313 Non-lethal somatic mutations leading to extensive skin diseases can also appear in the form of mosaicism. That is the case with epidermolytic ichthyosis, due to keratins 1 and 10 mutations, which can appear in the form of a linear verrucous lesion with identical histopathological features.1314 In these cases, the term ‘epidermolytic epidermal nevus’ was coined, but it has been long proved that such nevus bears K1 or K10 mutations.1270,1315 Another proof of the mosaic origin of nonepidermolytic epidermal nevus is the fact that patients with such

1309. Collin B, Taylor IB, Wilkie AO, et al. Fibroblast growth factor receptor 3 (FGFR3) mutation in a verrucous epidermal naevus associated with mild facial dysmorphism. Br J Dermatol. 2007;156:1353–1356. 1310. Hernández S, Toll A, Baselga E, et al. Fibroblast growth factor receptor 3 mutations in epidermal nevi and associated low grade bladder tumors. J Invest Dermatol. 2007;127:1664–1666. 1311. Hafner C, Hartmann A, Vogt T. FGFR3 mutations in epidermal nevi and seborrheic keratoses: lessons from urothelium and skin. J Invest Dermatol. 2007;127:1572–1573.

1312. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68:6084–6091. 1313. Sobey GJ, Quarrell OW, Williams S. Mosaic chromosome 6 trisomy in an epidermal nevus. Pediatr Dermatol. 2007;24:144–146. 1314. Lane EB, McLean WH. Keratins and skin disorders. J Pathol. 2004;204:355–366. 1315. Tsubota A, Akiyama M, Sakai K, et al. Keratin 1 gene mutation detected in epidermal nevus with epidermolytic hyperkeratosis. J Invest Dermatol. 2007;127:1371–1374.

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KERATINOCYTIC NEVI

linear manifestation had offspring with the generalized disorder epidermolytic hyperkeratosis.1316 A similar situation is the socalled ‘acantholytic dyskeratotic epidermal nevus’, which in fact is no more than a mosaic Blaschkolinear manifestation of the generalized Darier’s disease; the ATPA2A gene mutation responsible for Darier’s disease found in the nevus was not detected in the normal skin.1317 In other cases, however, no ATPA2A mutation has been found.1318 The same probably holds true for a type of eroded and crusted epidermal nevus with histological manifestations of benign familial chronic pemphigus (Hailey– Hailey disease), due to ATP2C1 mutations.1274 These examples highlight the long-standing trend of dermatologists to give the name of ‘epidermal nevus’ to any linear verrucous or keratotic lesion. X-linked mutations may also be responsible for epidermal nevi, and are thus heritable, in contrast to somatic mutations appearing during embryo development. In dominant X-linked disorders, lyonization leads to a mosaic heritable pattern of the skin (see Mosaicism, above). This is the case for CHILD nevus, a peculiar type of keratinocytic nevus which appears as a hallmark of CHILD syndrome, an acronym from Congenital Hemidysplasia, Ichthyosiform erythroderma and Limb Defects.1319 The ‘ichthyosis’ in CHILD syndrome is in fact a keratinocyte nevus with some histopathological peculiarities. CHILD nevus is the result of a metabolic anomaly due to mutations in the NAD(P)H steroid dehydrogenase-like protein (NSDHL) gene at Xq28, an enzyme involved in cholesterol biosynthesis.1320 Some lesions described under the term ‘epidermal’ or ‘keratinocytic’ nevus are most likely due to mosaic mutations in susceptibility genes of polygenic inflammatory skin disorders. An example of this is the so-called ‘inflammatory linear verrucous epidermal nevus’, or ILVEN. It has been suggested that ILVEN is indistinguishable from linear or ‘nevoid’ psoriasis,1321 and in fact, some patients with ILVEN appearing in early infancy later on in their lives developed generalized psoriasis, which is very suggestive of a superimposed segmental manifestation of a polygenic skin disorder.1322 A genetic demonstration of this is, however, still lacking. Finally, in some types of keratinocytic nevi, a genetic proof of mosaicism has not been demonstrated nor even tested. Gene identification may be expensive, especially if there is no suspected candidate gene. With time, hopefully all nevi will be characterized at the genetic level and cutaneous mosaicism will be demonstrated.

1316. Chassaing N, Kanitakis J, Sportich S, et al. Generalized epidermolytic hyperkeratosis in two unrelated children from parents with localized linear form, and prenatal diagnosis. J Invest Dermatol. 2006;126:2715–2717. 1317. Gilaberte M, Puig L, Vidal D, et al. Acantholytic dyskeratotic naevi following Blaschko’s lines: a mosaic form of Darier’s disease. J Eur Acad Dermatol Venereol. 2003;17:196–199. 1318. Huh WK, Fujiwara K, Takahashi H, et al. Congenital acantholytic dyskeratotic epidermal naevus following Blaschko’s lines versus segmental Darier’s disease. Eur J Dermatol. 2007;17:130–132. 1319. Happle R, Mittag H, Küster W. The CHILD nevus: a distinct skin disorder. Dermatology. 1995;191:210–216. 1320. Bornholdt D, König A, Happle R, et al. Mutational spectrum of NSDHL in CHILD syndrome. J Med Genet. 2005;42:e17. 1321. Saraswat A, Jain R, Kaur I, et al. Co-localization of epidermal nevi and psoriasis: are we closer to an explanation? Int J Dermatol. 2005;44:972–974.

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CLINICAL AND PATHOLOGICAL MANIFESTATIONS Keratinocytic nevi are not uncommon. They are reported to affect 0.1–0.5% of adults, and appear equally in both males and females. A common manifestation of every type of keratinocytic nevus is a more or less verrucous or hyperkeratotic lesion following the lines of Blaschko. Usually, these lesions are apparent at birth but its onset may be delayed until childhood. Keratinocytic nevi can be small and localized or otherwise can be large and widespread affecting many Blaschko lines. The lesions can affect both sides of the body or can be unilateral; extensive unilateral keratinocytic nevi were in the past sometimes referred to as naevus unius lateris. Any location of the body surface can be affected by keratinocytic nevi, including the palms, soles, and oral and genital mucosa,1323,1324 but they are very uncommon on the front, temples and scalp, the places where sebaceous nevi (see below) are most often seen. Keratinocytic nevi on the limbs can also affect the nails, leading to ridging, splitting, discoloration or other types of nail dystrophy.1323

Common, non-organoid keratinocytic nevus Common keratinocytic nevi usually appear as velvety, slightly elevated streaks or plaques following one or many lines of Blaschko (Fig. 7.112). The color is usually light brown, but may range to dark gray. At birth they can look macerated and lighter in color. Some patients present yellowish verrucous, hyperkeratotic papules in a linear arrangement. Some extreme cases with extensive dark and spiny hyperkeratotic papules exist, and weird terms such as ‘ichthyosis hystrix’ and ‘porcupine man’ have been used for description.1325 Flexural lesions may become more verrucous and foul smelling, and lesions located over bony prominences or extension areas of joints may become more hyperkeratotic and develop deep, painful fissures. In other cases, frankly papillomatous papules appear in a linear disposition. Less frequently, a verrucous or papillomatous round or oval plaque is seen. Common keratinocytic nevi rarely affect the scalp, and in such cases, a wooly hair nevus may overlie a keratinocytic nevus.1326 A case where acne developed exclusively on the areas affected by an extensive keratinocytic nevus has been reported.1327 Although the development of skin malignancies in keratino­ cytic nevi is rare, and much lower than that of sebaceous or apocrine nevi, sporadic reports of basal cell carcinoma, intraepithelial carcinoma, keratoacanthoma, malignant eccrine poroma,

1322. Hofer T. Does inflammatory linear verrucous epidermal nevus represent a segmental type 1/type 2 mosaic of psoriasis? Dermatology. 2006;212:103–107. 1323. Sethuraman G, Khaitan BK, Tejasvi T, et al. Verrucous epidermal nevus with unusual features. Pediatr Dermatol. 2006;23:98–99. 1324. Haberland-Carrodeguas C, Allen CM, Lovas JG, et al. Review of linear epidermal nevus with oral mucosal involvement – series of five new cases. Oral Dis. 2008;14:131–137. 1325. Capetanakis J, Stratigos J, Tsambaos D, et al. Ichthyosis hystrix of ‘porcupine man’ type. Report of a case. Dermatologica. 1975;151:177–183. 1326. Martín-González T, del Boz-González J, Vera-Casaño A. Woolly hair nevus associated with an ipsilateral linear epidermal nevus. Acta Dermosifiliogr. 2007;98:198–201. 1327. Hivnor CM, Yan AC, Honig PJ. Acne arising in an epidermal nevus. Pediatr Dermatol. 2007;24:534–535.

Genodermatoses

differentiated from common keratinocytic nevi because of a velvety histopathology showing mild compact hyperkeratosis, papillomatosis, and limited hyperplasia of the epithelium, thus indistinguishable from acanthosis nigricans.1331 Although not yet proved, it is most likely that the acanthosis nigricans form of epidermal nevus is due to a mosaic state of a gene mutation leading to any of the acanthosis nigricans-related syndromes. Interestingly, acanthosis nigricans is also a feature of thanatophoric dysplasia, due to activating FGFR3 gene mutations. Hypopigmented keratinocytic nevus may represent a variant type from the common keratinocytic nevus. It appears as whitish, very slightly hyperkeratotic streaks following the lines of Blaschko; it can be sometimes difficult to differentiate from ‘lichen striatus’ or hypopigmented mosaicism. This hypopigmented variant may be seen in children with other common keratino­ cytic nevi affecting other Blaschko lines. It is said that hypopigmented keratinocytic nevi are more common in dark skinned patients.

KERATINOCYTIC NEVI

Figure 7.112  Common, non-organoid keratinocytic nevus.

7

Epidermolytic keratinocytic nevus and squamous cell carcinoma exist.1328,1329 Most frequently, these tumors develop well after childhood, but have been reported to appear even at 17 years of age. There seems to be also an association between non-skin cancer and keratinocytic nevi, and there are examples of urinary tract papillary transitional cell carcinoma, breast adenocarcinoma, esophageal epidermoid carcinoma, astrocytoma, Wilms’ tumor, bladder rhabdomyosarcoma, yolk sac papillary adenocarcinoma, ameloblastoma, nephroblastoma, and embryonal rhabdomyosarcoma in patients with keratinocytic nevi.1330 Some of these tumors appeared during infancy and childhood. Patients with keratinocytic nevi should be followed and instructed to ask for consultation in case of changes in their nevus. On histopathology, a common keratinocytic nevus shows variable amounts of hyperkeratosis, acanthosis, and papillomatosis. Other variable features include hypergranulosis, columns of para­keratosis, a ‘church-spire’ pattern of acanthokeratosis, and horn pseudocysts. Thus, common keratinocytic nevi may resemble acrokeratosis verruciformis, seborrheic keratoses or acanthosis nigricans. This only reflects the fact that common keratinocytic nevus is not a single disease, but a common clinical manifestation of mosaicism of different disorders. As has been stated above, 33% and 27% of common keratinocytic nevi are due to mutations in FGFR3 or PIK3CA genes, respectively, also responsible for the development of seborrheic keratoses in adult life. It is not surprising that a number of keratinocytic nevi resemble both clinically and on histopatho­ logy seborrheic keratoses, which must be regarded as acquired keratinocytic nevi. The term acanthosis nigricans form of epidermal nevus refers to a clinically distinct type of keratinocytic nevus, that can be

As has been stated before, this type of nevus represents the Blaschko linear mosaic counterpart of epidermolytic ichthyosis (epidermolytic hyperkeratosis), and is due to mosaic mutations in keratins 1 and 10.1270,1315 Clinically, this nevus appears as streaks of slightly pigmented verrucous or warty papules with a Blaschkolinear arrangement (Fig. 7.113). Individual papules resemble the spiny keratotic papules that can be seen in patients with epidermolytic ichthyosis. In contrast, bullous lesions in early childhood are not usually reported in the mosaic state. Lesions may be single or multiple, unilateral or bilateral, and may affect any part of the body surface. Maceration of flexural lesions may lead to foul smell, and fissuring may be painful. On histopathology, this type of nevus shows hyperkeratosis, acanthosis and papillomatosis along with epidermolysis of the granular cells. This pattern is identical to that of epidermolytic ichthyosis.

1328. Affleck AG, Leach IH, Varma S. Two squamous cell carcinomas arising in a linear epidermal naevus in a 28-year-old female. Clin Exp Dermatol. 2005;30:382–384. 1329. Masood Q, Narayan D. Squamous cell carcinoma in a linear epidermal nevus. J Plast Reconstr Aesthet Surg. 2009;62:693–694. 1330. Flosadóttir E, Bjarnason B. A non-epidermolytic epidermal naevus of a soft, papillomatous type with transitional cell cancer of the bladder: a

case report and a review of non-cutaneous cancers associated with the epidermal naevi. Acta Derm Venereol. 2008;88:173–175. 1331. Ersoy-Evans S, Sahin S, Mancini AJ, et al. The acanthosis nigricans form of epidermal nevus. J Am Acad Dermatol. 2006;55:696–698. 1332. Al-Enezi S, Huber AM, Krafchik BR, et al. Inflammatory linear verrucous epidermal nevus and arthritis: a new association. J Pediatr. 2001;138:602–604.

Inflammatory linear verrucous epidermal nevus (ILVEN) It is debatable whether ILVEN (also called ‘dermatitic epidermal nevus’) is a ‘distinct’ type of keratinocytic nevus or a localized Blaschkolinear form of psoriasis or another dermatological disorder yet unidentified. The histopathological resemblances between ILVEN and psoriasis are well reported, and in some cases both disorders have been reported to appear together, suggesting type 2 mosaicism.1275 An association between ILVEN and arthropathy is best explained as nevoid psoriasis with psoriatic arthritis.1332 Furthermore, some cases of ILVEN have shown good response to anti-psoriatic therapy, including topical corticosteroids, topical tacrolimus, acitretin, narrow-band UVB light,

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Figure 7.113  (A,B). Epidermolytic epidermal nevus.

KERATINOCYTIC NEVI

A

B

Figure 7.114  Inflammatory linear verrucous epidermal nevus (ILVEN). and etanercept.1333–1337 Although a number of cases of ILVEN may represent true linear or ‘nevoid’ psoriasis, it is possible that others may represent linear manifestations of other mutations, both lethal and non-lethal. Anecdotal cases of familial ILVEN have been reported, though most cases are sporadic.1338 ILVEN usually occurs in children of both sexes as a linear, hyperkeratotic and highly pruritic plaque, with variable degrees of erythema and crusting (Fig. 7.114). Some cases have a frankly

1333. Mutasim DF. Successful treatment of inflammatory linear verrucous epidermal nevus with tacrolimus and fluocinonide. J Cutan Med Surg. 2006;10:45–47. 1334. Renner R, Rytter M, Sticherling M. Acitretin treatment of a systematized inflammatory linear verrucous epidermal naevus. Acta Derm Venereol. 2005;85:348–350. 1335. Ozdemir M, Mevlitoä Lu I, Balevi A. Acitretin narrow-band TL-01 phototherapy but not etanercept treatment improves a localized inflammatory linear verrucous epidermal naevus with concomitant psoriasis. J Eur Acad Dermatol Venereol. 2009;88(6):589–593.

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psoriatic appearance, whereas others look like eczema or even show itchy papules which resemble ‘lichen striatus’. ILVEN has been reported to occur predominantly on the lower limbs, particularly the left buttock. ILVEN has also been reported in the genital skin. Onset of the lesions occurred between the ages of 0 and 4 years of age, with approximately 25% of lesions appearing at birth and 50% within the first 6 months of life.1339 Extension of ILVEN beyond the original distribution was reported in 27% of patients in one series.1339 Widespread and extensive bilateral ILVEN may occur, and lesions involving distal limbs may also affect the nails. ILVEN has not been reported to be associated with abnormalities in other organ systems On histopathology, most cases show columns of hypergranulosis with overlying orthokeratotic hyperkeratosis, alternating with parakeratosis. A psoriasiform epidermal hyperplasia, along with spongiosis, exocytosis and even microabscess formation, is also seen, and features are very similar to psoriasis. There is also a superficial perivascular lymphohistiocytic infiltrate. In other cases, only chronic eczema-like features are observed. The histopathological and clinical heterogeneity suggests that ILVEN is not a single disease, but may be sometimes a mosaic form of psoriasis, chronic eczema, or other yet undisclosed mutations.

CHILD nevus CHILD nevus is a hallmark of CHILD syndrome, an acronym from Congenital Hemidysplasia, Ichthyosiform erythroderma

1336. Sotiriadis D, Patsatsi A, Lazaridou E, et al. Is inflammatory linear verrucous epidermal naevus a form of linear naevoid psoriasis? J Eur Acad Dermatol Venereol. 2006;20:483–484. 1337. Bogle MA, Sobell JM, Dover JS. Successful treatment of a widespread inflammatory verrucous epidermal nevus with etanercept. Arch Dermatol. 2006;142:401–402. 1338. Alsaleh QA, Nanda A, Hassab-el-Naby HM, et al. Familial inflammatory linear verrucous epidermal nevus (ILVEN). Int J Dermatol. 1994;33:52–54. 1339. Le K, Wong LC, Fischer G. Vulval and perianal inflammatory linear verrucous epidermal naevus. Australas J Dermatol. 2009;50:115–117.

Genodermatoses

Cowden nevus Patients with germline PTEN mutations with extensive segmental keratinocytic nevi have been reported.1346 In one of them, carrying a novel germline mutation inherited from his mother who had Cowden syndrome, loss of heterozygosity for this mutation was demonstrated in the widespread epidermal nevus.1347 This situation is best explained as type 2 mosaicism of Cowden disease, and the epidermal nevus which appears as a hallmark of the disease is called linear Cowden nevus or PTEN nevus (also an acronym for Papillomatous, Thick, Epidermal, Non-organoid nevus).1348 Clinically, linear Cowden nevus consists of erythematous, thick, hyperkeratotic and papillomatous confluent papules in a

1340. Bittar M, Happle R, Grzeschik KH, et al. CHILD syndrome in 3 generations: the importance of mild or minimal skin lesions. Arch Dermatol. 2006;142:348–351. 1341. Kim CA, Konig A, Bertola DR, et al. CHILD syndrome caused by a deletion of exons 6–8 of the NSDHL gene. Dermatology. 2005;211:155–158. 1342. König A, Happle R, Fink-Puches R, et al. A novel missense mutation of NSDHL in an unusual case of CHILD syndrome showing bilateral, almost symmetric involvement. J Am Acad Dermatol. 2002;46:594–596. 1343. Hashimoto K, Prada S, Lopez AP, et al. CHILD syndrome with linear eruptions, hypopigmented bands, and verruciform xanthoma. Pediatr Dermatol. 1998;15:360–366. 1344. Mehra S, Li L, Fan CY, et al. A novel somatic mutation of the 3betahydroxysteroid dehydrogenase gene in sporadic cutaneous verruciform xanthoma. Arch Dermatol. 2005;141:1263–1267.

Blaschkolinear arrangement, in contrast with soft, velvety appearance of common non-organoid keratinocytic nevi or epidermal nevi in Proteus syndrome. Histopathology of Cowden nevus has been very poorly described.

PENS nevus The term PENS (papular epidermal nevus with skyline basal cell layer) is a rare variant of keratinocytic nevus, consisting of multiple congenital, flat-topped, hyperkeratotic papules, appearing randomly on the skin surface (Torrelo A, Colmenero I, Kristal L, personal observation) (Fig. 7.115). They measure 0.3–1  cm and are not linear, but round, oval, or comma-shaped. On histopathology, they show a characteristic ichthyosiform compact orthokeratotic hyperkeratosis, regular acanthosis, wide and enlarged rete ridge, and a very well depicted basal cell layer which resembles the ‘skyline sign’ or ‘eyeliner sign’ present in lesions of Bowen’s disease. Genetic testing has been negative for hotspot mutation in FGFR3 and PIK3CA genes.

KERATINOCYTIC NEVI

and Limb Defects). It appears as a result of mosaicism from lyonization of the X-linked NSDHL gene. Clinically, CHILD nevus mostly affects females, and usually appears at birth, but occasionally does so later in childhood. Partial extension and regression are also possible. Usually, CHILD nevus presents as erythematous or yellowish warty areas following the lines of Blaschko, usually covered by waxy scales. They usually are confined to one side of the body, both in streaky or diffuse arrangement; bilateral and almost symmetrical cases have also been reported.1320,1340–1342 Other patients show more subtle skin manifestations as flat-topped, slightly verrucous or rather hypopigmented keratinocytic nevi, usually associated with minor or distal limb defects. Ptychotropism (a preference for flexural areas) is a typical feature of CHILD nevus, and flexural lesions may be oozing and vegetating. Histopathology shows a psoriasiform dermatitis with areas of parakeratosis and exocytosis of neutrophils. A characteristic feature of CHILD nevus is the development of verruciform xanthoma features in the dermis, especially in lesions located on body folds.1343 Dermal papillae appear widened and contain foamy histiocytes. Electron microscopy shows intracytoplasmic lipid containing vacuolae. In fact, verruciform xanthoma is a histopathologic pattern seen in different cutaneous or mucosal lesions, consisting of verrucous epithelial hyperplasia with aggregates of lipid-laden macrophages in the submucosa or papillary dermis.1344 It should be noted that verruciform xanthoma has been reported in epidermal nevi not associated to CHILD syndrome.1345 The mechanism by which the lipids accumulate is not well known, but the cholesterol synthesis abnormalities in CHILD syndrome must definitely play a role. Interestingly, somatic missense mutations in the NSDHL gene have been reported in verruciform xanthoma lesions from patients without CHILD syndrome.1344

7

Acantholytic and dyskeratotic epidermal nevi It is most likely that keratinocytic nevi showing variable degrees of acantholysis and dyskeratosis are mosaic linear forms of the acantholytic and dyskeratotic disorders called Darier’s disease and Hailey–Hailey disease. They can appear as type 1 or type 2 mosaicism of Happle. In patients with linear Darier’s disease, linear crusted keratotic papules appear, usually at puberty or thereafter, and may be aggravated by sun exposure. Nail involvement from linear Darier’s disease shows typical features of generalized Darier’s disease, and if the linear disorder affects the hands, pits and keratoses may be also seen. In linear Hailey–Hailey disease (also called ‘relapsing linear acantholytic dermatosis’), early onset, linear erythematous plaques with vesiculation, erosion and crusting develop. There may be episodes of spontaneous remission and relapse. Histopathology is identical to classical Hailey–Hailey disease. Type 2 mosaicism for ATP2C1 gene has been demonstrated at a mole­ cular level.1274 Some patients have been described with histopathological features of Darier’s disease and lacking ATPA2A mutations responsible for this disorder. It is reasonable to accept1349 that, in case of negative family history, childhood onset and absence of ATPA2A or ATP2C1 mutations, the diagnosis of acantholytic dyskeratotic epidermal nevus must be retained. A Blaschkolinear epidermal nevus with filiform hyperkeratoses, large cutaneous horns and lesions resembling giant

1345. Ko JY, Shin H, Lee CW. A verruciform xanthoma-like phenomenon in a linear epidermal naevus in the absence of a syndromic association. Br J Dermatol. 2008;159:493–496. 1346. Tekin M, Hişmi BO, Fitoz S, et al. A germline PTEN mutation with manifestations of prenatal onset and verrucous epidermal nevus. Am J Med Genet A. 2006;140:1472–1475. 1347. Loffeld A, McLellan NJ, Cole T, et al. Epidermal naevus in Proteus syndrome showing loss of heterozygosity for an inherited PTEN mutation. Br J Dermatol. 2006;154:1194–1198. 1348. Happle R. Linear Cowden nevus: a new distinct epidermal nevus. Eur J Dermatol. 2007;17:133–136. 1349. Starink TM, Woerdeman MJ. Unilateral systematized keratosis follicularis. A variant of Darier’s disease or an epidermal naevus (acantholytic dyskeratotic epidermal naevus)? Br J Dermatol. 1981;105:207–214.

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others, may present at birth or in infancy, as a mosaic ‘nevoid’ form of disorders with epidermal involvement. These lesions are treated elsewhere in this textbook.

MANAGEMENT

SEBACEOUS NEVUS

A

B

Figure 7.115  (A, B). Papular epidermal nevus with skyline basal cell layer (PENS).

comedones and linear hyperkeratotic plaques has been reported.1350 Histopathology showed acantholysis without dys­ keratosis. The term nevus corniculatus was chosen for this peculiar nevus, but so far no new similar cases or molecular elucidation have been reported.

Other nevoid conditions Other inflammatory conditions such as lichen nitidus, lichen planus, linear eczema/lichen striatus, linear porokeratosis, and

1350. Happle R, Steijlen PM, Kolde G. Naevus corniculatus: a new acantholytic disorder. Br J Dermatol. 1990;122:107–112. 1351. Panagiotopoulos A, Chasapi V, Nikolaou V, et al. Assessment of cryotherapy for the treatment of verrucous epidermal naevi. Acta Derm Venereol. 2009;89:292–294. 1352. Thual N, Chevallier JM, Vuillamie M, et al. CO2 laser therapy of verrucous epidermal nevus. Ann Dermatol Venereol. 2006;133:131–138.

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Most keratinocytic nevi do not require a treatment. Indications for therapy are cosmetic concerns, maceration, foul smell, or pain from fissuring. In case a treatment is desired, parents should be aware that treatment can be worse than the nevus itself, and cosmetic outcomes of treatments may offer unacceptable results. Topical applications are not curative. Keratolytic preparations with salicylic, lactic or retinoic acid may be helpful in verrucous lesions. Treatment with 5-fluorouracil has been advocated. Topical vitamin D derivates can be tried, but are most likely of little benefit. Topical tacrolimus and corticosteroids may be effective in patients with ILVEN, but will not be of help in the other types of keratinocytic nevi. Destructive methods such as cryotherapy and electrodesiccation can be potentially effective, but a relapse is very likely if the underlying dermis is removed or completely destroyed.1351 The same holds true for skin-shaving procedures and dermabrasion. Laser therapy seems appropriate under expertise, as good results have been obtained with argon laser, long-pulsed ruby laser, continuous wave CO2 laser, ultrapulsed, superpulsed lasers and scanners, and pulsed erbium:YAG laser.1352,1353 The risks for relapsing, hyper- or hypopigmentation and scarring must be considered and explained to parents. Conventional excision surgery can be helpful for troublesome lesions in usually covered locations; scarring is the major drawback of surgery. Medical systemic treatment has been occasionally effective. Oral acitretin can improve extensive epidermolytic keratinocytic nevi, and may be indicated in extensive linear forms of other keratinization disorders, such as linear Darier’s disease. ILVEN has been reported to improve with acitretin and etanercept (see above).

SEBACEOUS NEVUS Sebaceous nevus is an epidermal organoid nevus, as it consists of a hamartoma composed of a mixture of skin components such as epidermis, hair follicles and sebaceous, apocrine and eccrine glands; the term sebaceous nevus is used because sebaceous cells are the most predominant cell type. Follicular, apocrine and eccrine nevi have also been described (see below). Sebaceous nevus is a common lesion. It is said to affect 0.3% of all newborns. However, one-third of cases are not present at birth and become apparent during early childhood.1308 Although it is mostly a sporadic condition, a small number of familial cases have been reported, but the specific mode of inheritance is not clear.1354 Paradominant inheritance has been proposed as the cause of familial sebaceous nevus.1267,1354

1353. Paradela S, Del Pozo J, Fernández-Jorge B, et al. Epidermal nevi treated by carbon dioxide laser vaporization: a series of 25 patients. J Dermatol Treat. 2007;18:169–174. 1354. Hughes SM, Wilkerson AE, Winfield HL, et al. Familial nevus sebaceus in dizygotic male twins. J Am Acad Dermatol. 2006;54(2 Suppl):S47–S48.

Genodermatoses

PATHOLOGY Histopathology of sebaceous nevus varies with age.1359 In the infantile stage, there is acanthosis and hair follicles are small and incompletely formed, or may appear simply as cords of basaloid cells. The sebaceous glands are located at abnormally higher levels in the dermis, but are not very prominent. In adolescence, the lesion is considerably thicker, and shows acanthosis and

1355. Xin H, Matt D, Qin JZ, et al. The sebaceous nevus: a nevus with deletions of the PTCH gene. Cancer Res. 1999;59:1834–1836. 1356. Takata M, Tojo M, Hatta N, et al. No evidence of deregulated patchedhedgehog signaling pathway in trichoblastomas and other tumors arising within nevus sebaceous. J Invest Dermatol. 2001;117:1666–1670. 1357. Carlson JA, Cribier B, Nuovo G, et al. Epidermodysplasia verruciformisassociated and genital-mucosal high-risk human papillomavirus DNA are prevalent in nevus sebaceus of Jadassohn. J Am Acad Dermatol. 2008;59:279–294. 1358. Hamilton KS, Johnson S, Smoller BR. The role of androgen receptors in the clinical course of nevus sebaceus of Jadassohn. Mod Pathol. 2001;14:539–542.

variable degrees of hyperkeratosis and papillomatosis; these features are similar to keratinocytic nevi. Furthermore, at this stage, hyperplasia and malpositioning of numerous sebaceous glands is the predominant feature. Small and primordial hair follicles are also present, but there are virtually no normal terminal hair follicles. There are also variable degrees of hyperplasia of apocrine glands with dilated ducts and eccrine glands in almost 20% of cases. During adult life, epidermal hyperplasia, large sebaceous glands and ectopic apocrine glands are the main features, whereas the hair follicles remain primordial throughout life. Both benign and malignant neoplasias can develop in sebaceous nevus (see below).

CLINICAL FEATURES

SEBACEOUS NEVUS

As well as for other Blaschkolinear conditions of the skin, somatic mosaicism has been proposed as the mechanism of production of sebaceous nevi. Since a generalized counterpart of sebaceous nevus has not been reported, it is likely that sebaceous nevus represents one or several different lethal dominant mutations surviving by mosaicism. Alternatively, a recessive germline mutation, lethal in heterozygosity, with second-hit somatic mutations in the wild-type allele or loss of heterozygosity during embryo development might be responsible, and might also explain familial cases by paradominant inheritance. Again, it is likely that sebaceous nevus is not a single disease, but a phenotype of different mutations leading to hamartomatous sebaceous growth; the fact that there is clinical heterogeneity within sebaceous nevi and striking clinical variants (see below) favors this hypothesis. It is noteworthy that mutations leading to common non-organoid keratinocytic nevi (see above) are not involved in sebaceous nevus, and so far no mutation responsible has been demonstrated. PTCH allelic deletions (loss of heterozygosity) were detected in 8 of 20 sebaceous nevi in one report, possibly accounting for the development of neoplasia,1355 but a role for PTCH in the genesis of sebaceous nevus is less probable.1356 Furthermore, sebaceous nevi or histopathologically related lesions have not been reported to appear in adult life, as is the case with non-organoid keratinocytic nevi and seborrheic keratoses. A role for human papilloma virus (HPV) in the genesis of sebaceous nevi has been proposed, and a high prevalence of genital mucosa and epidermodysplasia verruciformis-associated HPV types in the lesions of sebaceous nevus has been demonstrated, HPV 16 being the most common type.1357 The results in this study are not definite, as a comparison of HPV infection status in the normal surrounding skin was not performed. It has been hypothesized that maternally transmitted HPV might cause epigenetic mosaicism or induce somatic mutation in ectodermal stem cells. Furthermore, epigenetic mosaicism might explain why a number of cases appear during childhood. The role of HPV in the development of secondary tumors in sebaceous nevus (see below) is also an attractive hypothesis. The presence of increased androgen receptors in sebaceous nevus has been reported, which may explain some of the changes observed in time both clinically and on histopathology.1358

7

Most cases of sebaceous nevi appear in the head and neck. Twothirds of the lesions appear on the scalp, followed by the forehead, cheek, neck, nose, chin, ears, eyebrows and eyelids. Mucosal lesions have also been reported.1359,1360 Less than 5% of cases appear on the back, chest and abdomen, and are virtually absent on the limbs. This distribution correlates with areas where sebaceous glands are more numerous, and is the inverse to the non-organoid keratinocytic nevi, which very rarely appear on the scalp. At birth, the typical appearance is that of an orange or yellowish round to oval patch completely or partially devoid of hair (Fig. 7.116). In some patients only a minimal decrease in hair density over the nevus is seen. A slight granulation or elevation may be present, probably because maternal hormones stimulate sebaceous gland growth. Shortly after, the lesion completely flattens till puberty, when the alopecic patch becomes elevated and hyperkeratotic. It should be noted that in one third of patients, sebaceous nevus is not present at birth, but appears during infancy or even during childhood. Some lesions have a different shape, and may resemble a teardrop or comma, or can be overtly Blaschkolinear. As has been stated before, the lines of Blaschko are the archetypical pattern of sebaceous nevi, but most likely late mutations during embryo development will lead to smaller round patches. There may be a single lesion or multiple ones, and in this latter case they clearly follow the lines of Blaschko; it has been stated that multiple linear lesions are more likely to be associated with abnormalities in the Schimmelpenning’s syndrome of nevus sebaceous (see below). Different clinical variants of sebaceous nevi exist, reflecting clinical and most likely genetic heterogeneity. The term large, papillomatous, pedunculated sebaceous nevus1361,1362 was coined for pink-to-yellow, exophytic, fleshy lesions, usually arising on the scalp and face, and which can appear isolated or within Blaschkolinear papillomatous lesions of sebaceous

1359. Simi CM, Rajalakshmi T, Correa M. Clinicopathologic analysis of 21 cases of nevus sebaceus: a retrospective study. Ind J Dermatol Venereol Leprol. 2008;74:625–627. 1360. Davison SP, Khachemoune A, Yu D, et al. Nevus sebaceus of Jadassohn revisited with reconstruction options. Int J Dermatol. 2005;44:145–150. 1361. Correale D, Ringpfeil F, Rogers M. Large, papillomatous, pedunculated nevus sebaceus: a new phenotype. Pediatr Dermatol. 2008;25:355–358. 1362. Saedi T, Cetas J, Chang R, et al. Newborn with sebaceous nevus of Jadassohn presenting as exophytic scalp lesion. Pediatr Neurosurg. 2008;44:144.

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SEBACEOUS NEVUS

Figure 7.116  Sebaceous nevus.

Figure 7.117  Leaf-like sebaceous nevus.

nevus. The cerebriform sebaceous nevus1363 is a tan pink, firm, lobulated skin growth with an irregular, lobulated surface. Large, flat, leaf-like lesions appear to be a further clinical variant of sebaceous nevus (Fig. 7.117). In Blaschkolinear lesions located on the trunk, a peculiar phenotype has been described showing a flat reddish central area surrounded by dark brown papules; such lesion has been named ‘nevus marginatus’,1364 and shows features of sebaceous nevus in the center area and non-organoid keratinocytic nevus in the dark surrounding papules. This latter variant has been observed in phacomatosis pigmentokeratotica.1306

Overall, neoplasms occur with an estimated incidence of 10– 30%, the risk increasing with age.1365–1367 According to large series, less than 1% of sebaceous nevi are complicated by malignant tumors. The most common benign tumors arising on sebaceous nevus are trichoblastomas, viral warts and tricholemmomas1365,1366,1367; other benign tumors reported are of sebaceous origin (sebaceous adenoma, sebaceous epithelioma, sebaceoma), apocrine origin (apocrine cystadenoma, apocrine hydrocystoma, syringocystadenoma papilliferum, nodular hydradenoma), eccrine origin (spiradenoma, syringoma, chondroid syringoma, syringofibroadenoma), pilar origin (trichoepithelioma, tri­ choadenoma, proliferating trichilemmal cyst, hybrid follicular cysts, rippled-pattern trichoblastoma with apocrine differ­ entiation), or others (leiomyoma, melanocytic nevus). 1357,1359,1360,1365–1370 Among malignant tumors, basal cell carcinoma is the most frequently reported, but isolated cases of squamous cell carcinoma, keratoacanthoma, sebaceous carcinoma, tricholemmal carcinoma, syringocystadenocarcinoma papilliferum, apocrine carcinoma, eccrine porocarcinoma, duct sweat gland carcinoma, adnexal carcinoma, leiomyosarcoma, and malignant melanoma have been reported.1357,1359,1365–1367,1371–1373 In some patients, more than one neoplasm may appear at presentation, and a mixture of up to five benign and malignant neoplasms has

TUMORS ARISING ON SEBACEOUS NEVUS It is well known that along a lifespan, a number of both benign and malignant tumors may appear in sebaceous nevi. Besides anecdotal reports of rare tumors arising within sebaceous nevi, a few large series have addressed the incidence and type of tumors more frequently related to sebaceous nevi.1365–1367 It should be stressed that most tumors are of benign nature; the fact that older series described a high rate of malignant tumors is due to misdiagnosis of basal cell carcinomas which were in fact trichoblastomas, a benign form of neoplasia.

1363. Bomsztyk ED, Garzon MC, Ascherman JA. Postauricular cerebriform sebaceous nevus: case report and literature review. Ann Plast Surg. 2008;61:637–639. 1364. Hafner C, Landthaler M, Happle R, et al. Nevus marginatus: a distinct type of epidermal nevus or merely a variant of nevus sebaceus? Dermatology. 2008;216:236–238. 1365. Domingo J, Helwig EB. Malignant neoplasms associated with nevus sebaceus of Jadassohn. J Am Acad Dermatol. 1979;1:545–556. 1366. Jaqueti G, Requena L, Sanchez Yus E. Trichoblastoma is the most common neoplasm developed in nevus sebaceus of Jadassohn: a clinicopathologic study of a series of 155 cases. Am J Dermatopathol. 2000;22:108–118. 1367. Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol. 2000;42:263–268. 1368. Swick BL, Baum CL, Walling HW. Rippled-pattern trichoblastoma with apocrine differentiation arising in a nevus sebaceus: report of a case and review of the literature. J Cutan Pathol. 2009;36(11):1200–1205.

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1369. Nakai K, Yoneda K, Moriue J, et al. Sebaceoma, trichoblastoma and syringocystadenoma papilliferum arising within a nevus sebaceous. J Dermatol. 2008;35:365–367. 1370. Miyake H, Hara H, Shimojima H, et al. Follicular hybrid cyst (trichilemmal cyst and pilomatricoma) arising within a nevus sebaceus. Am J Dermatopathol. 2004;26:390–393. 1371. Kazakov DV, Calonje E, Zelger B, et al. Sebaceous carcinoma arising in nevus sebaceus of Jadassohn: a clinicopathological study of five cases. Am J Dermatopathol. 2007;29:242–248. 1372. Kantrow SM, Ivan D, Williams MD, et al. Metastasizing adenocarcinoma and multiple neoplastic proliferations arising in a nevus sebaceus. Am J Dermatopathol. 2007;29:462–466. 1373. Ball EA, Hussain M, Moss AL. Squamous cell carcinoma and basal cell carcinoma arising in a naevus sebaceous of Jadassohn: case report and literature review. Clin Exp Dermatol. 2005;30:259–260.

Genodermatoses

MANAGEMENT According to the data discussed above, there is no general agreement about whether all sebaceous nevi should be treated prophylactically before neoplasia develops. Although large series indicate that prophylactic removal of every sebaceous nevus is not necessary, isolated reports and small series of malignancy may justify excision. Parents should be informed and reassured that neoplasias are extremely infrequent before puberty, but every change on the surface of a sebaceous nevus should be reported. It is noteworthy, however, that in some articles, the discovery of a neoplasia in a sebaceous nevus was incidental, and was not associated with any clinical change within the nevus.1377 The aid of an experienced pathologist is crucial for the correct diagnosis of any lesion complicating sebaceous nevi. In case treatment is desired, full thickness excision with a small 2–3 mm margin is the best choice. It should be noted that histopathological margins may be affected even in the absence of clinical involvement.1360 Most cases can be treated with simple closure or with rotation flaps. Other treatments such as derm­ abrasion, cryotherapy, electrocoagulation or carbon dioxide laser are frequently followed by recurrence, and can be used for improving cosmetic appearance in lesions difficult to excise; it should be stressed that these partial treatments do not eliminate the possibility of neoplasia in the future.

1374. Miller CJ, Ioffreda MD, Billingsley EM. Sebaceous carcinoma, basal cell carcinoma, trichoadenoma, trichoblastoma, and syringocystadenoma papilliferum arising within a nevus sebaceus. Dermatol Surg. 2004;30(12 Pt 2):1546–1549. 1375. Ackerman AB, Reddy VB, Soyer HP. Neoplasms with follicular differentiation. Kingsport, TN: Ardor Scribendi; 2001. 1376. Altaykan A, Ersoy-Evans S, Erkin G, et al. Basal cell carcinoma arising in nevus sebaceous during childhood. Pediatr Dermatol. 2008;25:616–619. 1377. Rosen H, Schmidt B, Lam HP, et al. Management of nevus sebaceous and the risk of basal cell carcinoma: An 18-year review. Pediatr Dermatol. 2009;26(6):676–681. 1378. Belhadjali H, Moussa A, Yahia S, et al. Simultaneous occurrence of two squamous cell carcinomas within a nevus sebaceous of Jadassohn in an 11-year-old girl. Pediatr Dermatol. 2009;26:236–237. 1379. Turhan-Haktanir N, Demir Y, Tokyol C. A case of eccrine spiradenoma arising in nevus sebaceous in an adolescent girl. Am J Dermatopathol. 2008;30(2):196–197. 1380. Ujiie H, Kato N, Natsuga K, et al. Keratoacanthoma developing on nevus sebaceous in a child. J Am Acad Dermatol. 2007;56(2 Suppl):S57–S58. 1381. Davis DA, Cohen PR. Hair follicle nevus: case report and review of the literature. Pediatr Dermatol. 1996;13:135–138. 1382. Ban M, Kamiya H, Yamada T, et al. Hair follicle nevi and accessory tragi: variable quantity of adipose tissue in connective tissue framework. Pediatr Dermatol. 1997;14:433–436.

FOLLICULAR NEVI Antonio Torrelo and Cristina López-Obregón HAIR FOLLICLE NEVUS Hair follicle nevus is a rare hamartoma with only 26 cases reported in the literature.1381–1387 It usually presents at birth as a solitary skin-colored papule, usually located on the face1388 and in 50% of cases in the territory of the first branchial arch. Multiple hair follicle nevi have also been reported, either in the form of lines of Blaschko on the face1385 or as extensive unilaterally distributed lesions.1386 A case of leptomeningeal angiomatosis and seizures accompanied by three hair follicle nevi around the eye and ipsilateral alopecia has been reported.1383 Histologically, the hair follicle nevus is characterized by the presence of multiple follicles in the dermis, with associated sebaceous glands and arrector pili muscles.1381 It is necessary to exclude the presence of cartilage or central epithelial lined cystic structures for a correct differential diagnosis with accessory tragus and trichofolliculoma, respectively. Simple excision for cosmetic reasons is the treatment of choice of hair follicle nevus.

FOLLICULAR NEVI

been reported.1374 It should be stressed that many neoplasms arising in sebaceous nevi do not correspond precisely to welldescribed entities, and thus are difficult to classify;1375 furthermore, misdiagnosis of some cases is possible, as is the case for pseudoepitheliomatous hyperplasia easily confused with squamous cell carcinoma. Although most cases of neoplasia from sebaceous nevus appear in adult life, there are some reports of benign and malignant tumors developed before or at puberty.1376–1379 Of these, malignant tumors are most worrisome, and basal cell carcinomas are the most frequent. So far, 14 cases of basal cell carcinoma on a sebaceous nevus have been reported in patients below the age of 17; furthermore, two documented cases of squamous cell carcinoma and one of keratoacanthoma have been reported in children.1380

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NEVUS COMEDONICUS AND MUNRO NEVUS Nevus comedonicus is a rare malformation of the pilosebaceous apparatus, which is usually present at birth but can appear in childhood or even later in adult life. It appears as multiple dilated follicular orifices with keratin, grouped in a plaque ranging from a few centimeters to lesions affecting one-half of the body1389 which usually follows the lines of Blaschko (Fig. 7.118). In other cases, round or oval plaques with grouped comedones are seen. The nevus comedonicus is often asymptomatic, but can become inflamed1390 leading to pustules, abscesses and scarring simulating acne vulgaris. Face, neck, upper arm, and chest are mainly affected. Palms, soles and glans penis, where pilosebaceous follicles are normally absent, may occasionally be involved, usually in association with lesions in more characteristic locations, and often contiguous to them.1391,1392

1383. Okada Y, Hamano K, Iwasaki N, et al. Leptomeningeal angiomatosis accompanied by hair follicle nevus. Childs Nev Syst. 1998;14:218–221. 1384. Kuwahara H, Lao LM, Kiyohara T, et al. Hair follicle nevus occurring in frontonasal dysplasia: an electron microscopic observation. J Dermatol. 2001;28:324–328. 1385. Germain M, Smith KJ. Hair follicle nevus in a distribution following Blaschko’s lines. J Am Acad Dermatol. 2002;46: S125-S127. 1386. Ikeda S, Kawada J, Yaguchi H, et al. A case of unilateral, systematized linear hair follicle nevi associated with epidermal nevus-like lesions. Dermatology. 2003;206:172–174. 1387. Motegi S, Amaro H, Tamura A, et al. Hair follicle nevus in a 2-year old. Pediatr Dermatol. 2008;25:60–62. 1388. Pippione M, Aloi F, Depaoli MA. Hair-follicle nevus. Am J Dermatopathol. 1984;6:245–247. 1389. Kirtak N, Inaloz HS, Karakok M, et al. Extensive inflammatory nevus comedonicus involving half of the body. Int J Dermatol. 2004;43:434–436. 1390. Vasiloudes PE, Morelli JG, Weston WL. Inflammatory nevus comedonicus in children. J Am Acad Dermatol. 1998;38:834–836. 1391. Harper KE, Spiel Vogel RL. Nevus comedonicus of the palm and wrist. J Am Acad Dermatol. 1985;12:185–188. 1392. Abdel-Aal H, Abdel-Aziz AHM. Nevus comedonicus: report of three cases localised on glans penis. Acta Derm Veneorol. 1975;55:78–80.

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FOLLICULAR NEVI

Figure 7.118  Nevus comedonicus. Nevus comedonicus is a sporadic condition, although there are some familial cases. Reports of adult-onset NC are often associated with pre-existing herpes zoster infection, lichen planus, furunculosis, vaccination or trauma.1393 However, most cases are probably caused by a defect in the development of the hair follicle, reflecting mosaicism for a variety of mutations that can predispose to acne.1394 Acneiform nevi with predominant inflammatory lesions may represent a clonal sensitivity to androgens1272,1395–1398; hormonal changes at puberty may thus worsen the condition.1398 Munro and Wilkie1272 identified a somatic mutation of FGFR2 in the comedones from a patient with an acneiform nevus, but not in the surrounding normal skin; the same mutation is responsible for Apert syndrome, associated with severe comedo and cystic acne. At least a number of NCs, the ‘Munro nevi’, are mosaic manifestations of Apert syndrome. Anomalies in the central nervous system, eyes (ipsilateral cataract, corneal changes), bones (hemivertebrae, scoliosis and absence of the fifth ray of a hand) and skin have been reported in some patients with nevus comedonicus, a situation that is referred to as comedonicus nevus syndrome1399 (see below). Histopathology of nevus comedonicus shows a wide invagination of acanthotic epidermis, filled with concentric lamellae of keratin.1400 This probably corresponds to dilated hair follicles as hair shafts are occasionally seen in the lower part of the invagina-

1393. Guldbakke K, Khachemoune A, Deng A, et al. Naevus comedonicus: a spectrum of body involvement. Clin Exp Dermatol. 2007;32:488–492. 1394. Rogers M. Epidermal nevi and the epidermal nevus syndrome. Pediatr Dermatol. 1992;9:342–344. 1395. Gonzalez-Hermosa MR, Escario E, de la Heras C, et al. Acne naevus. Clin Exp Dermatol. 1990;15:154–155. 1396. Hughes BR, Cunliffe WJ. An acne naevus. Clin Exp Dermatol. 1987;12:357–359. 1397. Cooper MF, Hay JB, McGibbon D, et al. Androgen metabolism and sebaceous activity in clonal acne. J Invest Dermatol. 1976;66:261. 1398. Beerman H, Homan J. Naevus comedonicus. Arch Klin Exp Dermatol. 1959;208:325–341. 1399. Patrizi A, Neri I, Fiorentini C, et al. Nevus comedonicus syndrome: A new pediatric case. Pediatr Dermatol. 1998;15:304–306. 1400. Nabai H, Mehregan AH. Nevus comedonicus: a review of the literature and report of twelve cases. Acta Derm Veneorol. 1973;53:71–74. 1401. Larralde M, Abad ME, Santos Muñoz A, et al. Childhood flexural comedones. Arch Dermatol. 2007;143:909–911.

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tion, and rudimentary sebaceous glands may open into them. Arrector pili muscles are absent. Nevus comedonicus must be differentiated from childhood flexural comedones,1401 usually located on the axillae; skin bio­ psies show open comedones with follicular plugging and infundibular dilatation. The disorder familial dyskeratotic comedones is treated elsewhere in this text. Malignancy of NC is extremely rare, but basal cell carcinoma has been reported.1402 No treatment is usually required, except for cosmetic reasons or for recurrent inflammation. Both topical retinoic acid (0.025%–0.1%) and 12% ammonium lactate may sometimes improve the appearance of lesions and may help prevent secondary inflammation.1403 Topical salicylic acid and tacalcitol were of limited efficacy.1404,1405 Regular use of a comedo extractor may be useful to achieve cosmetic improvement. Extensive lesions with recurrent inflammation and cyst formation may be treated with systemic antibiotics, intralesional corticosteroids, isotretinoin or incision and drainage. Surgical excision may be appropriate, as superficial shaving or dermabrasion are followed by recurrence.

‘ACNE-FREE’ NEVUS A single case has been reported in a male teenager with severe papulopustular acne vulgaris of the back. Within the affected area, there were four circumscribed, bilateral and symmetrical zones which were completely free of acne lesions.1406 Biopsy revealed sebaceous glands that were smaller than the rest, and a reduced sebum excretion rate. A reduced conversion of testosterone to 5-alphadihydrotestosterone in the acne free areas was also demonstrated.

BASALOID FOLLICULAR HAMARTOMA The skin lesions of basaloid follicular hamartoma consist of multiple 2–3 mm skin-colored papules, sometimes associated with telangiectasias, which occasionally show central ulceration or have a central comedo-like plug.1407 The segment involved by basaloid follicular hamartoma may be hypopigmented or hyperpigmented, and it may show areas of atrophoderma or include cysts, verrucous papules and stria-like areas. Palmar and plantar atypical pitting has been reported.1408 The face, scalp, and, occasionally, the trunk are most commonly involved sites. This hamartoma is generally present from birth, and can appear sporadically or as part of an inherited syndrome.

1402. Alpsoy E, Durusoy C, Ozbilim G, et al. Nevus comedonicus syndrome: a case associated with multiple basal cell carcinomas and a rudimentary toe. Int J Dermatol. 2005;44:499–501. 1403. Milton GP, DiGiovanna JJ, Peck GL. Treatment of nevus comedonicus with ammonium lactate lotion. J Am Acad Dermatol. 1989;20:324–328. 1404. Wakahara M, Kiyohara T, Kumakiri M, et al. Bilateral nevus comedonicus: Efficacy of topical tacalcitol ointment. Acta Derm Veneorol. 2003;83:51. 1405. Milton GP, DiGiovanna JJ, Peck GL. Treatment of nevus comedonicus with ammonium lactate lotion. J Am Acad Dermatol. 1989;20:324–328. 1406. Cunliffe WJ, Ead RD, Perera WHD, et al. An acne-free naevus. Br J Dermatol. 1977;96:287–290. 1407. Horio T, Komura J. Linear unilateral basal cell nevus with comedo-like lesions. Arch Dermatol. 1978;114:95–97. 1408. Burck U, Held KR. Unilateral skin lesions, cataracts, optic glioma and retardation: a variant of the epidermal nevus syndrome? Dermatologíca. 1982;208–214.

Genodermatoses

DILATED PORE NEVUS A single case has been reported of this entity clinically indistinguishable from comedo nevus.1415 Dilated pore nevus consists of multiple papules with dilated follicular orifices in their centers filled with keratotic plugs. Histology shows aggregates of dilated follicular cysts similar to the dilated pore of Winer.

1409. Saxena A, Shapiro M, Kasper DA, et al. Basaloid follicular hamartoma: a cautionary tale and review of the literature. Dermatol Surg. 2007;33:1130–1135. 1410. Camisa C, Rossana C, Little L. Naevoid basal cell carcinoma syndrome with unilateral neoplasm and pits. Br J Dermatol. 1985;113:365–367. 1411. Mehregan AH, Baker S. Basaloid follicular hamartoma: three cases with localized and systematized unilateral lesions. J Cutan Pathol. 1985;12:55–65. 1412. Brownstein MH. Basaloid follicular hamartoma: solitary and multiple types. J Am Acad Dermatol. 1992;27:237–240. 1413. Naeyaert JM, Pauwels C, Geerts ML, et al. Cd-34 and Ki-67 staining patterns of basaloid follicular hamartoma are different from those in fibroepithelioma of Oinkus and other variants of basal cell carcinoma. J Cutan Pathol. 2001;28: S38–S41. 1414. Jih DM, Shapiro M, James WD, et al. Familiar basaloid follicular hamartoma: lesional characterization and review of the literature. Am J Dermatopathol. 2003;25:130–137. 1415. Resnik KS, Kantor GR, Howe NR, et al. Dilated pore nevus: a histologic variant of nevus comedonicus. Am J Dermatopathol. 1993;15:169–171. 1416. Jackson CE, Callies QC, Krull EA, et al. Hairy cutaneous malformations of palms and soles: a hereditary condition. Arch Dermatol. 1975;111:1146–1149. 1417. Schnitzler ML. Dysembryoplasie pilarie cinconscrite des paumes: un cas familial. Bull Soc Fr Dermatol Syphiligr. 1973;80:323–324. 1418. Camacho F, Campora RG. Circumscribed pilary dysembryoplasia of the palms. Dermatologica. 1991;182:63–64. 1419. Tantcheva-Poor I, Reinhold K, Krieg T, et al. Trichilemmal cyst nevus: A new complex organoid epidermal nevus. J Am Acad Dermatol. 2007;57: S72–S77.

HAIRY MALFORMATION OF THE PALMS AND SOLES This entity is characterized by the presence of hair on the palms, wrists, and medial aspect of the soles. The patients had no other associated symptoms. Only two familial cases and a sporadic one have been reported.1416–1418 This rare disorder seems to be transmitted as an autosomal dominant trait with definite male-tomale transmission. Biopsy shows skin containing hair follicles with no other abnormality.

TRICHILEMMAL CYST NEVUS Trichilemmal cyst nevus is an epidermal nevus recently described in a woman who presented from birth with hyperkeratotic skin lesions with a linear arrangement on both sides of her face and scalp and half of her body.1419 Over the years, lesions became elevated forming multiple cystic tumors covered with multiple filiform hyperkeratoses and comedo-like plugs and forming inflammation and fistulae. Four similar occurrences had been previously reported with more limited degree of involvement.1420–1423 Microscopic examination shows cysts with walls of epidermal cells, thus mimicking trichilemmal cysts which are derived from the outer root sheath of the deeper parts of hair follicle. Trichilemmal cyst nevus may be treated for cosmetic reasons or because of complications. Surgery is the treatment of choice.

APOCRINE NEVI

Basaloid follicular hamartoma has been clinically classified into five different forms:1409 (1) solitary to multiple papules with no definite pattern of distribution or other association; (2) unilateral plaque following Blaschko’s lines; (3) plaque with alopecia (typical of the scalp); (4) a generalized dominantly inherited familial type; or (5) as generalized papules associated with diffuse alopecia and myasthenia gravis (if acquired) or cystic fibrosis (if congenital). An association of basaloid follicular hamartoma with bone changes and palmar pits has been reported, suggesting that these cases represent examples of mosaic Gorlin syndrome.1410 Histopathology shows strands of basaloid or squamous cells that proliferate downwards from the follicular infundibulum forming a network, and horn cysts surrounded by poor stroma.1411,1412 This histological pattern can simulate infundibulocystic basal cell carcinoma, a histological subtype of basal cell carcinoma involving the follicular epithelium. Immunohistochemical staining can be helpful in distinguishing these lesions, as bcl-2 is rarely found in the cytoplasm of basaloid follicular hamartoma but is abundantly positive in basal cell carcinoma.1413 The proliferation cell nuclear antigen and Ki-67 markers stain less intensely in basaloid follicular hamartoma compared to basal cell carcinoma.1413,1414 Finally, basaloid follicular hamartoma exhibits lower expression levels of Patched genes (PTCH), consistent with its benign behavior. Treatment, if required, is usually surgical.

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APOCRINE NEVI APOCRINE NEVUS ’True’ apocrine nevus is rare, and presents as a solitary nodule on the scalp1424 or as bilateral lesions located on the axillae or upper chest.1425–1428 On the other hand, apocrine structures can be an important part of the histology of organoid nevi, including sebaceous nevus1429 or syringocystadeno-

1420. Leppard BJ. Trichilemmal cysts arising in an extensive comedo nevus. Br J Dermatol. 1977;96:545–548. 1421. Iglesias Zamora ME, Vázquez-Doval FJ. Epidermal naevi associated with trichilemmal cysts and chromosomal mosaicism. Br J Dermatol. 1997;137:821–824. 1422. Sevila Llinares A, Belinchón Romero I, Silvestre Salvador JF, et al. Quistes de milium sobre nevo epidérmico. Piel. 1996;11:52–55. 1423. Flórez A, Peteiro C, Sánchez-Aguilar D, et al. Three cases of type 2 segmental manifestation of multiple glomus tumors: association with linear multiple trichilemmal cysts in a patient. Dermatology. 2000;200:75–77. 1424. Civatte J, Tsoitis G, Preaux J. Le naevus apocrine : étude de 2 cas. Ann Dermatol Syphiligr. 1974;101:251–261. 1425. Ando K, Hashikawa Y, Nakashima M, et al. Pure apocrine nevus. Am J Dermatopathol. 1991;13:71–76. 1426. Kim JH, Hur H, Lee CW, et al. Apocrine nevus. J Am Acad Dermatol. 1988;18:579–581. 1427. Neill JSA, Park HK. Apocrine nevus: light microscopic, immunohistochemical and ultrastructural studies of a case. J Cutan Pathol. 1993;20:79–83. 1428. Rabens SF, Naness JI, Gottlieb BF. Apocrine gland organic hamartoma (apocrine nevus). Arch Dermatol. 1976;112:520–522. 1429. Ng WK. Nevus sebaceus with apocrine and sebaceous differentiation. Am J Dermatopathol. 1996;18:420–423.

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matosus papilliferum nevus.1430 Histological examination shows the presence of apocrine glands extending from the upper dermis and reaching the subcutaneous fat. Malignant transformation of ‘pure’ apocrine nevi is rare but it has been reported.1431

SYRINGOCYSTADENOMA PAPILLIFERUM

ECCRINE NEVI

Syringocystadenoma papilliferum or syringocystadenoma­ tosus papilliferum nevus is a rare hamartoma of the apocrine skin structures. Its clinical presentation is varied.1432–1435 It sometimes appears as a linear group of nodules or a plaque, usually present at birth. The plaque is usually located in an alopecic area in the scalp, whereas the linear form is more common on the face and neck. The lesions may become more elevated, verrucous or hyperkeratotic, thus mimicking sebaceous nevus. More frequently, syringocystadenoma papilliferum is associated with a preexisting organoid nevus sebaceus and other adnexal nevi.1430 Syringocystadenoma papilliferum can also appear as a solitary nodule, often located on the shoulders, axillae or genitals. It usually grows during puberty as a pink or skin color solitary nodule with a central pore which sometimes drains material. Pathogenesis of this hamartoma is unknown but mutations have been identified in the PTCH or p16 tumor suppressor gene.1436 Histology of syringocystadenoma papilliferum is uniform and characteristic. Cystic invaginations are connected to the surface of the skin through the infundibular epithelium. Two layers of glandular epithelium (tall columnar luminal cells and cuboidal basaloid basal cells) are seen, often with papillary projections.1432,1433 Glandular epithelium sometimes shows decapitation secretion typical of apocrine glands. Plasma cells are the main component of the infiltrate in the stroma. Basal cell carcinoma has been reported to develop in up to 9% of cases of syringocystadenoma papilliferum, usually indicated by ulceration or rapid enlargement.1433 Verrucous carcinoma and ductal sweat carcinoma have also been described associated with syringocystadenoma papilliferum. These malignant neoplasms typically occur in syringocystadenoma papilliferum arising in sebaceous nevus. Although pulsed carbon dioxide laser treatment can be tried,1437 complete surgical excision of the lesion is the recommended therapy. 1430. Misago N, Narisawa Y. Syringocystadenoma papilliferum with extensive apocrine nevus. J Dermatol. 2006;33:303–305. 1431. Nishikawa Y, Tokusashi Y, Saito Y, et al. A case of apocrine adenocarcinoma associated with hamartomatous apocrine gland hyperplasia of both axillae. Am J Surg Pathol. 1994;18:832–836. 1432. Pinkus H. Life history of naevus syringocystadenomatous papilliferus. Arch Dermatol Syphilol. 1954;69:305–322. 1433. Helwing EB, Hackney VC. Syringadenoma papilliferum: lesions with and without naevus sebaceus and basal cell carcinoma. Arch Dermatol. 1955;71:361–372. 1434. Goldberg NS, Esterly NB. Linear papules on the neck of a child. Arch Dermatol. 1985;121:1197–1202. 1435. Rostan SE, Waller JD. Syringocystadenoma papilliferum in an unusual location: report of a case. Arch Dermaol. 1976;112:835–836. 1436. Boni R, Xin H, Hohl D, et al. Syringocystadenoma papilliferum: a study of potential tumour suppressor genes. Am J Dermatopathol. 2001;23:87–89.

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ECCRINE NEVI Different types of nevi of eccrine origin are recognized. As with other types of epidermal nevi, eccrine gland tissue may be the only hamartomatous growth present within the nevus (the ‘pure’ eccrine nevus) or may be part of an organoid epidermal nevus. Furthermore, other distinct eccrine gland derived nevi, the eccrine angiomatous hamartomas and the porokeratotic adnexal ostial nevus, will be discussed.

ECCRINE NEVUS Pure eccrine nevi are composed solely of an increased number and/or size of structurally normal eccrine glands.1438,1439 Eccrine nevi are rare, and fewer than 30 cases have been reported in the English literature.1438 They usually appear at birth or during childhood, but have been described to appear even at advanced age. Eccrine nevi affect equally males and females. A single localized patch of hyperhidrosis with minimal surface changes is the most common presentation; increased temperature, stress and exercise induce episodes of hyperhidrosis from the patch, but often sweating occurs in the absence of precipitating factors. Half the reported cases have appeared on the forearm, but the back and the trunk can also be affected. Other clinical presentations include skin-color or slight brown papules,1438 a centrally depressed patch with a scaly border,1438 and a coccygeal polypoid skin tag.1440 A linear distribution has also been reported,1441 as well as a segmental case which seemingly followed a broad Blaschko line or a single block.1438 So far, systemic non-cutaneous associations of ‘pure’ eccrine nevi have not been reported, and thus an ‘eccrine nevus syndrome’ does not exist. Treatment of ‘pure’ eccrine nevus includes topical preparations with aluminum chloride, and oral use of anticholinergic drugs, such as antidepressants and clonidine, though these are rarely required in children.1438 Surgical excision is not always practical. Intralesional injections of botulin toxin have been effective in a limited number of cases.1442 As previously stated, eccrine gland tissue may be part of an organoid nevus, usually with predominantly sebaceous hamartomatous growth. Furthermore, eccrine gland hamartomas have been reported to occur in association with syringocystadenoma papilliferum1443 and clear cell syringoma.1439 ‘Pure’ eccrine nevi may show histologically acanthosis, papillomatosis and ortho­ keratotic hyperkeratosis; a single case of overlapping features of eccrine nevus and acantholytic dyskeratotic epidermal nevus has been reported.1444 1437. Jordan JA, Brown OE, Biavati MJ, et al. Congenital syringocystadenoma papilliferum of the ear and neck treated with the CO2 laser. Int J Pediatr Otorhinolaryngol. 1996;38:81–87. 1438. Salama H, Shwayder T. Eccrine nevus presenting as a hypopigmented patch. Pediatr Dermatol. 2008;25:613–615. 1439. Lee WJ, Chang SE, Lee MW, et al. Bilateral mucinous eccrine nevus in an adult. J Dermatol. 2008;35:552–554. 1440. Oh SW, Kang TW, Kim YC, et al. Coccygeal polypoid eccrine naevus. Br J Dermatol. 2007;157:614–615. 1441. Morris ES, Sheel MM, Lundquist KF, et al. Grouped papules on the arm of an infant. Arch Dermatol. 2000;136:547–552. 1442. Honeyman JF, Valdés R, Rojas H, et al. Efficacy of botulinum toxin for a congenital eccrine naevus. J Eur Acad Dermatol Venereol. 2008;22:1275–1276. 1443. Philipone E, Chen S. Unique case: syringocystadenoma papilliferum associated with an eccrine nevus. Am J Dermatopathol. 2009;31:806–807. 1444. Shaffer HC, Schosser R, Phillips C. Acantholytic dyskeratotic epidermal nevus with eccrine differentiation: a case report and review of literature. J Cutan Pathol. 2009;36:1001–1004.

Genodermatoses

ECCRINE ANGIOMATOUS HAMARTOMAS Eccrine gland hamartomas may appear in close vicinity with blood vessel proliferations, leading to distinct clinicopathological entities and varieties that we group together under this headline.

Eccrine angiomatous hamartoma The eccrine angiomatous hamartoma (EAH) is present at birth in almost 50% of patients, or appears later in childhood in 25%;1449,1450 cases of adult onset are well recognized.1451 It affects equally males and females, and is usually a solitary lesion with a clear predisposition to be located on the extremities (>80%), followed by the trunk and neck.1449 Rarely, multiple lesions are present in a patient, and a familial case has been reported.1452 The clinical appearance is variable, as plaques, nodules, and papules with a red, blue-reddish, violaceous, yellow, or brown to flesh color. EAH is usually asymptomatic, but pain and hyperhidrosis have occurred in more than 40% and 30% of cases, respectively.1450 Most cases of EAH enlarge according to the relative body size, but sudden enlargement has been noted at puberty or during pregnancy, possibly because of hormonal stimulation. Exceptionally, EAH has shown spontaneous resolution. EAH has been reported in one patient with neurofibromatosis type 11453 and in one with Cowden syndrome.1454 Whether such associations are more than a chance is unknown.

1445. Chen J, Sun JF, Zeng XS, et al. Mucinous eccrine nevus: a case report and literature review. Am J Dermatopathol. 2009;31:387–390. 1446. Yoshizawa J, Hozumi Y, Katagiri Y, et al. Mucinous eccrine naevus. J Eur Acad Dermatol Venereol. 2009;23:348–349. 1447. Lee WJ, Chang SE, Lee MW, et al. Bilateral mucinous eccrine nevus in an adult. J Dermatol. 2008;35:552–554. 1448. España A, Marquina M, Idoate MA. Extensive mucinous eccrine naevus following the lines of Blaschko: a new type of eccrine naevus. Br J Dermatol. 2006;154:1004–1006. 1449. Larralde M, Bazzolo E, Boggio P, et al. Eccrine angiomatous hamartoma: report of five congenital cases. Pediatr Dermatol. 2009;26:316–319. 1450. Foshee JB, Grau RH, Adelson DM, et al. Eccrine angiomatous hamartoma in an infant. Pediatr Dermatol. 2006;23:365–368. 1451. Jeong E, Park HJ, Oh ST, et al. Late-onset eccrine angiomatous hamartoma on the forehead. Int J Dermatol. 2006;45:598–599. 1452. García-Arpa M, Rodríguez-Vázquez M, Cortina-de la Calle P, et al. Multiple and familial eccrine angiomatous hamartoma. Acta Derm Venereol. 2005;85:355–357. 1453. Castilla EA, Schwimer CJ, Bergfeld WF, et al. Eccrine angiomatous hamartoma in a neurofibromatosis type-1 patient. Pathology. 2002;34:378–380.

In EAH there is a combination of hyperplastic eccrine glands in intimate association with foci of dilated capillaries located at the dermal-subcutaneous level.1449 Both are embedded within a loose fibrous tissue stroma. In some cases, there are variable amounts of pilar, lipomatous, mucinous and lymphatic structures. In some patients, EAH is associated with prominent epidermal changes reminiscent of epidermal nevi, suggesting that EAH may be part of more complex hamartomas;1450 in this way, a linear hamartoma with features of verrucous epidermal nevus, sebaceous nevus, and EAH has been reported. Mucin deposition was prominent in two cases, which also had pilar structures.1455 In the so-called eccrine angiokeratomatous hamartoma, features of angiokeratoma or verrucous angioma overlie typical structures of EAH.1456 In another report of EAH, the lesion contained also a mixture of blood vessels with hybrid features of arterioles and venules.1457 All these cases highlight the complex nature of skin hamartomas. Treatment of EAH is usually unnecessary, but is indicated in case of severe pain, discomfort or cosmetic concern. Surgical removal may be a definite option. Botulinum toxin was successful in a single patient with EAH.1458

ECCRINE NEVI

A recognized variant of ‘pure’ eccrine nevus is the so-called mucinous eccrine nevus, which is characterized by mucin deposits surrounding the increased normal-looking eccrine structures.1445 It may appear at birth, during childhood or even in adult life, and presents as a solitary circumscribed area of hyperhidrosis, a solitary pore discharging a mucoid substance, a bandlike plaque or a papule, nodule, plaque or polypoid mass without hyperhidrosis.1445 Frequently involved sites are the extremities, buttocks and toes. Multiple grouped nodules,1446 as well as bilateral1447 lesions, have been described, and even a single patient with a Blaschkolinear arrangement.1448 The reasons for increased mucin deposits between the eccrine glands are largely unknown.

7

Other variants The term sudoriparous angioma has been used interchangeably with EAH in many reports, but some authors classify it as a separate entity, because of a more dominant angio­ matous component and because the eccrine elements are not truly hyperplastic but only dilated.1450 The term ‘angiomyxoid eccrine nevus’ has been coined for a unique eccrine hamartoma with abnormal eccrine coils and ramified strands of eosinophilic cells with ductal eccrine differentiation, that were associated with numerous capillary vessels and an abundant myxoid stroma.1459 Finally, a different type of eccrine angiomatous hamartoma consisting of congenital, multifocal, segmental lesions resembling nevus flammeus on the trunk of a boy showing hyperthermia and hyperhidrosis has been reported;1460 histopathologically, ectatic thin-walled vascular channels were intermingled with eccrine glandular coils.

1454. Oh JG, Yoon CH, Lee CW. Case of Cowden syndrome associated with eccrine angiomatous hamartoma. J Dermatol. 2007;34:135–137. 1455. Tsunemi Y, Shimazu K, Saeki H, et al. Eccrine angiomatous hamartoma with massive mucin deposition. Eur J Dermatol. 2005;15:291–292. 1456. Kanitakis J, Ly A, Claudy A. Eccrine angiokeratomatous hamartoma: a new variant of eccrine hamartoma with angiokeratoma. J Am Acad Dermatol. 2006;55(5 Suppl):S104–S106. 1457. Chien AJ, Asgari M, Argenyi ZB. Eccrine angiomatous hamartoma with elements of an arterio-venous malformation: a newly recognized variant. J Cutan Pathol. 2006;33:433–436. 1458. Barco D, Baselga E, Alegre M, et al. Successful treatment of eccrine angiomatous hamartoma with botulinum toxin. Arch Dermatol. 2009;145:241–243. 1459. Battistella M, Fraitag S, Cribier B. A unique presentation of eccrine hamartoma: eccrine nevus with abnormal eccrine structures and angiomyxoid stroma. Am J Dermatopathol. 2009;31(7):682–684. 1460. Toll A, Gallardo F, Jucglà A, et al. Multifocal segmental hyperthermic and hyperhidrotic naevus flammeus: a peculiar variant of eccrine angiomatous hamartoma? Clin Exp Dermatol. 2007;32:696–698.

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Neonatal and Inherited Disorders

THE GROUP OF EPIDERMAL NEVUS (EN) SYNDROMES

Figure 7.119  Porokeratotic adnexal ostial nevus (PAON).

POROKERATOTIC ADNEXAL OSTIAL NEVUS The term porokeratotic adnexal ostial nevus (PAON)1461 encompasses two types of nevi previously named porokeratotic eccrine ostial and dermal duct nevus (PEODDN) and porokeratotic eccrine and hair follicle nevus (PEHFN), which show evident clinical and histopathological overlap. Approximately 40 cases under the name PEODDN and two under PEHFN have been reported in the literature, but undoubtedly PAON is much more common than reported. PAON usually appears at birth or during childhood, but its onset may be delayed to puberty and adulthood.1461 Both sexes are equally affected. The disease is sporadic, and a mechanism of somatic lethal mutation surviving by mosaicism is suspected. Clinically, individual lesions present as asymptomatic keratotic or verrucous papules with punctuate pits filled with a comedo-like keratin plug (Fig. 7.119). The papules almost invariably show a linear arrangement, affecting a single line or multiple lines of Blaschko. Multiple lesions can be unilaterally or bilaterally distributed.1462 Widespread erosions and ulcerations resembling Goltz syndrome may be the presenting sign in newborns.1461 Solitary lesions tend to appear in acral regions, and the palms and soles are preferentially affected; nails may be dystrophic. Lesions in widespread disease involve proximal extremities, trunk, buttocks, scalp, face, and neck.

1461. Goddard DS, Rogers M, Frieden IJ, et al. Widespread porokeratotic adnexal ostial nevus: Clinical features and proposal of a new name unifying porokeratotic eccrine ostial and dermal duct nevus and porokeratotic eccrine and hair follicle nevus. J Am Acad Dermatol. 2009;61(6):1060.e1–e14. 1462. Solomon LM, Fretzin DF, Dewald RL. The epidermal nevus syndrome. Arch Dermatol. 1968;97:273. 1463. Happle R. The group of epidermal nevus syndromes. Part I. Well defined phenotypes. J Am Acad Dermatol. 2010;63:1–22. 1464. Happle R. The group of epidermal nevus syndromes. Part II. Less well defined phenotypes. J Am Acad Dermatol. 2010;63:25–30. 1465. Gobello T, Mazzanti C, Zambruno G, et al. New type of epidermal nevus syndrome. Dermatology. 2000;201:51.

552

The skin affected by PAON may present anhidrosis and hair loss. No consistent extracutaneous anomaly has been reported in PAON, even in systematized disease. Anecdotal reports of hemiparesis, seizures and scoliosis, polyneuropathy and hyperthyroidism, developmental delay and hearing loss, and breast hypoplasia have been reported, but these manifestations may appear by chance.1463,1464 Once they appear, lesions of PAON tend to persist, but may progress within the same line of Blaschko, and some flattening may occur leading to less verrucous lesions. Squamous cell carcinoma (SCC) has been reported to occur in two patients and Bowen disease in one with PAON, and thus long-term follow-up of PAON is recommended.1461,1465 On histopathology, PAON shows a cornoid lamella centered on a dilated acrosyringium with loss of granular layer and dyskeratosis. The cornoid lamella may also appear over follicular infundibula.1461 Furthermore, the epidermis shows compact hyperkeratosis, acanthosis, and papillomatosis. An inflammatory infiltrate may be seen in some cases, and was strikingly lichenoid in one patient who developed SCC.1461 Although immunohistochemical and electron microscopy studies support an eccrine origin for PAON, its exact histogenesis and the origin of the cornoid lamella are unknown. Topical treatments including corticosteroids, calcipotriol, urea, dithranol and retinoids have been of limited benefit, if any. Phototherapy and cryotherapy are ineffective, as well as oral retinoids. Carbon-dioxide laser is partly beneficial, needing repeated treatments.1461 Surgical excision is the most effective therapy, but is barely acceptable.

THE GROUP OF EPIDERMAL NEVUS (EN) SYNDROMES It is well known that different types of epidermal nevi may be associated with an array of extracutaneous defects.1462 Although the term EN can be applied to any nevus derived from any epidermal component (including keratinocytes and epidermal adnexae), it is clear that different types of EN syndrome exist, according to the cellular component of the EN involved and its expression, the consistent extracutaneous features associated, and the pattern of heredity.1463–1467

SCHIMMELPENNING SYNDROME Schimmelpenning syndrome (also called Schimmelpenning– Feuerstein–Mims or sebaceous nevus syndrome) associates sebaceous nevus (SN) with CNS, ocular and skeletal abnormalities (Fig. 7.120).1468–1470 It is not known the exact number of

1466. Oranje AP, Przyrembel H, Meradji M, et al. Solomon’s epidermal nevus syndrome (type: linear nevus sebaceus) and hypophosphatemic vitamin D-resistant rickets. Arch Dermatol. 1994;130:1167. 1467. Marsch WC, Taube KJ, Käsemann B. Ein Solitärfall von Ichthyosis hystrix gravior unilateralis – Klinische und morphologische Befunde. Z Hautkr. 1981;56:1073. 1468. Schimmelpenning GW. Klinischer Beitrag zur Symptomatologie der Phakomatosen. Fortschr Geb Röntgenstrahlen. 1957;87:716. 1469. Feuerstein R, Mims LC. Linear nevus sebaceus with convulsions and mental retardation. Am J Dis Child. 1962;104:125. 1470. Happle R. How many epidermal nevus syndromes exist? A clinicogenetic classification. J Am Acad Dermatol. 1991;25:550.

Genodermatoses

7

KERATINOCYTIC EPIDERMAL NEVUS (KEN) SYNDROME

THE GROUP OF EPIDERMAL NEVUS (EN) SYNDROMES

The existence of a true KEN syndrome is controversial.1470,1473 Approximately 7% of patients with KEN have systemic involvement,1473 mostly involving CNS, ocular, and skeletal systems. CNS abnormalities include developmental delay, seizures and variable structural disorders.1471,1473,1476 It must be emphasized that sebaceous hyperplasia may be minimal or absent in the lesions of a systematized nevus sebaceus involving the trunk or limbs,1477 and thus some patients with KEN may truly have Schimmelpenning syndrome. However, very recently a case has been reported of a FGFR3 mosaic mutation, the same as previously identified in epidermal nevi, in a patient with a systematized KEN and cerebral defects.1478 To date, no mutations in FGFR3 have been linked to sebaceous nevi.1264

NEVUS COMEDONICUS SYNDROME Figure 7.120  Schimmelpenning syndrome. This patient with large sebaceous nevus on his head and face has many CNS anomalies, as well as eyelid coloboma and lipodermoid.

This syndrome includes nevus comedonicus (NC), ipsilateral cataract, corneal changes, and skeletal defects such as hemivertebrae, scoliosis and absence of the fifth ray of a hand, usually ipsilateral.1464,1470,1479–1482 Cerebral involvement with EEG abnormalities and mental retardation has also occurred. A case with the development of multiple basal cell carcinomas has been reported.1482 NC syndrome most probably reflects a mosaic state of a lethal autosomal mutation.

children with SN who have associated CNS anomalies, but a figure of 200 µmol/L); phytanoyl-CoA hydroxylase activity assay in cultured fibroblasts; incr. phytanic acid/ pristanic acid ratio

Clinic; light microscopic hair shaft anaylysis under polarizing light

Peripheral blood smear to detect lipid vacuoles (oil stains on frozen skin biopsy material); molecular testing

Molecular testing fatty aldehyde; dehydrogenase activity assay in cultured fibroblasts

DIAGNOSTIC

ii Neonatal and Inherited Disorders

Ichthyosis and disorders of other cornification

PATHOGENESIS OF ICHTHYOSIS AND DISORDERS OF CORNIFICATION Gabriele Richard The skin is the barrier to the terrestrial environment. Its uppermost layer, the epidermis, is a highly specialized keratinizing epithelium designed to protect the organism from water loss and physical, chemical, and mechanical insults. In order to establish and constantly maintain this barrier, epidermal keratinocytes undergo a complex, highly organized and tightly controlled process of terminal differentiation, during which they migrate to the surface and form the stratum corneum. Keratin proteins are the major constituents of keratinocytes, representing 85% of the cellular protein.23 Keratins are a large family of over 20 proteins expressed in tissue and differentiation specific patterns. They form keratin intermediate filaments (KIF) and build an elaborate cytoskeleton, which provides structural stability and flexibility for epithelial cells.24 Keratins are expressed in pairs of acidic (type I) and basic (type II) proteins, the genes of which cluster on chromosomes 17q12–q21 and 12q11–q13. Keratin monomers are organized as a central, alpha-helical rod domain flanked by variable, non-helical head and tail domains. They form obligate heterodimers, which polymerize and assemble into KIF. Short, highly conserved regions at the boundaries of the

14. Anton-Lamprecht I. Ultrastructure of inborn errors of keratinization. I. Ichthyosis congenita. Arch Dermatol Forsch. 1972;243:88–100. 15. Anton-Lamprecht I. Ultrastructural identification of basic abnormalities as clues to genetic disorders of the epidermis. J Invest Dermatol. 1994;103: 6S–12S. 16. Niemi KM, Kanerva L, Kuokkanen K, et al. Clinical, light and electron microscopic features of recessive congenital ichthyosis type I. Br J Dermatol. 1994;130:626–633. 17. Niemi KM, Kanerva L, Wahlgren CF, et al. Clinical, light and electron microscopic features of recessive ichthyosis congenita type III. Arch Dermatol Res. 1992;284:259–265. 18. Niemi KM, Kanerva L, Kuokkanen K. Recessive ichthyosis congenita type II. Arch Dermatol Res. 1991;283:211–218. 19. Ghadially R, Williams ML, Hou SY, et al. Membrane structural abnormalities in the stratum corneum of the autosomal recessive ichthyoses. J Invest Dermatol. 1992;99:755–763. 20. Traupe H, ed. The ichthyoses. A guide to clinical diagnosis, genetic counseling, and therapy. Berlin: Springer Verlag; 1989. 21. Elias PM, Williams ML, Holleran WM, et al. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism. J Lipid Res. 2008;49:697–714.

rod segment, designated helix initiation motif (1A) and helix termination motif (2B), have been recognized as zones of overlap between aligned keratin proteins and are crucial for their proper assembly to KIF.25,26 In the epidermis, basal keratinocytes predominantly express keratins 5 and 14, while cells in the upper epidermis switch to the expression of the differentiation-specific keratins 1 and 10. Cells of the granular layers also produce keratin 2, which might assemble with keratin 10. Other sitespecific suprabasal keratins include keratin 9, found exclusively in palms and soles, and keratins 6, 16 and 17, which are expressed when the epidermis is stressed. Pathogenic mutations in 19 different keratin genes are responsible for a wide range of genodermatoses affecting skin, mucous membranes, hair, nails, and sebaceous glands. These mutations cluster at mutational ‘hot spots’ at the beginning and end of the central rod domain and disturb KIF assembly, resulting in perinuclear clumping of fragmented KIF and cell fragility, the hallmarks of keratin disorders. In analogy to a brick wall built from bricks and mortar, the stratum corneum contains two principal elements: protein-rich corneocytes (bricks) and a lipid-enriched extracellular matrix (mortar). The barrier function of the skin is accomplished by formation of the cornified cell envelope, an 8–15 nm structure that replaces the plasma membrane in terminally differentiating keratinocytes. It is a highly insoluble and tough polymer of proteins (protein envelope) and lipids (lipid envelope). The protein envelope results from sequential cross-linking of specialized precursor proteins, such as involucrin, small proline-rich proteins, elafin, cystatin A, and loricrin, with KIF and desmosomal proteins facilitated by epidermal transglutaminases.27 It confers chemical and mechanical resilience as well as water retention of corneocytes. The lipid envelope is formed by a monolayer of long-chain omega-hydroxyceramides, which are covalently attached to the outer surface of the protein envelope by ester bonds, a process which is again mediated by membranebound transglutaminase.28 These protein-linked ceramides coat the corneocytes and intervene with intercellular lipids in a comblike fashion. The lipid composition of the stratum corneum is markedly different from the lower epidermis. Instead of phospholipids, the stratum corneum contains large amounts of neutral lipids, such as cholesterol and free fatty acids, as well as polar lipids, such as ceramides and epidermis-specific omega-hydroxy and omega-hydroxyacyl ceramides. These lipids are synthesized in

PATHOGENESIS OF ICHTHYOSIS AND DISORDERS OF CORNIFICATION

and ultrastructural14–19 criteria, or combinations of them,1,20 which makes it difficult to correlate them with each other. Moreover, the nosology of ichthyoses is laden with descriptive names, eponyms and synonyms like few other dermatoses, resulting in much confusion and misconception. However, the spectacular advances in cell and molecular biology of the skin over the past 15 years have provided us with new means for establishing a refined classification that includes the molecular causes and the underlying pathomechanisms of disease, as attempted in Table 8.3. Recently, an international group of clinicians and researchers unified the nomenclature and classification of ichthyoses and other disorders of cornification to incorporate their molecular causes, and begin to establish a functional understanding of disease pathogenesis.13,21,22 The terms used in this chapter reflect some new designations from this consensus conference of international experts.22

8

22. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze. J Am Acad Dermatol. 2010; Jul 17 (epub). 23. Cheng J, Syder AJ, Yu QC, et al. The genetic basis of epidermolytic hyperkeratosis: a disorder of differentiation-specific epidermal keratin genes. Cell. 1992;70:811–819. 24. McLean WH, Lane EB. Intermediate filaments in disease. Curr Opin Cell Biol. 1995;7:118–125. 25. Lane EB. Keratin diseases. Curr Opin Genet Dev. 1994;4:412–418. 26. Fuchs E, Weber K. Intermediate filaments: structure, dynamics, function, and disease. Annu Rev Biochem. 1994;63:345–382. 27. Steinert PM, Marekov LN. The proteins elafin, filaggrin, keratin, intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope. J Biol Chem. 1995;270:17702–17711. 28. Nemes Z, Marekov LN, Fesus L, et al. A novel function for transglutaminase 1: attachment of long-chain omega-hydroxyceramides to involucrin by ester bond formation. Proc Natl Acad Sci USA. 1999;96: 8402–8407.

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Table 8.3  Etiological classification of disorders of cornification

Structural protein defects

SYSTEM

GENES

Keratin disorders

KRT1; KRT10 KRT2

PATHOGENESIS OF ICHTHYOSIS AND DISORDERS OF CORNIFICATION

Epidermolytic ichthyosis Superficial epidermolytic ichthyosis Epidermolytic KRT9 palmoplantar keratoderma Mosaic EI/epidermal KRT10; KRT1 nevus of the epidermolytic type KRT6A; KRT6B; Pachyonychia congenita KRT16; KRT17 I/II Focal non-epidermolytic KRT16 palmoplantar keratoderma Monilethrix KRT81 (hHb1); KRT86 (hHb6); KRT83 (hHB3) White sponge nevus KRT4; KRT13 Meesmann corneal KRT3; KRT12 dystrophy KRT1 KRT1

Disorders of the cornified cell envelope

LOR

FLG

Desmosomal disorders

Enzyme defects

574

Disorders of lipid metabolism and transport

DISORDER

DSP; DSG1

Mutations in epithelial keratin genes predominantly affect the boundaries of the alpha helical rod domain, and dominantly interfere with alignment and assembly of KIF. As a result, the KIF cytoskeleton is weakened and fragile, and may collapse under mechanical stress leading to cytolysis

Diffuse non-epidermolytic palmoplantar keratoderma Ichthyosis Curth–Macklin

Keratin mutations affecting the end domains of keratin-1, dominantly disturbing interaction with KIF-associated proteins and cytoplasmic KIF organization

Loricrin keratoderma (incl. mutilating keratoderma with ichthyosis and progressive symmetric erythrokeratoderma of the loricrin type) Ichthyosis vulgaris; presence of FLG mutations is most significant risk factor for atopic dermatitis, asthma associated with atopic dermatitis as well as systemic allergies Striate palmoplantar keratoderma

Frameshift mutations transform the tail domain of loricrin, impair formation of the cornified cell envelope and result in intranuclear accumulation of loricrin

JUP

Naxos disease

DSP

Dilated cardiomyopathy with wooly hair and keratoderma; skin fragility–wooly hair syndrome ARCI – lamellar ichthyosis ARCI – congenital ichthyosiform erythroderma

TGM1 (TGM1)

MECHANISM

Semidominant loss-of-function mutations lead to reduced or absent filaggrin expression, loss of protein cross-linking, and improper formation of the cornified cell envelope. The epidermal barrier function is disturbed, skin hydration is reduced and the skin is chronically exposed to irritants, allergens, and infectious agents Dominant mutations in desmoglein-1 and desmoplakin impair desmosomal cell adhesion and interaction with KIF (haploinsufficiency) Recessive mutations in plakoglobin and desmoplakin disrupt interactions of desmosomal proteins with KIF and weaken desmosomes and adherens junctions, thereby disturbing integrity of cells in skin, hair and myocardium

Recessive transglutaminase-1 mutations result in enzyme deficiency, which severely impairs protein cross-linking and esterification of epidermis-specific ceramides during formation of the protein and lipid envelope of corneocytes, and perturbs the skin barrier function

Ichthyosis and disorders of other cornification

8

Table 8.3  Etiological classification of disorders of cornification (continued) GENES

DISORDER

MECHANISM

ALOXE3

ARCI – congenital ichthyosiform erythroderma ARCI – congenital ichthyosiform erythroderma ARCI – congenital ichthyosiform erythroderma ARCI – lamellar ichthyosis

These two enzymes belong to the lipoxygenase family of non-heme, iron-containing dioxygenases, and function in hepoxilin pathway. LOXs catalyze oxygenation of free and esterified polyunsaturated fatty acids, involved in etablishing the epidermal lipid barrier

ALOX12B NIPAL4 (ICHTHYIN) CYP4F22 ABCA12 VPS33B

SNAP29

AP1S1

SLC27A4

Disorders of protein catabolism; proteases and their inhibitors

ARCI – harlequin ichthyosis ARCI – lamellar ichthyosis Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome CEDNIK syndrome (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) MEDNIK syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichtyosis, and keratodermia) Ichthyosis prematurity syndrome

ALDH3A2

Sjögren–Larsson syndrome

STS

X-linked recessive ichthyosis and other sulfatase deficiencies

EPB

X-linked dominant chondrodysplasia punctata

NSDHL

CHILD syndrome

MBTPS2

IFAP syndrome

ABHD5

Neutral lipid storage disease

SPINK5

Netherton syndrome

Transmembrane protein which is thought to serve as membrane receptor for lipid ligands (trioxylins) from the hepoxylin pathway Cytochrome P450 enzyme (ω-hydrolase) that also functions In lipoxygenase pathway ABC transporter responsible for energy-dependent transport of lipid substrates across membranes in keratinocytes PATHOGENESIS OF ICHTHYOSIS AND DISORDERS OF CORNIFICATION

SYSTEM

Recessive mutations inactivate a regulator of intracellular protein trafficking (SNARE-dependent membrane fusion), leading to abnormal secretion and entrapment of lamellar granules and disturbed permeability barrier Recessive null mutations result in loss of a SNARE protein involved in vesicle fusion, abnormal maturation of lamellar granules and mislocation of epidermal lipids and proteases Mutations disrupt the small subunit σ1A of the AP-1 complex, and hence perturb the assembly of clathrin-coated vesicles, cargo and vesicular trafficking between organelles

Fatty acid transporter protein, associated with reduced VLCFA-CoA synthetase activity and a reduced incorporation of VLCFA into neutral and polar lipids Recessive mutations inactivate fatty aldehyde dehydrogenase, which catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. As a result, the synthesis of epidermal lipids and the catabolism of ether phospholipids and sphingolipids in the brain are impaired Steroid sulfatase deficiency results in impaired hydrolysis of cholesterol sulfate leading to accumulation of cholesterol-3 sulfate in the epidermis. This inhibits epidermal serine proteases (kallikreins) and leads to retained corneodesmosomes and reduced and delayed desquamation Mutations in delta8-delta7 sterol isomerase (emopamil-binding protein) impair postsqualene cholesterol biosynthesis resulting in depletion of cholesterol and accumulation of intermediates. Cholesterol is a major structural element of plasma membranes and a precursor for the synthesis of steroids and bile acids. Sterol toxicity probably interferes with lipid biosynthesis Mutations in NSDHL impair postsqualene biosynthesis upstream to delta8-delta7 sterol isomerase Membrane zinc metalloprotease that activates signaling proteins involved in sterol control of transcription and ER stress response The encoded protein belongs to the subfamily of esterase/ lipase/thioesterase enzymes. It is thought that a defect in degradation of endogenously produced diacylgycerols to phospholipids results in widespread tissue deposition of neutral lipids Recessive mutations inactivate the serine proteinase inhibitor KAZAL type 5. Exact pathomechanisms remain to be elucidated

Continued

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Table 8.3  Etiological classification of disorders of cornification (continued) SYSTEM

GENES

DISORDER

MECHANISM

ST14

Autosomal recessive congenital ichthyosis with hypotrichosis Ichthyosis, follicular atrophoderma and hypotrichosis Papillon–Lefévre syndrome Haim–Munk syndrome

Recessive null mutations lead to deficiency of matriptase, a transmembrane serine protease, impaired degradation of corneodesmosomes, and retention hyperkeratosis

TAT

Richner–Hanhart syndrome

PEX7

Rhizomelic chondrodysplasia punctata type 1 Refsum disease

Tyrosine aminotransferase deficiency results in elevated serum tyrosine and deposition of tyrosine crystals in various tissues and body fluids Peroxisomal import disorder. Recessive mutations inactivate an import receptor for type 2 peroxisomal targeting sequences (PTS2). Several proteins depending on this pathway fail to be imported from cytosol into the peroxisomes, resulting in deficient plasmalogen biosynthesis and phytanic acid oxidation, while very long-chain fatty acid oxidation is normal. Recessive mutations inactivate the peroxisomal enzyme phytanoyl-CoA hydroxylase and impair degradation of phytanic acid, which subsequently accumulates in tissues and body fluids

ST14 CTSC CTSC

PATHOGENESIS OF ICHTHYOSIS AND DISORDERS OF CORNIFICATION

Disorders of amino acid metabolism Peroxisomal disorders

PHYH PEX7

Regulatory defects

Disorders of calcium homeostasis Disorders of cell–cell junctions

ATP2A2 ATP2C1

Darier disease Hailey–Hailey disease

Dominant mutations inactivate intracellular calcium pumps and thereby disturb calcium homeostasis of the epidermis

GJB3; GJB4

Erythrokeratodermia variabilis Diffuse palmoplantar keratoderma associated with hearing impairment Keratitis–Ichthyosis– Deafness syndrome Vohwinkel syndrome Oculodigitodental dysplasia Ichthyosis-sclerosing cholangitis syndrome

Dominant mutations in several epidermal connexin (gap junction protein) genes dominantly interfere with the formation or function of gap junctional intercellular channels and/or connexin hemichannels, which are implicated in cell-cell signaling and tissue homeostasis

GJB2 GJB2 (GJB6) GJB2 GJA1 CLDN1

Disorder of nucleotide excision repair and transcription defects

576

Allelic disorders caused by deficiency of the lysosomal protease cathepsin C (dipeptidyl aminopeptidase I), which is expressed in skin, gingiva, and a variety of immune cells. Exact pathomechanisms remain to be elucidated

ERCC2; ERCC3 Trichothiodystrophy GTF2H5, C7ORF11 Mal de Meleda ARS

Recessive mutations result in reduced or absent claudin 1, a tight junction protein, perhaps leading to defective epithelial polarization and/or regulation of permeability Recessive mutations inactivate two helicase subunits of the transcription/repair vector IFIIH, thereby impairing excision repair of UV-induced DNA damage. Recessive mutations result in deficiency of a secretory protein of the Ly-6/uPAR subfamily (SLURP-1), which is closely related to cytotoxins. Preliminary data suggest that SLURP-1 is involved in regulation of keratinocyte functions through the cholinergic pathways (via nicotinic acetylcholine receptors, has proapoptotic activity in vitro)

the spinous layers of the epidermis, where they are stored and transported as stacks of laminar sheets in lamellar bodies. With initiation of formation of the cornified cell envelope, lamellar bodies fuse with apical cell membranes in granular cells and extrude their contents into the intracellular space. Hydrolytic enzymes of the lamellar bodies transform glycolipids and phospholipids into free fatty acids and ceramides, respectively. Using the corneocyte lipid envelope as template, discharged lipids reorganize into intercellular lipid lamellae, which form broad double bilayers connecting with each other through intervening lipid monolayers. This arrangement results in the characteristic pattern of alternating electron dense and electron lucent bands visible by transmission electron microscopy with ruthenium tetroxide fixation. Together, lipid envelopes and intercellular lipid lamellae ‘glue’ corneocytes together and impede water loss through the skin. In a normal stratum corneum, 15–20 layers of corneocytes are stacked on top of each other. They are also held together by corneodesmosomes, which are successively degraded by proteolytic lamellar body enzymes to reduce their cohesiveness and allow desquamation of the outermost cells. Desquamation is a continuous, inconspicuous process by which individual corneocytes or small clumps of them are separated and exfoliated through frictional forces. Visible scaling as seen in ichthyosis is produced by exfoliation of clumps of 100– 500 or more adherent corneocytes. Normal desquamation is an orderly process of loss of corneocyte adhesion by proteolytic degradation of corneodesmosomes, which connect the corneocytes. This process mandates a strikingly delicate balance between several different proteases, their inhibitors and the pH milieu.13 Under normal conditions, epidermal cell proliferation and des­ quamation are in a steady-state. Any exogenous or endogenous process that disturbs this homeostasis is bound to impair the barrier function of the skin, eventually resulting in disease. Hyperkeratosis of the stratum corneum can stem from an increased number of cells produced by the epidermis (hyperproliferative ichthyosis), from delayed desquamation (retention hyperkeratosis), or a combination of both mechanisms. The formation of the stratum corneum is controlled by various factors. One of the most important regulators of key metabolic events during epidermal differentiation leading to barrier formation is intracellular calcium, the level of which increases from layer to layer throughout the epidermis.29 High intracellular calcium concentrations are critical for the expression and processing of differentiation-specific proteins, such as keratin-1, keratin10, profilaggrin, loricrin, involucrin, and others, as well as for the action of transglutaminases. Increased transepidermal water loss with ensuing changes in pH and ion concentration, in particular calcium and potassium, are thought to trigger factors for release of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-8, IL-10, interferon-γ, transforming growth factor (TGF)-α and -β and the adhesion molecule intercellular adhesion molecule-1 (ICAM1). These molecules can elicit a host of

different homeostatic responses, including: secretion of preformed lamellar bodies; increased lipid and lamellar body synthesis; stimulation of DNA synthesis to generate more corneocytes; and epidermal inflammation.30,31 Other modulators of terminal differentiation include retinoic acid, vitamin D, protein kinase C, urokinase, and transcription factors, all of which are still under investigation. In the last 15 years, genetic tools have been successfully applied to uncover the molecular basis of a large number of heritable disorders of the skin and its appendages, leading to identification of more than 300 disease genes.32 This knowledge substantially advanced our understanding of the process of cornification itself as well as the pathobiology of disorders of cornification. It is now possible to categorize ichthyoses and disorders of cornification, at least in part, on the basis of their underlying genetic defects and pathogenesis. These may affect: (1) structural (scaffolding) proteins of the epidermis, including keratins, desmosomal proteins, proteins of the cornified cell envelope; (2) proteins involved in lipid metabolisms and transport; (3) proteins involved in protein, and amino acid metabolism as well as (4) regulatory molecules controlling cornification such as calcium and connexins (Table 8.3). Keratin disorders, such as epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and epidermolytic palmoplantar keratoderma result from fragility of the KIF network of keratinocytes with ensuing epider­ molysis. However, faulty KIF may also directly interfere with the secretory function of lamellar bodies and other differentiationspecific proteins, thus impairing the permeability barrier of the skin. An increasing number of inherited congenital ichthyoses have been associated with defects in the lipid metabolism of the skin, hindering formation of the lipid envelope and intercellular lipid lamellae. For example, the lipid transporter protein encoded by the ABCA12 gene plays a pivotal role for maintaining the lipid balance in the epidermis, for transfer of epidermal lipids into lamellar bodies, and efflux of multiple lipids including cholesterol. If missing, as in patients with harlequin ichthyosis (a form of autosomal recessive congenital ichthyosis or ARCI) due to detrimental ABCA12 mutations, no lipid barrier is formed, the permeability barrier of the skin is completely deficient, and there is a lack of desquamation. Several other forms of ARCI stem from a lack of proteins that are directly involved in a common metabolic pathway catabolizing leukotriene derivates of arachidonic acid to 12(R)-hepoxilin A3 and other hydroxy­ epoxyalcohol end-products (hepoxilin pathway). PhytanoylCoA hydroxylase deficiency in Refsum disease impedes the normal synthesis of ceramides, while fatty aldehyde dehydrogenase deficiency in Sjögren–Larsson syndrome impairs synthesis of fatty acids. Loss of transglutaminase-1 activity in the ARCI phenotypes lamellar ichthyosis/congenital ichthyosiform erythroderma has profound effects on the cornified cell envelopes. The dual impairment of protein–protein cross-linkage as well as attachment of ceramides and formation of the lipid envelope

29. Menon GK, Elias PM. Ultrastructural localization of calcium in psoriatic and normal human epidermis. Arch Dermatol. 1991;127:57–63. 30. Elias PM, Feingold KR. Lipids and the epidermal water barrier: metabolism, regulation, and pathophysiology. Semin Dermatol. 1992;11: 176–182.

31. Proksch E, Holleran WM, Menon GK, et al. Barrier function regulates epidermal lipid and DNA synthesis. Br J Dermatol. 1993;128:473–482. 32. Leech SN, Moss C. A current and online genodermatosis database. Br J Dermatol. 2007;156:1115–1148.

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ICHTHYOSIS VULGARIS

leads to severe diminution of the skin barrier and hyperkeratosis. The basic defect in X-linked recessive ichthyosis is steroid sulfatase deficiency causing impaired hydrolysis of cholesterol sulfate and accumulation of cholesterol-3 sulfate in the epidermis. High levels of this metabolite inhibit the normal function of transglutaminase-1, thus explaining the partial phenotypic overlap between XLRI and lamellar ichthyosis, and underscoring the pivotal role of transglutaminase-1 in the cornified envelope formation and normal functioning of the stratum corneum. Disorders of cornification may also arise from genetic defects involving important regulators of epidermal differentiation. In the cases of Hailey–Hailey disease and Darier disease, a partially reduced function of intracellular calcium pumps negatively affects the calcium homeostasis of the epidermis and response to intercellular signaling. Connexin disorders are thought to arise from impaired gap junctional intercellular communication between keratinocytes and/or from ATP release through connexin hemichannels with ensuing effects on transport of ions such as calcium and cyclic nucleotides. The etiologic classification of ichthyoses and disorders of cornification based on the underlying genetic defects, although still preliminary and incomplete, is advancing the traditional nosology. Efforts to identify specific mutations and genotype– phenotype correlations advance our ability to diagnose these rare disorders with certainty, allow accurate family counseling, offer the opportunity for reliable and early prenatal testing, and will potentially lead to the development of targeted therapies for these disorders. This chapter will comprehensively review these forms of ichthyosis. Patient advocacy organizations such as the Foundation for Ichthyosis and Related Skin Types (FIRST: Tel: (800) 545 3286; e-mail: [email protected]; website: www.scalyskin.org) and the National Organization for Rare Disorders (NORD: Tel: (800) 999 6673; e-mail: [email protected]; website: www.rarediseases.org) offer valuable information material, facilitate personal contacts with other affected families, and support patients and their families.

ICHTHYOSIS VULGARIS Alan Irvine INCIDENCE Ichthyosis vulgaris (IV) is the most common disorder of kera­ tinization. Wells and Kerr studied 6061 pupils and found among them 24 children with ichthyosis vulgaris, which would correspond to a frequency of 4 in 1000 in the general population.33 In a much more recent and detailed study, Brown and colleagues examined 792 school-age children and found 10 of these children to have ichthyosis vulgaris – an incidence of 12.6 in 1000.34 33. Wells RS, Kerr CB. Clinical features of autosomal dominant and sex-linked ichthyosis in an English population. BMJ. 1966;1:947–950. 34. Brown SJ, Relton CL, Liao H, et al. Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children. Br J Dermatol. 2009;161:884–889. 35. Mevorah B, Marazzi A, Frenk E. The prevalence of accentuated palmoplantar markings and keratosis pilaris in atopic dermatitis, autosomal dominant ichthyosis and control dermatological patients. Br J Dermatol. 1983;112:679–685.

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Figure 8.1  Light gray scales in ichthyosis vulgaris covering the extensor surface of the legs (Courtesy Dr A. Torrelo).

CLINICAL FEATURES Signs of ichthyosis vulgaris are not present at birth, but usually develop during the first months of life. Typical cutaneous features of ichthyosis vulgaris include light white to gray scales covering mainly the extensor surfaces of the extremities and the trunk (Fig. 8.1). The groin and major flexures are always spared. Follicular keratoses projecting above the skin surface are a further characteristic sign of the disease, present in most affected children. According to Mevorah et al.35 follicular-based kera­tosis (keratosis pilaris) occurs in 75% of all ichthyosis vulgaris patients compared with 42% of the general population; Brown’s study found keratosis pilaris in 100% of patients with marked IV compared with 30% of the normal population.34 Accentuated palmoplantar markings (hyperlinearity) are a further hallmark of ichthyosis vulgaris and are found in 100% of patients homozygous for FLG mutations (see below) and 75% of those heterozygous for FLG null alleles.34 If the accentuation is marked, it may be of considerable diagnostic help (Fig. 8.2), but evaluation of accentuated palmoplantar creases may prove difficult if this sign is only mildly expressed, as is seen in many heterozygotes.36 Ichthyosis vulgaris is often associated with atopic dermatitis and carries an increased risk of associated asthma and food allergies.37 From a clinical point of view, it remains difficult to make a clear-cut distinction between X-linked recessive ichthyosis and ichthyosis vulgaris, and a survey showed that an accurate clinical diagnosis was achieved only in about 50% of the cases.38 In the author’s experience, the presence of palmar hyperlinearity 36. Smith FJD, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations in the filaggrin gene cause ichthyosis vulgaris. Nat Genet. 2006;38:337–342. 37. Irvine AD. Fleshing out filaggrin phenotypes. J Invest Dermatol. 2007;127:504–507. 38. Cuevas-Covarrubias SA, Kofman-Alfaro SH, Palencia AB, et al. Accuracy of the clinical diagnosis of recessive X-linked ichthyosis vs ichthyosis vulgaris. J Dermatol. 1996;23:594–597.

Ichthyosis and disorders of other cornification

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mother and daughter. When present this sign helps to rule out X-linked recessive ichthyosis. Some types of lamellar ichthyosis feature somewhat similar ‘ichthyosis hands’ (Courtesy Dr A. Torrelo).

Figure 8.3  Typical histology of ichthyosis vulgaris. Presence of follicular keratosis and marked reduction or even absence of the granular layer. Refsum disease and the Conradi–Hünermann–Happle syndrome can have a similar histology.

Until recently, the genetic basis of ichthyosis vulgaris was a matter of debate with predominantly autosomal dominant, but also recessive inheritance and multifactorial inheritance all postulated. In 2006 it was clearly shown that the condition was

inherited in an autosomal semi-dominant pattern with a more severe, classical phenotype in homozygotes and a milder (and occasionally absent) phenotype in heterozygotes.36 The same group clearly showed that IV was a monogenic disease caused by loss-of-function mutations in the FLG gene, which encodes the protein profilaggrin.36 Profilaggrin is maintained as an inactive pro-protein in the keratohyalin granules of the granular layer and subsequently is proteolytically cleaved to produce between 10 and 12 filaggrin polypeptide repeats. Filaggrin is responsible for keratin filament aggregation, conferring skin barrier function and also hydration of the stratum corneum via its breakdown products. (For a detailed review of filaggrin biology, see Sandilands et al.40) These loss-of-function mutations have since been shown to be the most significant genetic risk factors for eczema (atopic dermatitis) identified to date.41,42 Filaggrin mutations are highly population-specific; e.g., in the European and Japanese populations, the two best studied populations to date, several recurrent mutations are seen, but the recurrent European mutations are not seen in the Japanese population and vice versa.43 Thus, several founder mutations are likely to account for prevalent FLG mutations in many discrete populations, making mutation detection challenging. Furthermore, there are no particular highly mutated regions or ‘mutation hot spots’, as each mutation detected to date either is a missense mutation encoding a premature termination codon or insertions/deletions that predict downstream premature termination codons. The position of the mutations does not appear to have an effect on the disease given that any mutation upstream of the carboxy terminal appears to prevent full post-translational processing of profilaggrin into functional filaggrin repeats.40

39. Anton-Lamprecht I, Jofbauer UC. Ultrastructural distinction of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis. Hum Genet. 1972;15:261–264. 40. Sandilands A, Sutherland C, Irvine AD, et al. Filaggrin in the frontline: role in skin barrier function and disease. J Cell Sci. 2009;122:1285–1294. 41. Palmer CNA, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a

major predisposing factor for atopic dermatitis. Nat Genet. 2006;38: 441–446. 42. Baurecht H, Irvine AD, Novak N, et al. Towards a major risk factor for atopic eczema: meta-analysis of filaggrin mutation data. J Allergy Clin Immunol. 2007;120:1406–1412. 43. O’Regan GM, Sandilands A, McLean WH, et al. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2008;122:689–693.

and marked keratosis pilaris is often helpful. For a definite diagnosis, a detailed family history (including obstetric history of prolonged labor) and additional diagnostic measures, for example demonstrating in a skin specimen of reduced filaggrin (FLG) expression in IV or performing biochemical or genetic tests to exclude X-linked recessive ichthyosis, should be considered.

HISTOLOGIC AND ULTRASTRUCTURAL FEATURES A reduced granular layer, which may be completely lacking in parts of the biopsy, is the most outstanding histologic feature of ichthyosis vulgaris (Fig. 8.3). The stratum corneum usually displays a mild but compact orthohyperkeratosis. A reduced retepapillae pattern, occasional prominent follicular keratosis and reduction in the number of the sebaceous glands are further features of ichthyosis vulgaris.20 At the ultrastructural level, the diminished granular layer is reflected by reduced and abnormal keratohyalin granules which exhibit a crumbly and spongy appearance.39

BIOCHEMICAL AND GENETIC ASPECTS

ICHTHYOSIS VULGARIS

Figure 8.2  Accentuated palmoplantar markings in ichthyosis vulgaris in a

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Given the high cumulative population prevalence of filaggrin mutations in European populations of almost 10%, the possibility of these mutations modifying the expression of other ichthyotic disorders has been considered. Recently it has been shown in one family that carriage of a FLG loss of function mutation modifies the clinical severity of X-linked ichthyosis.44 Null mutations in FLG have also been associated with increased severity in patients with alopecia areata.45 The autosomal recessive mutation flaky tail (ft) mouse provides an interesting animal model for IV. Flaky tail mice have recently been shown to be null for FLG expression and to carry homozygous mutations in the murine filaggrin gene.46 Interestingly, they also are highly susceptible to transcutaneous allergen priming and allergic inflammation.46 RECESSIVE X-LINKED ICHTHYOSIS

THERAPY Usually, IV does not present a major therapeutic problem and responds well to topical ointments containing urea, lactic acid or NaCl. Urea should not be used on large body areas before the age of 1 year, and certainly IV should not be treated by ointments containing salicylate because this can cause life-threatening poisoning due to percutaneous absorption. Germann et al.47 reported a 7-year-old boy in whom therapy of IV with ointment containing 10% salicylic acid over large areas of the body surface resulted in a deep somnolent state after 4 weeks. The salicylate intoxication led to tinnitus, vomiting, wheezing and hyperventilation associated with metabolic acidosis and an anion gap. Therefore, in affected children, total body treatment with salicylic acid should be avoided.20

RECESSIVE X-LINKED ICHTHYOSIS Heiko Traupe INCIDENCE X-linked recessive ichthyosis (RXLI) is the second most common type of ichthyosis. Population genetics studies disclosed a minimum prevalence in the male population of 1 in 6390 in southern England33 and 1 in 9855 males in Japan.48 Routine screening of pregnancies in Denmark showed that the incidence of RXLI was 1 in 2000 males.49

CLINICAL FEATURES RXLI is the cutaneous manifestation of steroid sulfatase deficiency. Non-cutaneous manifestations of this enzyme defect include birth complications, cryptorchidism, and corneal opaci-

44. Liao H, Waters AJ, Goudie DR, et al. Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis. J Invest Dermatol. 2007;127:2795–2798. 45. Betz RC, Pforr J, Flaquer A, et al. Loss-of-function mutations in the filaggrin gene and alopecia areata: strong risk factor for a severe course of disease in patients comorbid for atopic disease. J Invest Dermatol. 2007;127:2539–2543. 46. Fallon PG, Sasaki T, Sandilands A, et al. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009;41:512–517. 47. Germann R, Schindera I, Kuch M, et al. Lebensbedrohliche Salizylatintoxikation durch perkutane Resorption bei einer schweren Ichthyosis vulgaris. Hautarzt. 1996;47:624–627.

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Figure 8.4  X-linked recessive ichthyosis. Typical rhombic yellow–brown hyperkeratosis in older children.

ties.50,51 Prenatal diagnosis of placental sulfatase deficiency has made it possible to follow the course of the disease from birth onwards. In a Danish study of 21 boys prenatally diagnosed as suffering from placental sulfatase deficiency, 19 displayed a general peeling of the skin with rather large, light and loosely attached scales over the entire integument at the age of 1–3 weeks.52 During the following weeks, this fine scaling was replaced by the typical polygonal dark and firmly attached scales of RXLI. The fine scaling in early life is not very striking, however, and usually escapes the attention of parents or nurses. When the patients or their parents are asked about the onset of the disease they usually say that it started at the age of 2–6 months. At that time, normally large thick dark-brown to yellow-brown hyperkeratoses cover the trunk, the extremities and the neck (Fig. 8.4). The face is spared except for preauricular scaling, and palms and soles are normal, which is of considerable clinical help in the differential diagnosis from ichthyosis vulgaris. The dark hyperkeratoses are especially prominent over the lateral aspects of the trunk and the back of the neck, resulting in ‘a dirty look’ which is a further typical feature of RXLI and usually not seen in ichthyosis vulgaris. Axillae and antecubital and popliteal

48. Sakura N, Nishimura SI, Matsumoto T, et al. Frequency of steroid sulfatase deficiency in Hiroshima. Acta Paediatr Jpn. 1998;40:63–64. 49. Lykkesfeldt G, Hoyer H, Ibsen HH, et al. Steroid sulfatase deficiency disease. Clin Genet. 1985;28:231–237. 50. Traupe H, Happle R. Clinical spectrum of steroid sulfatase deficiency: X-linked recessive ichthyosis, birth complications and cryptorchidism. Eur J Pediatr. 1983;140:19–21. 51. Unamuno P de, Martin C, Fernandez E. X-linked ichthyosis and cryptorchidism. Dermatologica. 1986;172:3226–3327. 52. Hoyer H, Lykkesfeldt G, Ibsen HH, et al. Ichthyosis of steroid sulfatase deficiency, clinical study of 76 cases. Dermatologica. 1986;172: 184–190.

Ichthyosis and disorders of other cornification

B RECESSIVE X-LINKED ICHTHYOSIS

A

8

Figure 8.5  X-linked recessive ichthyosis. Clinical aspects in a young boy and increased C

electrophoretic mobility in the patients (lanes P) contrasting with normal electromobility in the controls (lanes C). Patients with light-gray scaling are often misdiagnosed as having ichthyosis vulgaris (Courtesy Dr A. Torrelo).

fossae may be involved in some patients, but are often spared. This criterion therefore should not be used to separate the disease from ichthyosis vulgaris, which usually spares the antecubital and popliteal fossae completely. About 30% of patients do not have the classic dark-brown hyperkeratoses, but rather large, light-gray hyperkeratoses (Fig. 8.5). This occurs most commonly in younger boys, although brothers sharing the same mutation may show the classic yellow-brown hyperkeratoses in one and the other may show light-gray scaling. These latter patients are often erroneously thought to have ichthyosis vulgaris. Follicular keratosis (keratosis pilaris) is absent in RXLI clinically, although it may be seen occasionally in histopathological examinations. Female carriers of the disease gene may display a fine, silver-light scaling on the lower leg.53 Obstetric manifestations of steroid sulfatase deficiency include insufficient cervical dilatation, which may result in prolonged labor (failure-to-progress), necessitating cesarean section or forceps delivery. About 30% of boys postnatally diagnosed as having RXLI had a history of perinatal complications.39,51 Gonadal abnormalities are unusual, but include cryptorchidism (undescended testicles), which may be associated with decreased fertility, and in extreme cases, with hypogenitalism. One patient

with testicular cancer (but not cryptorchidism) has been described. At-risk pregnancies are detected by finding low maternal serum estriol on prenatal screening.54

53. Voss M. Clinical picture of X chromosome recessive ichthyosis. Dermatol Monatsschr. 1985;171:25–37 (in German). 54. Keren DF, Canick JA, Johansen MZ, et al. Low maternal serum unconjugated estriol during prenatal screening as an indication of placental steroid sulfatase deficiency and X-linked ichthyosis. Am J Clin Pathol. 1995;103:400–403.

55. Feinstein A, Ackermann AB, Ziprkowski L. Histology of autosomal dominant ichthyosis vulgaris and X-linked ichthyosis. Arch Dermatol. 1970;101:524–527. 56. Kerr CB, Wells, Sanger R. X-linked ichthyosis and the Xg groups. Lancet. 1964;2:1369–1370.

HISTOLOGICAL FEATURES Biopsied skin of patients with RXLI shows non-specific epidermal hyperplasia (Fig. 8.6), usually associated with a prominent granular layer and orthohyperkeratosis.20,55 Biopsy does not allow RXLI to be distinguished from mild forms of autosomal recessive congenital ichthyosis (ARCI, includes lamellar ichthyosis).

BIOCHEMICAL AND GENETIC ASPECTS RXLI was one of the first genetic skin diseases that was mapped by classic linkage analysis, namely a close linkage with the Xg-blood group to the X-chromosome.56 The family tree may help to make the diagnosis, especially if a maternal grandfather and other maternal male relatives are involved with sparing of female carriers (indicating an X-linked recessive mode of inheritance) (Fig. 8.7).

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KERATINOPATHIC ICHTHYOSES: EPIDERMOLYTIC ICHTHYOSIS (EI) AND SUPERFICIAL EPIDERMOLYTIC ICHTHYOSIS (SEI)

Figure 8.6  X-linked recessive ichthyosis. Typical histology with prominent granular layer and orthohyperkeratosis. It is not possible to exclude mild forms of autosomal recessive lamellar ichthyosis such as transglutaminase-1-deficiency by routine histopathology.

with the number of X-chromosomes.59 Female carriers can be detected by fluorescent in situ hybridization (FISH) on meta­ phase blood cells; about 90% of all patients have a large deletion (2–3 megabases) on the short arm of the X-chromosome.60 Testing steroid sulfatase activity is the ultimate way to make an accurate diagnosis of the disease, but the test is performed in few laboratories. An increased electromobility of β-lipoprotein is a convenient way to screen for steroid sulfatase deficiency, but must be determined by a trained reader.61,62 Highly elevated serum cholesterol sulfate levels (10-fold) can be determined by chromatography,63 but these techniques are usually not available for routine diagnosis. The development of scaling in RXLI has been attributed to the perturbed epidermal cholesterol sulfate cycle and the accumulation of cholesterol sulfate. Increased cholesterol sulfate inhibits epidermal serine proteases such as kallikreins.64 This results in retained corneodesmosomes and consequently in decreased and delayed desquamation of corneocytes and the features of a ‘retention hyperkeratosis’. Rarely, patients with RXLI present with additional clinical features due to a contiguous gene deletion, in particular, mental retardation, Kallmann syndrome (short statue and chondrodysplasia punctata), sometimes in association with hypertrophic pyloric stenosis and unilateral renal aplasia.

Therapy *

Figure 8.7  X-linked recessive mode of inheritance visualized by drawing a pedigree. The index patient (arrow) also suffered from severe hypogonadism and cryptorchidism (asterisk). These clinical features of steroid sulfatase deficiency were absent in his likewise affected maternal grandfather and in his maternal cousin who also suffered from RXLI. His mother and maternal aunt did not have visible signs of the disease, but were obligate carriers of the mutation.

Therapeutic approaches vary considerably depending on the continent. In the USA, keratolytic agents such as 12% ammonium lactate are used to facilitate the release of retained corneocytes, whereas in Europe, topicals containing urea and, more recently, creams containing up to 15% of glycerol65 are popular.

KERATINOPATHIC ICHTHYOSES: EPIDERMOLYTIC ICHTHYOSIS (EI) AND SUPERFICIAL EPIDERMOLYTIC ICHTHYOSIS (SEI) Gabriele Richard

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More than 30 years ago, steroid sulfatase deficiency was found to underlie RXLI.57 The gene is located at the distal end of the X-chromosome in a region that escapes X-inactivation, which means that fibroblast enzyme activity in female carriers is similar to that of healthy men.58 However, the expression of steroid sulfatase is variable among cells, and does not always correlate

Synonyms for this disease are: bullous congenital ichthyosiform erythroderma of Brocq (BCIE); epidermolytic hyperkeratosis (EHK); bullous ichthyosis (OMIM 113800); ichthyosis exfoliativa (OMIM 146800). As early as 1897, Nikolski recognized the characteristic histopathology of the bullous form of congenital ichthyosis.66 In

57. Hernandez-Martin A, Gonzalez-Sarmiento R, de Unamuno P. X-linked ichthyosis: an update. Br J Dermatol. 1999;141:617–627. 58. Müller CR, Migl B, Traupe H, et al. X-linked steroid sulfatase: evidence for different gene-dosage in males and females. Hum Genet. 1980;54: 201–204. 59. Miranda-Duarte A, Valdes-Flores M, Miranda-Ramora R, et al. Steroid sulfatase activity in leukocytes: a comparative study in 45, X; 46, Xi(Xq) and carriers of steroid sulfatase deficiency. Biochem Mol Biol Int. 1999;47: 137–142. 60. Aviram-Goldring A, Goldman B, Netanelov-Shapira I, et al. Deletion patterns of the STS gene and flanking sequences in Israeli X-linked ichthyosis patients and carriers: analysis by polymerase chain reaction and fluorescence in situ hybridization techniques. Int J Dermatol. 2000;39:182–187. 61. Traupe H, Kövary PM, Schriewer H. X-linked recessive ichthyosis vulgaris: rapid identification by lipoprotein electrophoresis. Arch Dermatol Res. 1983;275:63–65.

62. Arndt T, Pelzer M, Nenoff P, et al. Lipoprotein- und Apolipoproteinelektrophorese bei X-chromosomal rezessiver Ichthyose. Hautarzt. 2000;51:490–495. 63. Serizawa S, Nagai T, Ito M, et al. Simplified determination of serum cholesterol sulfate by gas-liquid chromatography combined with cyclohexylsilane-bonded phase column purification. Arch Dermatol Res. 1989;281:411–416. 64. Elias PM, Crumrine D, Rassner U, et al. Basis for abnormal desquamation and permeability barrier dysfunction in RXLI. J Invest Dermatol. 2004;122: 314–319. 65. Blanchet-Bardon C. Efficacy and safety of DEXERYL® cream in the symptomatic treatment of ichthyosis in children. A lecture during the symposium skin barrier disorders, EADV Congress, Paris, September, 2008. 66. Nikolski P. Contribution à l’étude des anomalies congénitales de kératinisation. Comptes-Rendus du XII Congres International de Medicine, Moscuo. 1897;iv:433–442.

1902, Brocq first differentiated between dry (non-bullous) and wet (bullous) forms of congenital ichthyosiform erythroderma.7 The term ‘epidermolytic hyperkeratosis’ was coined by Frost and Van Scott in 1965 for the autosomal dominant blistering form of congenital ichthyosis, which is named for the distinctive histopathologic features of vacuolar degeneration and hyperkeratosis of the epidermis.9 Although these structural abnormalities are not unique to EI, the name EHK had widely replaced other descriptive terms until recently. Ichthyosis bullosa of Siemens was first described as a distinct type of EI with a milder phenotype and sparing of palms and soles in 1937.67 In recognition of the underlying keratin gene mutations in this group of disorders, an international group of experts in the ichthyoses proposed renaming this group of keratin disorders ‘keratinopathic ichthyoses’, with subgroups of epidermolytic ichthyosis (EI; KRT1/ KRT10 mutations) and superficial epidermolytic ichthyosis (SEI; KRT2), respectively.22

It is possible that a parent of a patient with EI has a somatic mutation that has arisen post-zygotically during early embryogenesis and may result in a mosaic form of EI following the lines of Blaschko (a.k.a. nevoid EI, linear epidermolytic epidermal nevus (OMIM 600648)).70,71 Extensive unilateral or bilateral mosaic involvement with massive hyperkeratosis has also been

described as ‘ichthyosis hystrix’. In the case of epidermal mosaicism, it is possible that the somatic mutation also involves gonadal cells and thereby can be transmitted from the germline to the offspring resulting in generalized disease.71 Several families have been well documented, in which a parent with linear epidermolytic epidermal nevi had offspring with generalized EI, thus underscoring the need for clinical examination of the parents of an affected proband and for appropriate genetic counseling. If a parent has mosaic involvement, the risk that the offspring will develop full-blown EI is elevated (up to 50%) and has to be considered. Several unusual variants of EI have recently been recognized and characterized on a molecular level. Patients with ‘cyclic ichthyosis with epidermolytic hyperkeratosis’ (OMIM 607602) or ‘annular epidermolytic ichthyosis’ typically have episodic flares of annular polycyclic plaques with scale, which coalesce to involve most of the body surface. Episodes may persist for several weeks or months, and the skin may be normal between flares. While the clinical features may closely resemble erythrokeratodermia variabilis, the histological and ultrastructural features are characteristic for EI. These EI variants are caused by mutations that alter the conserved end domain (2B) of the keratin 1 and keratin 10 rod, respectively.72–75 Such mutations outside the immediate helix boundaries are rare and generally tend to be associated with a milder phenotype. Ichthyosis (hystrix) Curth–Macklin (OMIM 146590) is a rare autosomal dominant disorder of cornification that may clinically mimic EI but displays no skin fragility. Since the first description in 1954, only a few families and sporadic cases of IHCM have been reported. The clinical expression varies not only between but also within families, and ranges from palmoplantar keratoderma, which may be severe and mutilating, to generalized skin involvement with dramatic hystrix-like verruciform hyperkeratosis. Ichthyosis Curth–Macklin (ICM) can be differentiated from EI by its peculiar ultrastructural abnormalities of the KIF cytoskeleton in differentiating keratinocytes. KIF are not arranged in thick bundles but instead form a shell-like, interspersed network of tangled filaments often associated with perinuclear vacuolization and formation of binucleated cells. In contrast to EI, there is no evidence for epidermolysis or keratin clumping. As demonstrated in two families, ichthyosis hystrix Curth–Macklin is another KRT1 disorder. However, mutations are located outside the typical hot spot regions and introduce a frameshift that drastically alters the keratin 1 tail in its composition, chemical character, structure and properties, thereby interfering with supramolecular organization of KIF and their interactions with other differentiation-specific proteins such as loricrin.76,77

67. Siemens HW. Dichtung und Wahrheit ueber die Ichthyosis bullosa, mit Bemerkungen zur Systematik der Epidermolysen. Derm Syph. 1937;175: 590–608. 68. Mueller FB, Huber M, Kinaciyan T, et al. A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis. Hum Mol Genet. 2006;15:1133–1141. 69. Tsubota A, Akiyama M, Kanitakis J, et al. Mild recessive bullous congenital ichthyosiform erythroderma due to previously unidentified homozygous keratin 10 nonsense mutation. J Invest Dermatol. 2008;128: 1648–1652. 70. Happle R. Acanthokeratolytic epidermal nevus: acanthokeratolysis is hereditary, not the nevus. Hautarzt. 1990;41:117–118. 71. Paller AS, Syder AJ, Chan YM, et al. Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med. 1994;331:1408–1415. 72. Joh GY, Traupe H, Metze D, et al. A novel dinucleotide mutation in keratin 10 in the annular epidermolytic ichthyosis variant of bullous congenital ichthyosiform erythroderma. J Invest Dermatol. 1997;108:357–361.

73. Suga Y, Duncan KO, Heald PW, et al. A novel helix termination mutation in keratin 10 in annular epidermolytic ichthyosis, a variant of bullous congenital ichthyosiform erythroderma. J Invest Dermatol. 1998;111:1220–1223. 74. Sybert VP, Francis JS, Corden LD, et al. Cyclic ichthyosis with epidermolytic hyperkeratosis: A phenotype conferred by mutations in the 2B domain of keratin K1. Am J Hum Genet. 1999;64:732–738. 75. Sheth N, Greenblatt D, McGrath JA. New KRT10 gene mutation underlying the annular variant of bullous congenital ichthyosiform erythroderma with clinical worsening during pregnancy. Br J Dermatol. 2007;157:602–604. 76. Sprecher E, Ishida-Yamamoto A, Becker OM, et al. Evidence for novel functions of the keratin tail emerging from a mutation causing ichthyosis hystrix. J Invest Dermatol. 2001;116:511–519. 77. Richardson ES, Lee JB, Hyde PH, et al. A novel mutation and large size polymorphism affecting the V2 domain of keratin 1 in an AfricanAmerican family with severe, diffuse palmoplantar keratoderma of the ichthyosis hystrix Curth-Macklin type. J Invest Dermatol. 2006;126:79–84.

Genetics EI and SEI are autosomal dominant disorders with complete penetrance but extensive clinical variability. Both genders are affected equally, and an affected person faces, in each pregnancy, a 50% risk of transmitting the disorder to the offspring. EI is a rare disorder with an estimated incidence of 1 in 200 000 to 1 in 300 000 individuals. EI is caused by heterozygous mutations in the genes encoding keratin 1 and keratin 10 (KRT1, KRT10), which are expressed in the differentiated layers of the epidermis. Mutations in a minor keratin expressed in the outermost spinous and granular layers of the epidermis, KRT2, are associated with SEI, which has a milder phenotype then EI. In El, half of all cases occur sporadically and represent new mutations, explaining why the parents in such cases are clinically unaffected (although germline mosaicism cannot be excluded). A very rare autosomal recessive form of EI has been reported in a few inbred (consanguineous) families, in which affected individuals were homozygous for a stop codon mutation, leading to a complete lack of keratin 10 in the epidermis, while heterozygous mutation carriers (parents) were unaffected.68,69

Mosaicism and unusual clinical variants

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Ichthyosis and disorders of other cornification

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CLINICAL FEATURES

In the neonatal period, infants show erythema, large erosions, peeling, and widespread areas of denuded skin reminiscent of epidermolysis bullosa, although focal areas of hyperkeratosis may already be present (Fig. 8.8). Later during infancy and childhood, the bullous component becomes less prominent, while severe hyperkeratosis prevails. The clinical presentation of EI is extremely variable, although it tends to be consistent within a family. Based on a survey of 52 patients with histologically confirmed EI from 21 families, DiGiovanna and Bale78 recognized six clinical phenotypes of EI

(Table 8.4). They distinguished between two major subtypes, namely EI with severe involvement of palms and soles (palm/ sole types PS1–3) and without (non-palm/sole types NPS1–3). EI of PS type 1 is characterized by hyperkeratosis predominantly restricted to palms, soles and flexural areas. The palmoplantar keratoderma is diffuse, has a smooth surface and sharply demarcated erythematous border, and often displays areas of peeling. Severe, diffuse palmoplantar keratoderma in PS type 2 leads to fissures and digital contractures, and is associated with generalized, mild to moderate erythroderma as well as hyperkeratosis with a fine, white scale (Figs 8.9, 8.10). The rare PS type 3 is characterized by a distinct, cerebriform appearance of palms and soles and generalized hyperkeratosis with ridged or verrucous pattern. In contrast, the generalized, non-erythrodermic hyper­ keratosis seen in NPS type 1 almost completely spares the skin of palms and soles. The thickened, yellow to dark brown, dirtyappearing skin has a verrucous surface or sharp, protruding spines, which has been described as ichthyosis hystrix (Fig. 8.11). The extremities over the joints, back, areas around umbilicus and areolae, and the scalp are most severely affected. While the hyperkeratosis usually forms a linear, ridged pattern in

Figure 8.8  Neonate with epidermolytic hyperkeratosis of Brocq (EI, bullous

Figure 8.9  Diffuse palmar hyperkeratosis with flexural contractures, fissures

congenital ichthyosiform erythroderma). Note erythema and widespread areas of denuded skin (Courtesy Dr M. Williams).

and underlying erythema in a patient with EI type PS-2 (Courtesy Dr J.J. DiGiovanna).

EI usually presents at birth with erosions and widespread areas of denuded skin and erythroderma, which stem from increased epidermal fragility and are provoked by the frictional trauma during passage through the birth canal. Over time, blistering diminishes while hyperkeratosis develops.

PHYSICAL EXAMINATION Skin

KERATINOPATHIC ICHTHYOSES: EPIDERMOLYTIC ICHTHYOSIS (EI) AND SUPERFICIAL EPIDERMOLYTIC ICHTHYOSIS (SEI)

Table 8.4  Clinical subtypes of epidermolytic ichthyosis CLINICAL FEATURES

PS-1

PS-2

PS-3

NPS-1

NPS-2

NPS-3

Palmoplantar hyperkeratosis

1

1

1

2

2

2

Surface characteristic

Smooth

Smooth

Cerebriform

Normal

Normal

Hyperlinear

Contractures

2

1

2

2

2

2

Scale

Mild

White scale, peel

Tan

Hystrix

Brown

Fine, white

Distribution

Localized

Generalized

Generalized

Generalized

Generalized

Generalized

Erythroderma

2

1

2

2

2

1

Blistering

Localized

1

Neonatal

1

1

1

PS, epidermolytic ichthyosis with severe palmoplantar hyperkeratosis; NPS, epidermolytic ichthyosis without severe palmoplantar hyperkeratosis. 1, feature present; 2, feature absent. Modified from: DiGiovanna and Bale, Arch Dermatol. 1994;130:1026–1035.

78. DiGiovanna JJ, Bale SJ. Clinical heterogeneity in epidermolytic hyperkeratosis. Arch Dermatol. 1994;130:1026–1035.

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Ichthyosis and disorders of other cornification

Figure 8.10  Generalized erythroderma, scaling and peeling. Epidermolytic ichthyosis type PS-2 (Courtesy Dr A. Torrelo).

Figure 8.12  Severe hyperkeratosis with cobblestone surface pattern over the extensor surface of the elbow knee joint and linear arrangement in the knee fold. Epidermolytic ichthyosis type PS-1 (Courtesy Dr A. Torrelo).

In SEI, erythroderma and blistering become apparent at birth or during early infancy and subsequently subside, while hyperkeratosis develops with predilection to flexures, over joints, and on the dorsa of hands and feet. The skin surface may appear ridged, shiny or lichenified. Characteristic are superficially denuded areas with collarette-like borders described as ‘molting’ or ‘Mauserung,’ which develop due to superficial blistering and shedding of the stratum corneum.79 The clinical features of SEI and EI overlap widely, and KRT2 mutations have been reported in patients previously misdiagnosed as having EI.81 Figure 8.11  Generalized skin involvement with thick, dark brown, verrucous hyperkeratosis. Note the ridged pattern in the knee folds. Epidermolytic ichthyosis type NPS-1 (Courtesy Dr A. Torrelo).

flexural areas, it has a cobblestone appearance over the extensor surface of the joints (Fig. 8.12). The face is relatively spared. Patients with NPS type 2 have a similar but much milder disease resembling SEI. NPS type 3 is associated with a generalized mild erythroderma, and a fine white scale. In general, focal episodes of blistering are common, and often triggered by secondary infections and trauma or friction. Patients shed the thickened, hard superficial epidermis in large plates, most likely due to intraepidermal blistering, thereby revealing a tender, erythematous base or erosions.

79. Corden LD, McLean WH. Human keratin diseases: hereditary fragility of specific epithelial tissues. Exp Dermatol. 1996;5:297–307. 80. Reis A, Hennies HC, Langbein L, et al. Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma (EPPK). Nat Genet. 1994;6: 174–179.

Hair, nails, teeth, and mucous membranes Severe scalp involvement with encasement of the hair shafts is a common feature of EI. Lips, eyes, mucous membranes and teeth are normal, but linear arrayed hyperkeratosis in the corners of the mouth is not uncommon.

Systemic manifestations Although EI affects primarily the skin, there is perinatal morbidity and potential mortality in affected infants due to sepsis, as well as fluid and electrolyte imbalance. Posture and gait abnormalities are not infrequent and might be a result of pain in the skin overlying the joints. EI is accompanied by a very distinct, pungent body odor, which is disturbing to patients and their families and impairs their social life.

81. Rothnagel JA, Traupe H, Wojcik S, et al. Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nat Genet. 1994;7:485–490.

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LABORATORY FINDINGS Prenatal diagnosis

KERATINOPATHIC ICHTHYOSES: EPIDERMOLYTIC ICHTHYOSIS (EI) AND SUPERFICIAL EPIDERMOLYTIC ICHTHYOSIS (SEI)

EI and SEI are inherited keratin disorders of the epidermis, which can be detected early during fetal development by electron microscopy of fetal skin or amniotic fluid cells. Diagnostic findings are an abnormal expression pattern of epidermal keratins and cytoplasmic clumping of keratin intermediate filaments (KIF) in the upper epidermis.82,83 However, these methods have been widely replaced by molecular testing. It is estimated that approximately 80% of all patients with EI/SEI have a disease-causing mutation in the keratin 1, 2 or keratin 10 gene (KRT1, KRT2, KRT10), which can be identified by DNA sequencing. DNA sequence analysis or other methods of mutation detection have been successfully performed from CVS or amniotic fluid material, allowing prenatal diagnosis as early as the 10th–12th week of gestation.84

HISTOLOGIC AND ULTRASTRUCTURAL FINDINGS

586

Figure 8.13  Characteristic histopathologic features of EI. Massive hyperkeratosis and vacuolar degeneration of the upper spinous layers of the acanthotic and papillomatous epidermis.

EI is characterized by distinct structural and ultrastructural abnormalities that separate EI from other congenital ichthyoses (Fig. 8.13). A strikingly acanthotic epidermis with hypergranulosis is covered by a massive thickened, dense, orthokeratotic stratum corneum with focal parakeratosis. Keratinocytes of the suprabasal and granular layers exhibit marked intracellular vacuolization and dense clumps of keratin intermediate filaments (KIF), which may appear as unusual dyskeratosis.85 Cytolysis may lead to formation of small intraepidermal blisters with a cleavage plane in the middle or upper spinous layers. A mild perivascular lymphohistiocytic infiltrate is usually present in the upper dermis. Collectively, these histopathological changes are described as ‘epidermolytic hyperkeratosis’. In patients with EI, these changes are present continuously throughout the spinous/granular layers, while a focal involvement is found in patients with mosaic EI.79 The pathological changes in SEI are similar but limited to the uppermost, granular cell layers, which express keratin 2. Ultrastructural analysis in EI reveals fragmented, clumped KIF in the lower, and perinuclear KIF shells in the upper epidermal layers. The assembly of the cornified cell envelope is altered but keratohyaline granules appear normal. Collapse of the cytoskeleton also impairs association of KIF with desmosomal proteins, thus resulting in cell fragility, acantholysis and cytolysis. Despite the massive hyperkeratosis, the barrier function of the skin is markedly disturbed, leading to increased transepidermal water loss87 and bacterial colonization of the stratum corneum, in particular with Staphylococcus aureus. Epidermal proliferation in EI is markedly increased.88

Different approaches including genetic linkage analysis, ultrastructural examination, and mouse models of EI led almost simultaneously to the discovery of the molecular basis of EI.23,89,90 EI is an inherited disorder of epidermal cell fragility resulting from heterozygous mutations in the genes KRT1 and KRT10 localized on chromosomes 17q12–q21 and 12q11–q13. Keratins 1, 2 (type II) and 10 (type I) are the principal, differentiation-specific keratins in the upper epidermis. Their expression pattern correlates with fragility and cytolysis of the superficial epidermis in EI and SEI, while the basal expression of keratins 5 and 14 parallels the site of disease pathology in epidermolysis bullosa simplex. To date, at least 35 distinct pathogenic mutations have been identified in KRT1 and KRT10 in >90 patients/families with EI, while >10 unique KRT2 mutations were reported in 30 cases of SEI. The mutations are non-randomly distributed, and more than 90% cluster at the 1A and 2B boundaries of the rod domains representing mutational ‘hot spots’.24,79,91 The most common mutations, present in more than 30% of all EI patients, affect the arginine codon 156 in KRT10, which contains a methylated and hypermutable CpG dinucleotide.24 In KRT2, mutations often alter glutamic acid codon 487 (E487K) in the helix termination motif. In vivo and in vitro studies demonstrated that these mutations perturb proper keratin alignment, and thereby oligomerization, filament assembly and integrity. As a result, the KIF network is fragile, disrupted and less resistant to stress, thus

82. Holbrook KA, Dale BA, Sybert VP, et al. Epidermolytic hyperkeratosis: ultrastructure and biochemistry of skin and amniotic fluid cells from two affected fetuses and a newborn infant. J Invest Dermatol. 1983;80: 222–227. 83. Eady RA, Gunner DB, Carbone LD, et al. Prenatal diagnosis of bullous ichthyosiform erythroderma: detection of tonofilament clumps in fetal epidermal and amniotic fluid cells. J Med Genet. 1986;23:46–51. 84. Tsuji-Abe Y, Akiyama M, Nakamura H, et al. DNA-based prenatal exclusion of bullous congenital ichthyosiform erythroderma at the early stage, 10 to 11 weeks of pregnancy, in two consequent siblings. J Am Acad Dermatol. 2004;59:86–90. 85. Bergman R, Khamaysi Z, Sprecher E. A unique pattern of dyskeratosis characterizes epidermolytic hyperkeratosis and epidermolytic palmoplantar keratoderma. Am J Dermatopathol. 2008;30:101–105. 86. Ross R, DiGiovanna JJ, Capaldi L, et al. Histopathologic characterization of epidermolytic hyperkeratosis: A systematic review of histology from the

National registry for Ichthyosis and Related Skin Disorders. J Am Acad Dermatol. 2008;59:86–90. Frost P, Weinstein GD, Bothwell JW, et al. Ichthyosiform dermatoses. III. Studies of transepidermal water loss. Arch Dermatol. 1968;98:230–233. Frost P, Weinstein GD, Van Scott EJ. The ichthyosiform dermatoses. II. Autoradiographic studies of epidermal proliferation. J Invest Dermatol. 1966;47:561–567. Rothnagel JA, Dominey AM, Dempsey LD, et al. Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis. Science. 1992;257:1128–1130. Chipev CC, Korge BP, Markova N, et al. A leucine–proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis. Cell. 1992;70:821–828. Szeverenyi I, Cassidy AJ, Chung CW, et al. The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Hum Mutat. 2008;29:351–360.

MOLECULAR AND BIOCHEMICAL ASPECTS

87. 88. 89. 90. 91.

Ichthyosis and disorders of other cornification

92. Reichelt J, Doering T, Schnetz E, et al. Normal ultrastructure, but altered stratum corneum lipid and protein composition in a mouse model for epidermolytic hyperkeratosis. J Invest Dermatol. 1999;113:329–334. 93. Magin TM, Vijayaraj P, Leube RE. Structural and regulatory functions of keratins. Exp Cell Res. 2007;313:2021–2032. 94. Jensen JM, Schutze S, Neumann C, et al. Impaired cutaneous permeability barrier function, skin hydration, and sphingomyelinase activity in keratin 10 deficient mice. J Invest Dermatol. 2000;115:708–713.

DIFFERENTIAL DIAGNOSIS Widespread blistering and denuded skin in a neonate with EI are difficult to distinguish clinically from different forms of epidermolysis bullosa, staphylococcal scalded skin syndrome, and toxic epidermal necrolysis. Light and electron microscopic examination of frozen skin biopsy material obtained from the margin of a fresh blister and bacterial cultures usually lead to the diagnosis. If epidermolysis bullosa is suspected, immunomapping and/or ultrastructural analysis are necessary to determine the specific subtype. Neonates with AEC syndrome (Hay–Wells syndrome, MIM 106260) may present with erosions and collodion membrane, but have also ankyloblepharon, hair and nail dystrophy, and cleft lip/cleft palate. Incontinentia pigmenti can be discriminated by the nevoid distribution of vesicles and different histopathology. In addition, one should consider bullous mastocytosis, congenital syphilis, and herpes simplex. Later during infancy and childhood, EI is readily distinguished from congenital recessive ichthyoses clinically because of generalized blistering at birth and occurrence of focal blisters thereafter. These clinical impressions can be confirmed by skin biopsy revealing the distinctive light microscopic features of epidermolytic hyperkeratosis. Similar histologic findings may be also seen in the epidermolytic form of palmoplantar keratoderma (type Vörner, MIM 144200), which is clinically characterized by isolated, diffuse palmoplantar keratoderma with a striking red margin. This autosomal dominant genodermatosis is very similar to PS type 1 but is caused by mutations in the KRT9 gene that is predominantly expressed in the suprabasal epidermis of palms and soles.79,80 SEI can be distinguished from EI by the absence of erythroderma, the characteristic molting of the outer layer of the epidermis (Mauserung) as well as by the very superficial epidermolysis of the granular cell layers seen on light microscopy. The different site of skin pathology (granular versus spinous cell layers of the epidermis) is paralleled by the distinct expression pattern of keratin 2, which is structurally altered due to dominant mutations in the KRT2 gene.79,81 ICM may closely resemble EI with ridged, verrucous hyper­ keratosis over joints and flexures in some patients, while others have only limited hyperkeratosis restricted to palms and soles. In contrast to EI, there is no clinical or histological evidence for blister formation and epidermolysis. Instead, ultrastructural analysis reveals cytoplasmic shells of fine, tangled KIF in the upper differentiated cell layers of the epidermis associated with perinuclear vacuolization and binucleated cells.76,77 Mosaic EI may occur unilaterally or bilaterally distributed along the lines of Blaschko. Extensive involvement exhibiting marked hyperkeratosis with verrucous surface or porcupine-like spines has often been described as ichthyosis hystrix. Ichthyosis hystrix is not a disorder per se but a descriptive name for a clinically and genetically heterogeneous group of skin disorders with massive, spiky, or verrucous hyperkeratosis, including EI, erythrokeratodermia variabilis, ICM, hyperkeratotic epidermal nevi and others.

KERATINOPATHIC ICHTHYOSES: EPIDERMOLYTIC ICHTHYOSIS (EI) AND SUPERFICIAL EPIDERMOLYTIC ICHTHYOSIS (SEI)

compromising mechanical strength and cell integrity of the epidermis and leading to cytolysis and blistering. Compensatory overexpression of the alternate (hyperproliferative) keratins 6 and 16 in affected skin might contribute to the improvement of skin fragility with age. The etiology of acanthosis and hyperkeratosis in EI/SEI is not as well understood, and probably includes hyperproliferation of the epidermis combined with decreased desquamation and other factors.92 Experimental studies have demonstrated that keratin 10 normally inhibits proliferation and cell cycle progression of keratinocytes, while loss of keratin 10 leads to increased keratinocyte turnover.93 Keratin 1 or 10 mutations also have a deleterious effect on the permeability barrier function of the epidermis, as becomes evident in mice completely deficient in keratin 10, which have an eight-fold increase in transepidermal water loss compared to normal mice, while heterozygous animals exhibit a delay in barrier repair and reduced hydration of the stratum corneum. Although the stratum corneum in EI appears ultrastructurally normal, its lipid composition is significantly altered with a decreased ratio of ceramides to total lipids due to reduced activity of acid sphingomyelinase.92,94 Recent biochemical and ultrastructural studies in patients with EI largely confirmed these observations and revealed incomplete lamellar body secretion as evident by decreased delivery of acid lipase to the stratum corneum. This secretion deficiency is likely a direct effect of altered KIF structure and interaction with lamellar bodies (rather than increased fragility of corneocytes or an abnormal cornified cell envelope).95 Because KIF formation in suprabasal keratinocytes requires the presence of both keratin 1 and keratin 10, mutations in either gene may produce a similar phenotype. Nevertheless, there is a close relationship between the clinical subtype of EI (PS versus NPS) and the causative gene. KRT1 mutations are usually associated with severe palmoplantar keratoderma whereas mutations in KRT10 result in EI with no or mild involvement of palms and soles.78 This difference is explained by the limited expression of KRT10 in palmoplantar epidermis, where KRT9 is an alternate expression partner for KRT1. Epidermal nevi of the epidermolytic hyperkeratotic type (OMIM 600648) represent a mosaic form of EI due to postzygotic, somatic mutations in KRT1 and KRT10 that occur during embryogenesis. Paller et al.71 studied a family in which the parent of a child with generalized EI had mosaic skin involvement following Blaschko’s lines. Mutation analysis in cultured keratinocytes from the affected skin of the parent identified a heterozygous mutation in KRT10, which was absent in keratinocytes from normal skin but identical to the mutation of the affected child. A mouse model for mosaic EI allowed the temporary activation of a somatic KRT10 mutation in the murine epidermis, and demonstrated that the lack of selective pressure against this mutation in epidermal stem cells leads to the mosaic phenotype.96

8

95. Yosipovitch G, Williams ML, Hintner H, et al. Pathogenesis of the permeability barrier abnormality in epidermolytic hyperkeratosis. J Invest Dermatol. 2001;116:164. 96. Arin MJ, Longley MA, Wang XJ, et al. Focal activation of a mutant allele defines the role of stem cells in mosaic skin disorders. J Cell Biol. 2001;152:645–649.

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THERAPEUTICS AND PROGNOSIS Neonatal period Infants with erythema, blistering, widespread erosions, and denuded skin require management in a neonatal intensive care nursery. They should be handled gently to avoid further trauma to the skin and blistering, and placed in protective isolation and monitored for development of sepsis. In some patients, treatment with broad-spectrum antibiotics may be necessary. Dehydration and electrolyte imbalances are not uncommon and have to be treated accordingly. Erosions and denuded skin generally heal rapidly, which can be supported by the use of lubricants and protective padding.

Topical therapy AUTOSOMAL RECESSIVE CONGENITAL ICHTHYOSES

The treatment for EI, like other congenital ichthyoses, is symptomatic and often difficult. It should be tailored to the specific needs of the patient depending on the acute clinical presentation at the time of consultation. It is important to avoid mechanical trauma to the skin because of the increased skin fragility (e.g., comfortable clothing and shoe wear). Extensive, thick, hard hyperkeratosis requires hydration, lubrication, and keratolytic treatment. Recurrent and long bathing are suitable to moisten the skin and facilitate mechanical abrasion of the thickened stratum corneum (gentle scrubbing with a soft brush, sponges, etc.). Additional use of antiseptics such as antibacterial soaps, chlorhexidine, or dilute bleach in the bathwater may help control bacterial colonization. The use of lubricants and emollients at least twice daily is recommended, but specific agents and formulations may be selected, based on individual preferences of the patient. Many commercially available keratolytic creams and lotions containing urea, salicylic acid, alpha-hydroxy acids, or propylene glycol are effective to diminish and remove scale, and to soften the skin. However, they are often not well tolerated, especially in children, because of burning and stinging when the skin is fissured or denuded. Occlusion may enhance the effect but should be used with care in children or patients with heat intolerance. Widespread topical application of salicylic and lactic acid should be avoided because of the risk of systemic absorption. Topical tretinoin and vitamin D preparations are effective but costly and may cause skin irritation. A therapeutic option is treatment of the exposed skin areas only, rendering the visible parts more acceptable.97 Bacterial skin infections are common in EI and often trigger blistering, thus requiring topical treatment with antibiotic ointments or even courses of oral antibiotics.98

Systemic management Synthetic oral retinoids (see also CIE, below) may be very effective in decreasing hyperkeratosis and frequency of infections in patients with generalized EI. Nevertheless, these drugs augment

97. Bogenrieder T, Landthaler M, Stolz W. Bullous congenital ichthyosiform erythroderma: Safe and effective topical treatment with calcipotriol ointment in a child. Acta Derm Venereol. 2002;83:52–54. 98. ten Freyhaus K, Kaiser H-W, Proelss J, et al. Successful treatment of bullous congenital ichthyosiform erythroderma with erythromycin. Dermatology. 2007;215:81–83. 99. Happle R, van de Kerkhof PC, Traupe H. Retinoids in disorders of keratinization: their use in adults. Dermatologica. 1987;175:107–124. 100. Lacour M, Mehta-Nikhar B, Atherton DJ, et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029.

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the epidermal fragility of EI and may lead to exacerbation of blistering.99 It is advisable to start therapy at very low doses with the aim of reaching the lowest possible maintenance dose and carefully monitoring patients.100,101 Methotrexate has limited efficacy in this disorder. Although oral antibiotics are helpful during episodes of blistering and bacterial superinfections, continuous preventive therapy (oral or topical antibiotics) should be avoided because of the risk of development of resistant bacterial strains.

Prognosis Severe neonatal blistering rapidly improves and most children exhibit only focal blistering in response to trauma or secondary infection. Adult patients may experience little to no blistering. The hyperkeratosis progresses during childhood and persists throughout life but occasionally may improve. Clinical type and course of EI are relatively consistent within families. The acrid body odor and disfigurement in EI may pose social problems and can harm the psychosocial development of children and should be addressed.

AUTOSOMAL RECESSIVE CONGENITAL ICHTHYOSES The autosomal recessive congenital ichthyoses (ARCI) form a rare, clinically and genetically heterogeneous group of disorders with generalized excessive scaling of the skin from birth. They occur worldwide with an estimated prevalence of 1 in 200 000 persons, but may be more common in inbred populations.102 Terminology and nosology of these disorders have continuously evolved, resulting in much confusion. More than 100 years ago, the allcomprising group of ‘ichthyosis congenita’ was separated into harlequin ichthyosis and a bullous and non-bullous form of congenital ichthyosiform erythroderma.7 Frost and Van Scott9 fortified this distinction and proposed the descriptive terms ‘lamellar ichthyosis’ for all autosomal recessive forms and, based on distinctive histopathological features, ‘epidermolytic’ hyperkeratosis for the autosomal dominant form of congenital ichthyosis. Subsequently, Traupe et al.103 identified a rare autosomal dominant form of congenital ichthyosis with clinical features indistinguishable from the recessive forms. The considerable clinical heterogeneity of autosomal recessive ichthyoses both prompted and limited arduous attempts to further refine their distinction using clinical, histological, biochemical, and ultrastructural markers, which were further hampered by the limited number of patients available for study. Bernhardt and Baden104 recognized four subtypes predominantly based on severity of disease, while Bergers et al.10 used discrepancies in the activity of hydrolytic enzymes in the scale of patients to differentiate between an erythrodermic and non-erythrodermic form of autosomal recessive lamellar

101. Zhang X-B, Luo Q, Li C-X, et al. Clinical investigation of acitretin in children with severe inherited keratinization disorders in China. J Dermatol Treatment. 2008;19:221–228. 102. Wells RS. Ichthyosis. BMJ. 1966;2:1504–1506. 103. Traupe H, Kolde G, Happle R. Autosomal dominant lamellar ichthyosis: a new skin disorder. Clin Genet. 1984;26:457–461. 104. Bernhardt M, Baden HP. Report of a family with an unusual expression of recessive ichthyosis. Review of 42 cases. Arch Dermatol. 1986;122: 428–433.

Ichthyosis and disorders of other cornification

8.6). LI in its classic presentation with large, dark, plate-like scales, ectropion without discernible erythroderma can be readily distinguished from classic CIE with generalized redness and fine white scaling. In many patients, however, the skin disorder demonstrates intermediate phenotypes with variable degrees of erythema and scaling. Histological, biochemical, ultrastructural features and even the underlying molecular causes are often not able to conclusively discriminate between LI, CIE, and intermediate phenotypes. Therefore, recent efforts have been made in reaching an international consensus on a commonly accepted and consistent classification, which also incorporates the underlying molecular defects and pathomechanisms.22

LAMELLAR ICHTHYOSIS LAMELLAR ICHTHYOSIS

ichthyosis. Based predominantly on ultrastructural abnormalities of the stratum corneum, Anton-Lamprecht and others identified three major types of congenital autosomal recessive ichthyoses including the accumulation of lipid droplets in type I, formation of ‘cholesterol’ clefts in type II, and lamellated membrane structures in type III.14,16,19,105 However, these correlate only loosely with the clinical subtypes of ichthyoses. Clinical scrutiny together with the incorporation of up-to-date knowledge on ichthyoses led Traupe20 to define lamellar ichthyosis as an isolated congenital ichthyosis with three forms: erythrodermic, non-erythrodermic and autosomal dominant lamellar ichthyosis. Using clinical, biochemical, and histologic criteria, combined with differences in the epidermal proliferation rate,11 Williams and Elias12 further discriminated the two distinct phenotypes among the recessive forms of non-bullous congenital ichthyoses, distinguishing between lamellar ichthyosis (LI) and (non-bullous) congenital ichthyosiform erythroderma (CIE; Table 8.5). In our current, and certainly preliminary, understanding, the clinical presentation of autosomal recessive ichthyoses encompasses a range of phenotypes with these two entities on each end of the spectrum (Fig. 8.14).110 Both disorders frequently present at birth with a collodion membrane, which over time develops into lamellar ichthyosis, congenital ichthyosiform erythroderma, other disorders,111 or may spontaneously resolve (self-healing collodion baby)112 (Table

8

Gabriele Richard Synonym: ichthyosis congenita type 2, OMIM 242300, 601277, 604777, 146750. Lamellar ichthyosis (LI) is a severe disorder of cornification, which usually presents at birth with collodion membrane, and is characterized by generalized skin involvement with large, dark brown scale, ectropion, eclabium, and scarring alopecia (Fig. 8.15). The descriptive name derives from the platelike, lamellar appearance of the scale.

Table 8.5  Within the ARCI spectrum, differences between congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI) CIE

LI

Clinical

Fine, white scale Bright red erythroderma, but intensity may vary

Thick, dark, plate-like scale Erythroderma absent or mild

Histopathological

SC thickened Parakeratosis to variable extent Prominent mucin or glycosaminoglycans in SC cell membranes

SC massively thickened No parakeratosis No PAS 1 membranes

Ultrastructural

Abnormal and increased number of lamellar bodies Numerous lipid droplets within cornified cells Extensive bilayer stacks in intercellular spaces of SC Not seen Seen only in few patients

Normal lamellar bodies Not seen Not seen Cholesterol clefts in SC Absent or diminished cornified cell envelope

Molecular

Heterogeneous Mutations in TGM1 (rare), ALOX12B, and ALOXE3 (~12–17%), NIPAL4 (~90% in patients), with specific ultrastructural subtype from scandinavia; far less common elsewhere

Heterogeneous Mutations in TGM1 (65–90%), ABCA12, CYP4F22 (rare, in patients from Mediterranean or n. Africa)

Biochemical

Abnormal intracellular accumulation of TG1 and moderately

Absent or strongly diminished TG activity in vivo and in vitro diminished activity in a small number of patients (≤10% in cultured keratinocytes) in about 12 of patients Butyrase/glucosidase ratio 45

CIE, congenital ichthyosiform erythroderma; SC, stratum corneum; TG, transglutaminase-1; TGM1, transglutaminase-1 gene. Data from Ghadially et al. 1992,19 Bergers et al. 1990,10 Finlay 1982,106 Laiho et al. 1999,107 Niemi et al. 1991,18 Choate et al. 1998,108 Hohl et al. 1998,109 Lefevre et al.,121,122,148 Dahlqvist et al. 147

105. Arnold ML, Anton-Lamprecht I, Melz-Rothfuss B, et al. Ichthyosis congenita type III. Clinical and ultrastructural characteristics and distinction within the heterogeneous ichthyosis congenita group. Arch Dermatol Res. 1988;280:268–278. 106. Finlay AY. Major autosomal recessive ichthyoses. Semin Dermatol. 1982;7:26–36. 107. Laiho E, Niemi KM, Ignatius J, et al. Clinical and morphological correlations for transglutaminase 1 gene mutations in autosomal recessive congenital ichthyosis. Eur J Hum Genet. 1999;7:625–632. 108. Choate KA, Williams ML, Khavari PA. Abnormal transglutaminase 1 expression pattern in a subset of patients with erythrodermic autosomal recessive ichthyosis. J Invest Dermatol. 1998;110:8–12.

109. Hohl D, Aeschlimann D, Huber M. In vitro and rapid in situ transglutaminase assays for congenital ichthyoses – a comparative study. J Invest Dermatol. 1998;110:268–271. 110. Bale SJ, Russell LJ, Lee ML, et al. Congenital recessive ichthyosis unlinked to loci for epidermal transglutaminases. J Invest Dermatol. 1996;107:808–811. 111. Larrègue M, Ottavy N, Bressieux JM, et al. Collodion baby: 32 new case reports. Ann Dermatol Venereol. 1986;113:773–785. 112. Ragunath M, Hennies HC, Ahvazi B, et al. Self-healing collodion baby: a dynamic phenotype explained by a particular transglutaminase-1 mutation. J Invest Dermatol. 2003;120:224–228.

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A

B

LAMELLAR ICHTHYOSIS

Figure 8.14  The clinical phenotypes of congenital recessive ichthyoses span a wide range depending on the degree of erythroderma as well as size and quality of scale. On one end of the spectrum lies lamellar ichthyosis with large, dark, plate-like scales, ectropion and without discernible erythroderma (A). The other extreme is represented by congenital ichthyosiform erythroderma, characterized by bright red erythroderma and fine, white scale (C). The intermediate phenotypes fall anywhere between with variable degrees of erythema and scaling (B).

C

Table 8.6  Disorders with collodion membrane presentation DISORDER

FREQUENCY

ARCI Lamellar ichthyosis

Common

Congenital ichthyosiform erythroderma

Common

CIE/LI intermediate phenotypes

Common

Self-healing collodion baby

Always

Autosomal dominant LI/CIE

Rare

Sjögren–Larsson syndrome

Rare

Trichothiodystrophy

Rare

Infantile Gaucher disease

Rare

Neutral lipid storage disease with ichthyosis

Very rare

Hay–Wells syndrome

Very rare

Data from Larrègue et al. 1986,111 Jagell and Lidén 1982,113 Stone et al.114

113. Jagell S, Lidén S. Ichthyosis in the Sjögren–Larsson syndrome. Clin Genet. 1982;21:243–252. 114. Stone DL, Carey WF, Christodoulou J, et al. Type 2 Gaucher disease: the collodion baby phenotype revisited. Arch Dis Child Fetal Neonatal Ed. 2000;82:F163–F166. 115. Farasat S, Wei M-H, Liewehr D, et al. Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA. J Med Genet. 2009;46:103–111.

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EPIDEMIOLOGY Incidence Although the true incidence is unknown, LI is estimated to occur in 1 in 200 000 to 1 in 300 000 live births. Both genders are affected equally. It has been observed worldwide without ethnic clustering, although it is more common in certain regions, such as Norway (1 in 91 000), or in inbred populations with a high degree of consanguinity.

Genetics LI is inherited as an autosomal recessive trait and families with an affected child face a recurrence risk of 25% for each pregnancy. Mutations in the gene encoding transglutaminase-1 (TGM1) located on chromosome 14q12 are the leading cause of ARCI, accounting for ARCI in ~55% of patients in the USA.115 In patients with classic non-erythrodermic LI, the mutation detection rate is much higher, between 65% and 90%.115–118 The

116. Hennies HC, Kuster W, Wiebe V, et al. Genotype/phenotype correlation in autosomal recessive lamellar ichthyosis. Am J Hum Genet. 1998;62:1052–1061. 117. Huber M, Rettler I, Bernasconi K, et al. Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science. 1995;267:525–528. 118. Russell LJ, DiGiovanna JJ, Rogers GR, et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nat Genet. 1995;9:279–283.

Ichthyosis and disorders of other cornification

the splice site mutation c.877–2 A > G (IVS5–2 A > G), which results in alternative splicing of the TGM1 message, is the most common TGM1 mutation detected on 28% of disease alleles. It accounts for the majority of mutant alleles in patients of northern European descent, and probably originates from a German predecessor.115,119,120 However, LI is genetically heterogeneous and other genes have been implicated in its pathoetiology. Individuals from nine families with LI of Northern African descent (Morocco, Mali, Algeria), were found to have missense mutations in the ABCA12 gene on chromosome 2q35.121 Mutations seem to alter the first nucleotide binding fold of this ABC transporter that is responsible for the energy-dependent transport of lipid substrates across membranes, especially in lamellar bodies of keratinocytes. Mutations in the CYP4F22 gene on chromosome 19p13.12, which encodes a cytochrome P450 enzyme thought to function in lipoxygenase pathways, were reported in patients with LI associated with hyperlinear palms (but without collodion membrane) from 12 consanguineous families from Algeria, France, Italy and Lebanon.122 In addition, exceedingly rare forms of autosomal dominant congenital ichthyosis with LI or CIE features have been reported,103,123 which has important implications for genetic counseling.

LAMELLAR ICHTHYOSIS

A

8

CLINICAL FEATURES LI is apparent at birth. Most affected newborns are encased in a tight, shiny, translucent covering called a collodion membrane. Over the first weeks of life, this thick horn layer dries, cracks, and is gradually replaced by generalized large scales.

Skin

B

Figure 8.15  Classical lamellar ichthyosis. (A) Ectropion and madarosis. (B) Large, brown, plate-like scales (Courtesy Dr A. Torrelo).

TGM1 gene comprises 14 kb including 15 coding exons. Over 94 distinct mutations have been identified so far,115 most of which are scattered across the gene and either truncate the gene product (39% nonsense, frameshift and splice site mutations) or impair its function in the epidermis (61% missense mutations), thus resulting in functional null alleles. Due to a founder effect,

119. Shevchenko YO, Compton JG, Toro JR, et al. Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies. Hum Genet. 2000;106: 492–499. 120. Pigg M, Gedde-Dahl T Jr, Cox D, et al. Strong founder effect for a transglutaminase 1 gene mutation in lamellar ichthyosis and congenital ichthyosiform erythroderma from Norway. Eur J Hum Genet. 1998;6: 589–596.

LI is characterized by dark brown, large and plate-like scales, which form a mosaic or bark-like pattern and involve the entire body surface, including the face, flexures and palms and soles (Fig. 8.15). The scales are centrally attached and often have raised borders leading to superficial fissures. Severe tautness of facial skin commonly results in ectropion and eclabium as well as a significant hypoplasia of nasal and auricular cartilage. While an underlying erythroderma can usually be appreciated during infancy, children and adults have minimal to no erythroderma. Palmoplantar keratoderma may vary, ranging from accentuated skin markings to severe thickening with cracking and fissuring.

Hair, nails, teeth, and mucous membranes Severe scarring alopecia, especially at the periphery of the scalp, is a common feature of LI.124 Hair shafts emerging from the scalp are encased by the thickened stratum corneum and the taut skin

121. Lefevre C, Audebert S, Jobard F, et al. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum Mol Genet. 2003;12:2369–2378. 122. Lefèvre C, Bouadjar B, Ferrand V, et al. Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3. Hum Mol Genet. 2006;15:767–776. 123. Toribio J, Fernandez Redondo V, Peteiro C, et al. Autosomal dominant lamellar ichthyosis. Clin Genet. 1986;30:122–126. 124. Traupe H, Happle R. Alopecia ichthyotica. A characteristic feature of congenital ichthyosis. Dermatologica. 1983;167:225–230.

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exerts traction and compression. Inflammation of the nail folds may produce secondary nail dystrophy with thickening of the nail plates and ridging. The thickened, firm stratum corneum in LI also constricts the sweat ducts, often resulting in severe heat intolerance. Although lips and mucous membranes tend to be spared, severe ectropion may lead to madarosis, conjunctivitis, and incomplete lid closure with ensuing keratitis.

Systemic manifestations LI is not primarily associated with systemic manifestations (see also CIE). Collodion babies have an increased incidence of premature birth with concomitant perinatal morbidity and mortality. They are at increased risk for sepsis, fluid and electrolyte imbalance and particularly hypovolemic hypernatremia.111 LAMELLAR ICHTHYOSIS

LABORATORY FINDINGS Ultrastructural and immunohistochemical studies of skin biopsies in at least half of all LI patients reveal thin or absent cornified cell envelopes.18,125 Biochemical in vitro assays of cultured keratinocytes often demonstrate drastically reduced transglutaminase-1 activity,126 although it can be normal due to genetic heterogeneity.127,128 Recently, rapid screening procedures were developed to identify patients with transglutaminase-1 abnormalities, using in situ detection of tranglutaminase-1 expression and activity109,129 and cross-linked cell envelopes,130 although these studies are not widely available for diagnostic purposes. In contrast, DNA-based molecular testing for mutations in the TGM1 and ABCA12 genes is commercially available for diagnostic and prenatal testing and carrier detection in LI.

Prenatal diagnosis In families with identifiable TGM1 or ABCA12 mutations or linkage to these gene loci, prenatal diagnosis can be performed by mutation and/or genotype analysis from chorionic villus sampling or amniocentesis material at an early gestational age.131 Invasive fetal skin biopsies or fetoscopy for light and electron microscopic examination has proven problematic, can only be successfully performed during the second trimester (after 21 weeks’ gestation), and is not widely available.132,133

125. Hohl D, Huber M, Frenk E. Analysis of the cornified cell envelope in lamellar ichthyosis. Arch Dermatol. 1993;129:618–624. 126. Huber M, Yee VC, Burri N, et al. Consequences of seven novel mutations on the expression and structure of keratinocyte transglutaminase. J Biol Chem. 1997;272:21018–21026. 127. Lavrijsen AP, Maruyama T. Absent transglutaminase TGK expression in two of three patients with lamellar ichthyosis. Arch Dermatol. 1995;131:363–364. 128. Huber M, Rettler I, Bernasconi K, et al. Lamellar ichthyosis is genetically heterogeneous – cases with normal keratinocyte transglutaminase. J Invest Dermatol. 1995;105:653–654. 129. Raghunath M, Hennies HC, Velten F, et al. A novel in situ method for the detection of deficient transglutaminase activity in the skin. Arch Dermatol Res. 1998;290:621–627. 130. Jeon S, Djian P, Green H. Inability of keratinocytes lacking their specific transglutaminase to form cross-linked envelopes: absence of envelopes as

592

HISTOLOGICAL AND ULTRASTRUCTURAL FEATURES The histological abnormalities in LI are non-specific and include massive orthokeratotic hyperkeratosis with relatively mild acanthosis, regular papillomatosis, and dilated capillaries in the superficial dermis. In contrast to CIE, the epidermal proliferation rate is normal or only slightly elevated.11 Elongated cholesterol clefts as well as a variable number of translucent lipid droplets in the stratum corneum and a thin or absent cornified cell envelope have been described as significant ultrastructural abnormalities in LI, although these findings widely overlap with those found in CIE.18,105,134

Molecular and biochemical aspects Autosomal recessive loss-of-function mutations in the gene TGM1 encoding the epidermally expressed enzyme transglutaminase-1 on chromosome 14q11 account for LI in the vast majority of patients exhibiting the classic (nonerythrodermic) phenotype. TGM1 mutations have also been reported in some patients with LI/CIE overlap (e.g., mild to moderate erythroderma, white or gray, small, sometimes platelike scales)107,115,116,119 and in patients with so-called ‘bathing suit ichthyosis’, a rare subtype that tends to spare the extremities and face.135 The clinical spectrum of TGM1 mutations even extends to the very mild phenotype of self-healing collodion baby. The molecular basis of congenital ichthyosis in patients with CIE or LI/CIE intermediate phenotypes, however, is heterogeneous and may involve several other genes of the epidermal lipid metabolism (see section below on CIE). A recent genotype–phenotype comparison in a large cohort of 104 patients with ARCI predicts that individuals born with a collodion membrane with plate-like scale, ectropion and/or alopecia are 4 times more likely to have TGM1 mutations than patients without one or more of these features.115 Transglutaminases are a superfamily of enzymes that catalyze the calcium-dependent cross-linking of proteins through the formation of Nε-(γ-glutamyl)lysine isopeptide bonds widely expressed throughout the body. In the epidermis, TGM1 (together with TGM3) is expressed in the upper, most-differentiated keratinocytes of the epidermis, where its gene product

a simple diagnostic test for lamellar ichthyosis. Proc Natl Acad Sci USA. 1998;95:687–690. 131. Schorderet DF, Huber M, Laurini RN, et al. Prenatal diagnosis of lamellar ichthyosis by direct mutational analysis of the keratinocyte transglutaminase gene. Prenat Diagn. 1997;17:483–486. 132. Akiyama M, Holbrook KA. Analysis of skin-derived amniotic fluid cells in the second trimester; detection of severe genodermatoses expressed in the fetal period. J Invest Dermatol. 1994;103:674–677. 133. Perry TB, Holbrook KA, Hoff MS, et al. Prenatal diagnosis of congenital non-bullous ichthyosiform erythroderma (lamellar ichthyosis). Prenat Diagn. 1987;7:145–155. 134. Kanerva L, Lauharanta J, Niemi KM, et al. New observations on the fine structure of lamellar ichthyosis and the effect of treatment with etretinate. Am J Dermatopathol. 1983;5:555–568. 135. Oji V, Hautier JM, Ahvazi B, et al. Bathing suit ichthyosis is caused by transglutaminase-1 deficiency: evidence for a temperature-sensitive phenotype. Hum Mol Genet. 2006;15:3083–3097.

Ichthyosis and disorders of other cornification

DIFFERENTIAL DIAGNOSIS

dermic) ichthyosis. This variant may be caused by mutations in TGM1, ALOX12B, or ALOXE3, which were shown to be fully inactivating only in utero, but not after birth.112,140 Therefore, it has been speculated that a self-healing collodion baby is a ‘dynamic’ phenotype that is dependent on environmental conditions, which influence the stability of the mutant protein.

THERAPEUTICS AND PROGNOSIS Therapy Congenital autosomal recessive ichthyoses are characterized by severe impairment of desquamation and barrier function of the skin resulting in substantial loss of water, ions and proteins in the neonatal period. Sufficient dietary protein and fluid intake are required, particularly during infancy and childhood to avoid or minimize growth failure.141 Secondary hypohidrosis due to obstruction of eccrine sweat ducts results in heat intolerance, which is aggravated in a hot climate and may limit physical activity. External cooling by dousing with cool water and the use of air conditioning can ameliorate the symptoms. Accumulation of scale in the external ear canals often leads to occlusion and bacterial colonization with ensuing recurrent ear infections, which may be prevented by periodic scale removal and otologic care. Severe ectropion demands ophthalmologic follow-up and, if necessary, surgical repair to prevent irreversible corneal damage (see also CIE, below). Congenital recessive ichthyoses are often severely disfiguring and pose a challenge to the development of a positive body image and hence to normal psychosocial development. Families and patients need continuous support in dealing with psychosocial problems. Patient support organizations such as the Foundation for Ichthyosis and Related Skin Types (FIRST) and the National Organization for Rare Disorders (NORD) have been of tremendous benefit to patients and their families (see their details above).

CONGENITAL ICHTHYOSIFORM ERYTHRODERMA (CIE) AND LI/CIE INTERMEDIATE PHENOTYPES

transglutaminase-1 serves a dual role during the cornification. The enzyme facilitates the formation of the insoluble protein envelope by cross-linking numerous structural proteins such as involucrin, small proline-rich proteins, loricrin, KIF, and desmosomal proteins.27 In addition, it is paramount for the ester linkage of epidermis-specific omega-hydroxyceramides to the plasma membrane and formation of the lipid envelope.28 TGM1 mutations resulting in lack of transglutaminase-1 expression and/or diminished function125–127 therefore hinder the formation of the protein envelope as well as the lipid envelope and perturb the normal process of cornification and desquamation.18,19,125,136 Studies of mice deficient in transglutaminase-1 provided additional insight into the pathophysiology of lamellar ichthyosis.137 The mice exhibit a phenotype similar to LI, including taut, erythrodermic and scaling skin with impaired barrier function. The faulty cross-linking activity of transglutaminase-1 was shown to result in the complete loss of the cornified cell envelope, disturbed degradation of the nuclei and keratohyaline granules as well as cytoplasmic accumulation of loricrin. The transepidermal water loss and percutaneous absorption rate were tremendously increased, indicative of a severely impaired skin barrier. These results strongly emphasize the essential role of transglutaminase-1 in the development and maturation of the stratum corneum, and in the adaptation of the skin to a dry environment after birth.137 LI has become a prototype for therapeutic cutaneous gene delivery. In the human skin/immunodeficient mouse xenograft model, Choate et al. succeeded in short-term correction of the molecular, histological and functional abnormalities of LI skin in vivo.138 Transglutaminase-1 deficient primary keratinocytes from LI patients were transduced with a retroviral vector driving the expression of transglutaminase-1, and then grafted on to the skin of nude mice. This bioengineered LI epidermis showed a transient normal expression of the enzyme as well as other differentiation markers and normal barrier function of the skin. However, keratinocytes retained the transglutaminase-1 gene only for a short period of time. Therefore, this and other approaches139 are not yet practicable for use in humans, but demonstrate that, in vivo, functional correction of the primary defect as well as therapeutic gene delivery is feasible.

8

Prognosis Lamellar ichthyosis is a severe disorder persisting unremittingly throughout life.

In the neonatal period, there is considerable clinical overlap with other congenital ichthyoses that may manifest as collodion baby, including CIE (see below), Netherton syndrome, Sjögren– Larsson syndrome, and trichothiodystrophy. In addition, the possibility of ‘self-healing collodion membrane’ has to be considered. In this rare form of ARCI (a.k.a. ‘lamellar exfoliation of the newborn’), the collodion membrane may spontaneously resolve, leaving normal skin or very mild generalized (erythro-

CONGENITAL ICHTHYOSIFORM ERYTHRODERMA (CIE) AND LI/CIE INTERMEDIATE PHENOTYPES

136. Candi E, Melino G, Lahm A, et al. Transglutaminase 1 mutations in lamellar ichthyosis. Loss of activity due to failure of activation by proteolytic processing. J Biol Chem. 1998;273:13693–13702. 137. Matsuki M, Yamashita F, Ishida-Yamamoto A, et al. Defective stratum corneum and early neonatal death in mice lacking the gene for transglutaminase 1 (keratinocyte transglutaminase). Proc Natl Acad Sci USA. 1998;95:1044–1049. 138. Choate KA, Medalie DA, Morgan JR, et al. Corrective gene transfer in the human skin disorder lamellar ichthyosis. Nat Med. 1996;2: 1263–1267.

139. Huber M, Limat A, Wagner E, et al. Efficient in vitro transfection of human keratinocytes with an adenovirus-enhanced receptor-mediated system. J Invest Dermatol. 2000;114:661–666. 140. Harting M, Brunetti-Pierri N, Chan CS, et al. Self-healing collodion membrane and mild nonbullous congenital ichthyosiform erythroderma due to 2 novel mutations in the ALOX12B Gene. Arch Dermatol. 2008;144: 351–356. 141. Moskowitz DG, Fowler AJ, Heyman MB, et al. Pathophysiologic basis for growth failure in children with ichthyosis: an evaluation of cutaneous ultrastructure, epidermal permeability barrier function, and energy expenditure. J Pediatr. 2004;145:82–92.

Gabriele Richard Synonyms are: non-bullous congenital ichthyosiform erythroderma (NBCIE); ichthyosis congenita type 1 (OMIM 242100,

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612281, 604781). This is another distinct type of congenital autosomal recessive ichthyosis, with characteristic clinical and biochemical phenotypic features (see Differential diagnosis below and Table 8.5). It can be clinically distinguished from LI by the presence of marked erythroderma and small, white scale. Nevertheless, there is considerable intra- and interfamilial variability of the phenotype. Many patients may exhibit overlapping features with a variable degree of erythroderma, quality as well as size of scales, and do not fit exactly into one or the other disease category. They represent the LI/CIE intermediate forms of ARCI.

Incidence CONGENITAL ICHTHYOSIFORM ERYTHRODERMA (CIE) AND LI/CIE INTERMEDIATE PHENOTYPES

CIE might be more common than LI, but its incidence probably does not exceed 1 in 200 000.

Genetics

erythroderma with fine, white scales (Courtesy Dr A. Torrelo).

In the vast majority of families, CIE is inherited as an autosomal recessive trait, although autosomal dominant inheritance has been occasionally observed.123,142 In general, parents of an affected child are presumed carriers of a recessive mutation. There is a 25% risk with each pregnancy that both mutant alleles are transmitted to the offspring and the child will be affected. Even more than LI, CIE is clinically and genetically very heterogeneous and its molecular causes have not been fully elucidated. A few CIE patients carry pathogenic mutations in the gene TGM1 encoding the epidermal cross-linking enzyme transglutaminase-1,116,117,119 whereas most TGM1 mutations produce a LI phenotype. To date, at least five other genes have been implicated in the pathoetiology of CIE phenotypes, including the ABCA12 gene on chromosome 2q34 (5% of mutations), the ALOX12B and ALOXE3 genes on chromosome 17p13.1 (12–17% of mutations), the ichthyin gene (NIPAL4) on chromosome 5q33 (16%), and the CYP4F22 gene on chromosome 19p13.12 (8%).22 Another locus for congenital ichthyosis has been mapped, while others await identification.

Scarring alopecia is less common than in patients with LI.124 The impediment of sweat ducts and pores results in hypohidrosis and heat intolerance. Secondary nail dystrophy (thickened nail plates, ridging) and onychomycosis may develop, while lips, mucous membranes, and teeth tend to be spared.

PRESENTING HISTORY

Systemic manifestations

Similar to LI, most infants present at birth with a collodion membrane, which subsequently evolves into generalized scaling and pronounced erythroderma.

CIE has no primary systemic manifestations (see also LI). While most patients with CIE show normal growth and development, severely erythrodermic children may show growth retardation, likely due to ample chronic loss of water and calories caused by a defective permeability barrier of the skin.141 Adult patients anecdotally report joint pain, gait abnormalities, and flexural contractures associated with palmoplantar keratoderma. An increased incidence of non-melanoma skin cancers has been reported in a few patients with ARCI, including the development of multiple aggressive squamous cell carcinoma of the skin even during long-term low-dosage treatment with systemic retinoids.143,144 Therefore, long-term follow-up for adult patients with

CLINICAL FEATURES Skin The clinical manifestations of CIE are usually milder than in lamellar ichthyosis and demonstrate a greater variability in the intensity of erythema, size and type of scale, even within a family. Generally, scales are white, fine and powdery (Fig. 8.16),

142. Rossmann-Ringdahl I, Anton-Lamprecht I, Swanbeck G. A mother and two children with nonbullous congenital ichthyosiform erythroderma. Arch Dermatol. 1986;122:559–564. 143. Arita K, Akiyama M, Tsuji Y, et al. Squamous cell carcinoma in a patient with non-bullous congenital ichthyosiform erythroderma. Br J Dermatol. 2003;148:367–369.

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Figure 8.16  Classical congenital ichthyosiform erythroderma. Intense

although they may become larger, darker or plate-like on the extensor surface of the lower extremities. Severely affected patients show an intense red erythroderma (Fig. 8.16) and develop ectropion and scarring alopecia. Marked hyperkeratosis of palms and soles with cracks and deep fissures often contrasts the fine, translucent scale elsewhere on the body. Patients with milder disease exhibit less or minimal erythroderma but generalized scaling and variable palmoplantar involvement.

Hair, nails, teeth, and mucous membranes

144. Elbaum DJ, Kurz G, MacDuff M. Increased incidence of cutaneous carcinomas in patients with congenital ichthyosis. J Am Acad Dermatol. 1995;33:884–886.

Ichthyosis and disorders of other cornification

HISTOLOGIC FEATURES The histopathological features of CIE are not diagnostic and do not allow a definite distinction from LI. However, they are valuable to exclude epidermolytic hyperkeratosis. Compared with LI, there is pronounced acanthosis of the epidermis with hypergranulosis, mild to moderate hyperkeratosis and focal to extensive parakeratosis. The epidermal cell turnover rate in CIE is markedly increased, indicative of epidermal hyperproliferation.11

Molecular and biochemical aspects The extensive clinical and genetic heterogeneity of CIE suggests that several different genetic and metabolic defects result in CIE and LI/CIE intermediate phenotypes. To date, mutations in five genes have been reported, including TGM1, ALOX12B, ALOXE3, NIPAL4, ABCA12, and others that remain to be identified. In contrast to LI, only a small subset of patients with clinical features of CIE were found to carry inactivating TGM1 mutations, leading to transglutaminase-1 deficiency with ensuing abnormal formation of the cornified cell envelope and perturbed barrier function of the skin.116,117,119 However, there is no obvious correlation between the specific location and nature of recessive TGM1 mutations and their phenotypic expression as LI or CIE.116 Mutations in the two related ALOXE3 and ALOX12B genes on 17p13.1 account for approximately 12% of patients in whom TGM1 mutations have been ruled out. Some 60% of these mutations were found in the ALOX12B gene and the remaining 4% in the ALOXE3 gene.145,146 These genes code for the enzymes 12R-LOX and eLOX, which are preferentially synthesized in the epidermis and function in sequence to generate epoxy alcohol metabolites, which are crucial for formation of the epidermal lipid barrier. While 12R-LOX is responsible for generating fatty acid hydroperoxide, eLOX functions as hydroperoxide isomerase to generate epoxy alcohols. While most individuals with ALOX gene mutations were born with a collodion membrane and later showed mild to moderate CIE, a few individuals had mild LI or selfhealing collodion baby presentation.140,146 Autosomal recessive mutations in a gene named NIPAL4 on chromosome 5q33.3 appear to be the leading cause of congenital ichthyosis in TGM1negative Scandinavian patients (>90%) with specific ultrastructural features, such as abnormal lamellar bodies in the stratum granulosum and perinuclear, elongated membranes.147 Clinically, patients with ichthyin mutations had a CIE phenotype but mostly lacked a collodion presentation at birth. Two missense mutations, A176D and G230R, accounted for approximately 90% of disease alleles in this cohort. In addition, several con-

145. Jobard F, Lefevre C, Karaduman A, et al. Lipoxygenase-3 (ALOXE3 ) and 12(R)-lipoxygenase (ALOX12B ) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13. 1. Hum Mol Genet. 2002;11:107–113. 146. Eckl KM, Krieg P, Kuester W, et al. Mutation spectrum and functional analysis of epidermis-type lioxygenases in patients with autosomal recessive congenital ichthyosis. Hum Mut. 2005;26(4):351–361. 147. Dahlqvist J, Klar J, Hausser I, et al. Congenital ichthyosis: Mutations in ichthyin associated with specific structural abnormalities in the granular layer of epidermis. J Med Genet. 2007;44(10):615–620.

sanguineous families with ichthyin (NIPAL4) mutations from the Mediterranean and South America have been reported.148 The encoded transmembrance protein ichthyin is homologous to both transporters and G-protein coupled receptors, and may represent a membrane receptor for ligands (trioxilins A3 and B3) from the hepoxilin pathway. It is highly expressed in brain, lung, stomach, leukocytes, and keratinocytes.148 Finally, autosomal recessive ABCA12 mutations have to be considered as a molecular cause of severe CIE. While ABCA12 mutations typically present at birth as harlequin ichthyosis, overlap with severe collodion membrane has been observed. Moreover, surviving children with harlequin ichthyosis show a phenotypic shift and develop features of severe CIE, often including alopecia, failure to thrive, and growth retardation. Therefore, ABCA12 mutations should be taken into account for this phenotype. (For details, see the section on ‘Harlequin ichthyosis’.) Ultrastructural and biochemical abnormalities in CIE, although not very well correlated with the clinical phenotypes, are suggestive for abnormalities in the lamellar body secretory system. Electron microscopic examinations reveal abnormal and an increased number of lamellar bodies, many of which appeared to be retained within corneocytes, thereby resulting in accumulation of lipid droplets in the stratum corneum.14,16,19 Intercellular lipid lamellae of the stratum corneum, which derive from the secretion and reorganization of lamellar body contents, appear highly disorganized in CIE. These structural aberrations are accompanied by differences in the activity of lamellar body enzymes in the stratum corneum,10 which may play a role in the abnormal persistence of desmosomes.19 Collectively, these changes might result in a disturbed skin barrier function with increased transepidermal water loss, which in turn has been shown to stimulate epidermal hyperplasia.30,149 Nevertheless, many ultrastructural features are not specific for CIE and have been observed in other hyperproliferative disorders.19

CONGENITAL ICHTHYOSIFORM ERYTHRODERMA (CIE) AND LI/CIE INTERMEDIATE PHENOTYPES

ARCI should include the consideration of skin cancer, even if a patient is treated with retinoids.

8

Prenatal diagnosis Prenatal diagnosis based on molecular approaches is only available for families carrying known mutations in TGM1, ALOX12B, ALOXE3 or ichthyin. Fetoscopy and ultrastructural skin examination are problematic and are not available before the 21st week of gestation.150

DIFFERENTIAL DIAGNOSIS Severe forms of CIE and lamellar ichthyosis can be distinguished based on clinical, histological and ultrastructural findings (Table 8.5). CIE is defined by the presence of generalized, bright red erythema and fine white scale. Patients with lamellar ichthyosis have generalized thick, plate-like scale with minimal to no erythroderma. Both disorders may present as a collodion baby.

148. Lefevre C, Bouadjar B, Karaduman A, et al. Mutations in ichthyin, a new gene on chromosome 5q33 in a new form of autosomal recessive congenital ichthyosis. Hum Mol Genet. 2004;13:2473–2482. 149. Williams ML, Elias PM. From basket weave to barrier. Unifying concepts for the pathogenesis of the disorders of cornification. Arch Dermatol. 1993;129:626–629. 150. Holbrook KA, Dale BA, Williams ML, et al. The expression of congenital ichthyosiform erythroderma in second trimester fetuses of the same family: morphologic and biochemical studies. J Invest Dermatol. 1988;91:521–531.

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Ectropion, eclabium, and scarring alopecia are more commonly seen in lamellar ichthyosis. Keratinocytes in lamellar ichthyosis show a normal granular layer, cell proliferation, and lamellar bodies but massively thickened stratum corneum without para­ keratosis.10,19 The presence of cholesterol clefts in the stratum corneum by electron microscopic examination is suggestive of LI, while a larger number of lipid droplets are more common in CIE.14,16,18 The mitotic rate in CIE is increased11 as is the number of lamellar bodies, and the stratum corneum is thickened with focal to complete parakeratosis. The distinction of LI and CIE based on elevated levels of N-alkanes in CIE has been refuted because they may originate from exogenous sources. Other types of ichthyosis can be differentiated from CIE and LI based on specific clinical, histological, and biochemical parameters (Table 8.2). In contrast to IV (which dose not tend to present as a collodion baby), skin involvement in LI and CIE is typically generalized, including all flexures, and results in taut facial skin with ensuing ectropion/eclabium and alopecia. However, the distinction between LI/CIE intermediate phenotypes and IV may be difficult. XLRI can be excluded by biochemical testing. Chanarin–Dorfman syndrome (neutral lipid storage disease) can usually be identified by examining a peripheral blood smear. Skin findings in Netherton syndrome may closely resemble CIE, but this disorder is often associated with failure to thrive, recurrent or systemic infections, pruritus, highly elevated plasma IgE levels, and hair shaft abnormalities, and has a psoriasiform histopathology. Trichothiodystrophy can be eliminated by light and polarizing microscopy of hair. Finally, epidermolytic hyperkeratosis can be distinguished clinically based on the occurrence of blisters, flexural accentuation, and absence of ectropion, as well as by its distinctive histopathology.

Topical therapy Topical management of autosomal recessive ichthyosis is a therapeutic cornerstone and complements systemic therapy, although its efficacy is limited by the need for continuous applications. It is aimed to diminish scaling, and to rehydrate and lubricate the skin. Most patients require topical treatment with keratolytic agents, such as urea, salicylic acid, alpha-hydroxy acids (lactic acid, glycolic acid), propylene glycol, or combinations of them.151 Their use may be limited because of skin irritation and the risk of systemic absorption due to an impaired skin barrier function, especially in children. Nevertheless, one study of nine children with congenital ichthyosis treated with 0.05–0.1% tazarotene gel topically on 20–90% of their body surface area for 1 month to 2 years showed little systemic absorption.152 Topical vitamin D3 derivatives,153 tazarotene (a receptor-selective retinoid),154,155 as well as special formulations of lactic acid and propylene glycol in a lipophilic cream base156 have been effective in reducing scale in patients with congenital recessive ichthyoses.151 Adjuvant use of emollients such as petrolatum or lanolin may increase the patient’s comfort.

Systemic management

Newborns with a collodion membrane are at risk for thermoinstability, hypernatremic dehydration, complications due to increased transcutaneous water loss, skin infections and sepsis. They should be carefully monitored for temperature, fluid and electrolyte imbalances and signs of pneumonia secondary to restricted lung ventilation and aspiration of amniotic fluid containing scales. Skin treatment is aimed at the gradual, cautiously peeling and desquamation of the collodion membrane. The infant should be placed in a humidified incubator and the skin treated with wet compresses as well as lubricants and light (nonocclusive) emollients that can increase elasticity and pliability of the skin.151 Manual removal of the collodion membrane and use of topical keratolytic agents are not advisable, because of the increased risk of infections and percutaneous absorption. Exfoliative erythroderma, especially during infancy, may also pose a substantial metabolic stress on the growing child. For

Oral retinoids can have dramatic benefit in the treatment of autosomal recessive ichthyoses. Etretinate as well as acitretin have been shown to effectively alleviate hyperkeratosis and scaling but are less effective to suppress the erythroderma. In an LI patient with transglutaminase-1 deficiency, therapy with etretinate was shown to restore expression of the cross-linking enzyme, possibly due to an upregulation of gene transcription.157 It did not, however, have any discernible effect on the ultrastructural abnormalities found in LI.157,158 Acitretin treatment is usually initiated at a low dose followed by titration to the minimal effective dose, which is dictated by course and severity of disease. In a therapeutic series of nine children with LI and CIE, Lacour et al. observed an excellent to moderate response to acitretin treatment.100 The therapeutic benefits included improvement of ectropion, avoiding eye complications and reconstructive eyelid surgery. Side-effects were related to vitamin A toxicity and included mucocutaneous dryness, skin fragility, fissures, and excessive peeling, the latter especially in LI. Abnormalities of serum lipids and liver function tests were transient and did not necessitate cessation of treatment.100 Remarkable improvement was also reported in eight children with LI and six children with

151. Vahlquist A, Ganemo A, Virtanen M. Congenital ichthyosis: An overview of current and emerging therapies. Acta Derm Venereol. 2008;88:4–14. 152. Nguyen V, Cunningham BB, Eichenfield LF, et al. Treatment of ichthyosiform diseases with topically applied tazarotene: Risk of systemic absorption. J Am Acad Dermatol. 2007;57:S123–S124. 153. Lucker GP, van de Kerkhof PC, van Dijk MR, et al. Effect of topical calcipotriol on congenital ichthyoses. Br J Dermatol. 1994;131:546–550. 154. Hofmann B, Stege H, Ruzicka T, et al. Effect of topical tazarotene in the treatment of congenital ichthyoses. Br J Dermatol. 1999;141:642–646.

155. Kundu RV, Garg A, Worobec SM. Lamellar ichthyosis treated with tazarotene 0.1% gel. J Am Acad Dermatol. 2005;55:S94–S95. 156. Ganemo A, Virtanen M, Vahlquist A. Improved topical treatment of lamellar ichthyosis: a double-blind study of four different cream formulations. Br J Dermatol. 1999;141:1027–1032. 157. Hashimoto K, Gee S, Tanaka K. Lamellar ichthyosis: response to etretinate with transglutaminase 1 recovery. Am J Dermatopathol. 2000;22:277–280. 158. Williams ML, Elias PM. Nature of skin fragility in patients receiving retinoids for systemic effect. Arch Dermatol. 1981;117:611–619.

THERAPEUTICS AND PROGNOSIS Neonatal period

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example, 10 children (ages 2–13 years) with ARCI had on average a three-times higher transepidermal water loss than children without ichthyosis and lost up to 10-times more calories per day, in one case up 1015 kcal/day. Therefore, adequate intake of water, calories, protein and iron should be ensured.141

Ichthyosis and disorders of other cornification

Prognosis CIE may be severely disfiguring and persists with little change throughout life, although marked improvement was noted in some patients at puberty.

morbidity and mortality, especially in the newborn period. The first description of the condition has been identified in a diary in 1750. The oldest report by a physician was that of Richter in 1792. In 1900, the dermatologist Riecke delineated the histological findings and distinguished harlequin ichthyosis from the other forms of ichthyosis.

INCIDENCE Harlequin ichthyosis is very rare and its true incidence is unknown. It has been observed worldwide in consanguineous as well as non-consanguineous families.

Genetics Harlequin ichthyosis (OMIM 242500) is an autosomal recessive inherited disorder and the recurrence risk for this disorder in a family with an affected child is 25%. The vast majority of patients with HI were found to have deleterious loss-offunction mutations or multi-exon deletions in the ABC transporter gene ABCA12 on chromosome 2q34.162,163 The gene codes for a membrane protein of epidermal lamellar bodies (lamellar granules) that is involved in energy-dependent lipid transport. Mutations result in complete absence of this protein, thus leading to abnormal or absent lamellar bodies, faulty processing of essential epidermal lipids (such as glucosylceramide), a lack of intercellular lipid lamellae in the stratum corneum and ultimately to a massive breakdown of the permeability barrier and massive cell retention in the stratum corneum.162,164 Genotype–phenotype correlations based on more than 50 HI patients with ABCA12 mutations suggest that those mutations leading to protein truncation or mRNA decay (nonsense, frameshift and splice mutations, exonic deletions) result in the severe phenotype of HI, while missense mutations were associated with CIE/LI. Most mutations are private, although there is some evidence for a few founder mutations, such as c.7322delC in the Pakistani-Indian population.162,163,165

CLINICAL FEATURES

Harlequin ichthyosis (HI) is the most extreme and distinct form of autosomal recessive congenital ichthyosis with significant

Babies with HI are usually born prematurely and, despite intensive care and intervention, may succumb to complications of prematurity, respiratory distress, sepsis, hypothermia and/or hypernatremic dehydration within a few days or weeks. The newborn is encased in a hard, armor-like covering that con­ stitutes extremely thickened stratum corneum and severely restricts movements. The taut cast has a yellow to gray color and

159. Peck GL, DiGioranna J. The retinoids. In: Freedberg IM, Eisen AZ, KW, et al. eds. The retinoids. New York: McGraw-Hill; 1999:2810–2820. 160. Paige DG, Judge MR, Shaw DG, et al. Bone changes and their significance in children with ichthyosis on long-term etretinate therapy. Br J Dermatol. 1992;127:387–391. 161. van Steensel MAM. Emerging drugs for ichthyosis. Expert Opin Emerging Drugs. 2007;12:647–656. 162. Akiyama M, Sugiyama-Nakagiri Y, Sakai K, et al. Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer. J Clin Invest. 2005;115:1777–1784.

163. Kelsell DP, Norgett EE, Unsworth H, et al. Mutations in ABCA12 underlie the severe congenital skin disease harlequin ichthyosis. Am J Hum Genet. 2005;76:794–803. 164. Dale BA, Holbrook KA, Fleckman P, et al. Heterogeneity in harlequin ichthyosis, an inborn error of epidermal keratinization: variable morphology and structural protein expression and a defect in lamellar granules. J Invest Dermatol. 1990;94:6–18. 165. Thomas AC, Sinclair C, Mahmud N, et al. Novel and recurring ABCA12 mutations associated with harlequin ichthyosis: implications for prenatal diagnosis. Br J Dermatol. 2008;158:611–613.

HARLEQUIN ICHTHYOSIS Gabriele Richard

HARLEQUIN ICHTHYOSIS

CIE treated with 0.77–1 mg/kg per day acitretin.101 The most common side-effects in this cohort were cheilitis, increased skin fragility and dry mouth. Adverse effects of systemic retinoids on the musculoskeletal system occur infrequently, but should be considered before initiating a long-term treatment. Osteoporosis, hyperostoses, calcification of tendons and ligaments, and premature epiphyseal closure were reported in children or adults treated with higher doses of oral retinoids (≥1.0 mg/kg per day).159 In contrast, lower dose treatment over 1 month to 11 years in 42 British children with a series of inherited disorders of cornification did not show evidence for skeletal toxicity or growth retardation.160 Based on a study by Lacour et al.,100 guidelines for oral acitretin treatment in children have been suggested. In general, a baseline assessment is recommended prior to therapy or within the first month, which may include full blood count, fasting lipids, liver function tests, and checks for pregnancy in adolescents who might become pregnant. A limited skeletal survey (including all four limbs and lateral spine) might be considered if long-term therapy is planned. The follow-up, including fasting lipids, liver function tests, and urine analysis, is suggested monthly for the next 3–6 months, then with larger intervals thereafter. Periodic radiographic examinations of cervical and thoracic spine and epiphyses might complement the regimen. Overall, systemic retinoids appear to be relatively safe for the long-term treatment of congenital ichthyoses, as long as patients are monitored carefully. Because retinoids are potent teratogens, their use in sexually active females requires concomitant use of reliable methods of birth control. Recently, a new class of retinoid acid metabolism blocking agents (RAMBAs) have emerged as alternatives to synthetic retinoids. In early trials, these drugs promise similar effects as retinoids, with less sideeffects and a shorter post-treatment teratogenicity period due to their more favorable pharmacokinetic profile.151,161 However, the new compounds, which inhibit cytochrome P450(CYP)26, the rate limiting enzyme(s) in the catabolism of retinoid acid, have not been sufficiently tested and are currently not available nor approved by the FDA.161

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HARLEQUIN ICHTHYOSIS

Figure 8.18  Harlequin ichthyosis: severe fissuring of the skin. Note hypoplastic fingers with ischemia. (Reproduced from Morillo M, Novo R, Torrelo A, et al. Feto arlequin. Actas Dermosifiliogr. 1999;90:185–187.)

intolerance are common. Although these children may have delayed growth and development, intelligence is usually normal. Figure 8.17  Harlequin ichthyosis: severe hyperkeratosis with eclabium and ectropion. (Reproduced from Morillo M, Novo R, Torrelo A, et al. Feto arlequin. Actas Dermosifiliogr. 1999;90:185–187.)

HISTOLOGICAL AND ULTRASTRUCTURAL FEATURES

an offensive odor. It cracks and forms large, diamond-shaped, adherent plates, which are separated by broad, deep, and intensely red fissures (Fig. 8.17). The tautness of the skin results in facial deformities, such as microcephaly, hypoplastic nose and ears, pronounced ectropion and eclabium, which give the infant a characteristic and grotesque appearance (Fig. 8.17). Eyelashes and eyebrows are usually missing, while scalp hair may be present. The limbs remain in rigid semiflexion and hands and feet may be swollen with a mitten- or claw-like appearance (Fig. 8.18). Micromelia has been reported.166 Constriction of the chest and abdomen often interferes severely with respiration and feeding;167 however, abnormalities of inner organs are rare, including congestion, patent ductus arteriosus, polydactyly, enlarged thymus, thyroid aplasia, and renal tubular defects. In recent years, an increasing number of patients with prolonged survival due to retinoid therapy have been reported.168 After shedding the armor-like cast, the appearance of the skin changes to severe exfoliative ichthyosiform erythroderma/CIE with intense redness and generalized fine or larger, whitish scale. Alopecia, thickening of the skin on palms and soles, and heat

Conventional histology is non-diagnostic and variable, featuring a very thick and compact orthokeratotic stratum corneum. Para­ keratosis has also been observed. Hair follicles and sweat ducts have prominent hyperkeratotic plugging, which was used previously as a helpful feature for making a prenatal diagnosis of HI from a fetal skin biopsy. Ultrastructural features of HI skin at 20–24 weeks’ gestation and in the newborn were similar to those in amniotic fluid cells at 17 weeks’ gestation, including abnormal or missing lamellar bodies in the granular layer (Fig. 8.19), absent extracellular lipid lamellae, and the presence of lipid inclusions or remnant organelles in the stratum corneum. Less frequently reported abnormalities were: small or absent keratohyalin granules, giant mitochondria, absence of keratins K6 and K16 and defective filaggrin processing.164,169–172 Based on recent molecular advances it has become clear that harlequin ichthyosis is a primarily a disorder of keratinocyte lipid transport and metabolism, resulting in a defective epidermal permeability barrier. As shown in mice lacking this ABC transporter protein, the failure to form extracellular lipid lamellae and decreased proteolytic activity in the epidermis seems to result in decreased desquamation, confirming a retention-type hyperkeratosis in harlequin ichthyosis.162,173,174

166. Charles A, Moulinasse R, Versailles L. Harlequin fetus and micromelia. Prenat Diagn. 1989;9:709–713. 167. Rogers M, Scarf C. Harlequin baby treated with etretinate. Pediatr Dermatol. 1989;6:216–221. 168. Haftek M, Cambazard F, Dhouailly D, et al. Longitudinal study of a harlequin infant presenting clinically as non-bullous congenital ichthyosiform erythroderma. Br J Dermatol. 1996;135:448–453. 169. Hashimoto K, De Dobbeleer G, Kanzaki T. Electron microscopic studies of harlequin fetuses. Pediatr Dermatol. 1993;10:214–223. 170. Akiyama M, Kim DK, Main DM, et al. Characteristic morphologic abnormality of harlequin ichthyosis detected in amniotic fluid cells. J Invest Dermatol. 1994;102:210–213.

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171. Akiyama M, Dale BA, Smith LT, et al. Regional difference in expression of characteristic abnormality of harlequin ichthyosis in affected fetuses. Prenat Diagn. 1998;18:425–436. 172. Suzumori K, Kanzaki T. prenatal diagnosis of harlequin ichthyosis by fetal skin biopsy: report of two cases. Prenat Diagn. 1991;11:451–457. 173. Smyth I, Hacking DF, Hilton AA, et al. A mouse model of harlequin ichthyosis delineates a key role for Abca12 in lipid homeostasis. PLoS Genet. 2008;19:e1000192. 174. Zuo Y, Zhuang DZ, Han R, et al. ABCA12 Maintains the epidermal lipid permeability barrier by facilitating formation of ceramide linoleic esters. J Biol Chem. 2008;283:36624–36635.

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THERAPEUTICS AND PROGNOSIS

Figure 8.19  Harlequin ichthyosis: abnormal lamellar bodies under electron microscopy.

Prenatal diagnosis Prenatal diagnosis of harlequin ichthyosis is possible by mole­ cular genetic testing, 3- and 4-dimentional ultrasonography and electron microscopic examination of keratinized hair canals and amniotic fluid cells.169,175,176 Although the latter is a wellestablished method for prenatal diagnosis, it requires invasive procedures, provides reliable results only in the late second trimester,171,177 and is not widely available. In contrast, DNA-based testing is offered by diagnostic laboratories and, once the pathogenic ABCA12 mutations have been identified in a family, can be reliably used to identify mutation carriers and perform early prenatal diagnosis (from the 10th week of gestation).

DIFFERENTIAL DIAGNOSIS Although the clinical presentation of HI is striking and characteristic, there is some overlap with severe collodion baby presentation. Facial features and taut, scaling skin in Neu–Laxova syndrome may be reminiscent of HI, but this very rare autosomal recessive disorder is associated with microcephaly, lissencephaly (few and shallow convolutions of the brain), syndactyly and many other congenital malformations.178 175. Bongain A, Benoit B, Ejues L, et al. Harlequin fetus: three-dimensional sonographic findings and new diagnostic approach. Ultrasound Obstet Gynecol. 2002;20:82–85. 176. Yanagi T, Akiyama M, Sakai K, et al. DNA-based exclusion of harlequin ichthyosis. J Am Acad Dermatol. 2008;58:653–656. 177. Akiyama M, Suzumori K, Shimizu H. Prenatal diagnosis of harlequin ichthyosis by the examination of keratinized hair canals and amniotic fluid cells at 19 weeks’ estimated gestational age. Prenat Diagn. 1999;19: 167–171. 178. Curry CJR. Further comments on the Neu-Laxova syndrome. Am J Med Genet. 1982;13:441–444.

SJÖGREN–LARSSON SYNDROME

Advanced neonatal intensive care and nursing are necessary to provide sufficient nutrition, monitor and manage body temperature, correct fluid and electrolyte imbalances, and prevent and treat pulmonary dysfunction, pneumonia or sepsis. The use of humidified incubators and topical treatment with lubricants and light emollients is indicated. Severe ectropion demands ophthalmologic care.179 Human skin equivalents for repair of cicatricial ectropion have been suggested.180 Early use of systemic retinoids, in particular acitretin,181 may improve survival, accelerate shedding and improve ectropion and eclabium; nevertheless, the prognosis of babies with HI is poor and the frequency of complications such as pulmonary failure, sepsis, dehydration, and renal failure with a fatal outcome is high. In children surviving the critical neonatal period, a lifelong severe exfoliative erythroderma persists, often associated with flexural contractures and growth and developmental delay. It is therefore critical to discuss prognosis, long-term multidisciplinary care, therapeutic options, and potential side-effects with each family, especially before weighing the risks and benefits of retinoid therapy.

SJÖGREN–LARSSON SYNDROME Gabriele Richard Sjögren–Larsson syndrome (OMIM 270200) is an autosomal recessive neurocutaneous disorder characterized by the clinical triad of congenital ichthyosis, di- and tetraplegia, and mental retardation.182 This rare disorder is most common in Sweden, where it has a prevalence of 0.4 in 100 000 persons, but it occurs worldwide.183 The disorder presents at birth with varying degrees of erythema and ichthyosis, but a collodion membrane or ectropion is rarely seen. Erythema is unusual after the first year of life, although a yellowish hue to the skin is common. In contrast to many other ichthyoses, persistent pruritus is common. The morphology of the scaling may range from fine white scales to larger plate-like scales to non-scaling hyperkeratosis. However, most typical is thickening of the skin with accentuated skin markings (Fig. 8.20) and the appearance of lichenification, particularly in flexural areas. Due to the clinical overlap with congenital ichthyosiform erythroderma and other congenital recessive ichthyoses, the diagnosis of Sjögren–Larsson syndrome is often delayed until the onset of neurological symptoms and/ or appearance of perifoveal glistening white dots (Fig. 8.21). Predilection sites are the lower abdomen, especially around the umbilicus, the side and nape of the neck, as well as the large flexures. In >50% of patients, mild palmoplantar keratoderma is present. The histopathologic features are non-specific and include hyperkeratosis, papillomatosis, and acanthosis with a well-preserved granular layer. Electron microscopic features 179. Chua CN, Ainsworth J. Ocular management of harlequin syndrome. Arch Ophthalmol. 2001;119:454–455. 180. Culican SM, Custer PL. Repair of cicatricial ectropion in an infant with harlequin ichthyosis using engineered human skin. Am J Ophthalmol. 2002;134:442–443. 181. Singh S, Bhura M, Maheshwari A, et al. Successful treatment of harlequin ichthyosis with acitretin. Int J Dermatol. 2001;40:472–473. 182. Sjögren T, Larsson T. Oligophrenia in combination with congenital ichthyosis and spastic disorder. Acta Psychiatr Neurol Scand. 1957;32:1–113. 183. Liden S, Jagell S. The Sjögren–Larsson syndrome. Int J Dermatol. 1984;23: 247–253.

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Figure 8.20  Generalized hyperkeratosis of the skin with accentuated skin markings in the axillary fold (Courtesy Dr W.B. Rizzo).

Figure 8.21  Perifoveal glistening dots of the retina (Courtesy Dr W.B. Rizzo).

are reminiscent of those seen in other congenital recessive ichthyoses. During the first 2–3 years of life, central nervous system involvement manifests with abnormal gait, pyramidal signs, and di- or tetraplegia. The lower extremities are usually far more severely affected than the arms.184 Delay in neuromotor develop-

184. Haddad FS, Lacour M, Harper JI, et al. The orthopaedic presentation and management of Sjögren–Larsson syndrome. J Pediatr Orthop. 1999;19: 617–619. 185. Verhoog J, Fuijkschot J, Ketelaar M, et al. Sjögren-Larsson syndrome: motor performance and everyday functioning in 17 patients. Dev Med Child Neurol. 2008;50:38–43. 186. van Domburg PH, Willemsen MA, Rotteveel JJ, et al. Sjögren–Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients. Neurology. 1999;52:1345–1352. 187. De Laurenzi V, Rogers GR, Hamrock DJ, et al. Sjögren–Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nat Genet. 1996;12:52–57. 188. Fuijkschot J, Cruysberg JRM, Willemsen MAAP, et al. Subclinical changes in the juvenile crystalline macular dystrophy in Sjögren-Larsson syndrome detected by optical coherence tomography. Ophthalmol. 2008;115:870–875. 189. Sillen A, Anton-Lamprecht I, Braun-Quentin C, et al. Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren–Larsson syndrome. Hum Mutat. 1998;12:377–384.

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ment and development of contractures are gradually progressive and accompanied by speech defects, and severe mental retardation.185 Seizures are present in about one-third of patients. Neuroimaging studies reveal that most patients have white matter disease with retarded myelination and a variable degree of dysmyelination due to accumulation of free lipids in the periventricular white matter.186 An almost pathognomonic finding in Sjögren–Larsson syndrome is the presence of perifoveal glistening white dots in the ocular fundus (Fig. 8.21), a specific form of juvenile macular dystrophy.187,188 These develop during the first year of life in many but not all patients, and increase in number over time.186 Other features of the syndrome reported in some patients are corneal dystrophy, dental and/or osseous dysplasia, and hypertelorism. The combination of congenital ichthyosis with glistening white dots or spasticity is diagnostic for Sjögren–Larsson syndrome. Sjögren–Larsson syndrome is caused by recessive mutations in the fatty aldehyde dehydrogenase (FALDH) gene FALDH3A2 on the short arm of chromosome 17, which result in enzyme deficiency.187,189 This microsomal enzyme catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids, a pathway that is important for the synthesis of epidermal lipids as well as the catabolism of ether phospholipids and sphingolipids in the brain.190–192 Cultured SLS keratinocytes show accumulation of fatty alcohols, which are diverted into the biosynthesis of wax esters and other epidermal lipids and may interfere with lamellar body membranes and the epidermal permeability barrier. In addition, FALDH may catalyze processes in the hepoxilin and trioxilin pathway, which are metabolites of arachidonic acid, thus tying together the ichthyosis in SLS with CIE caused by mutations in ichthyin, ALOX12B and ALOXE3.192 The measurement of enzyme activity in cultured fibroblasts or leukocytes is a specific and reliable diagnostic test that also allows detection of unaffected carriers who exhibit half of normal levels, but is not widely available.190 Another sensitive marker for the enzymatic defect in SLS is the detection of elevated free fatty alcohols in cultured fibroblasts and plasma.191 Nevertheless, DNA-based molecular testing has almost replaced biochemical tests in the diagnosis of SLS due to its high sensitivity, availability, ease, and possibility for carrier and prenatal testing once the underlying mutations are known.193,194 To date, sequence analysis of the ALDH3A2 gene has revealed disease-causing mutations in all SLS patients tested, making the clinical sensitivity of this test very high. More than 72 distinct ALDH3A2 mutations have been reported in at least 121 SLS families from around the

190. Rizzo WB, Craft DA. Sjögren–Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol: NAD1 oxidoreductase in cultured fibroblasts. J Clin Invest. 1991;88: 1643–1648. 191. Rizzo WB, Craft DA. Sjögren–Larsson syndrome: accumulation of free fatty alcohols in cultured fibroblasts and plasma. J Lipid Res. 2000;41: 1077–1081. 192. Rizzo WB. Sjögren–Larsson syndrome: molecular genetics and biochemical pathogenesis of fatty aldehyde dehydrogenase deficiency. Mol Genet Metabolism. 2007;90:1–9. 193. Rizzo WB, Carney G, Lin Z. The molecular basis of Sjögren–Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene. Am J Hum Genet. 1999;65:1547–1560. 194. Rizzo WB, Carney G. Sjögren–Larsson syndrome: diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene (ALDH3A2). Hum Mut. 2005;26:1–10.

Ichthyosis and disorders of other cornification

REFSUM DISEASE Gabriele Richard Synonyms: heredopathia atactica polyneuritiformis; phytanic acid storage disease; phytanic acid oxidase deficiency; hereditary motor and sensory neuropathy IV (OMIM 266500). This is a rare autosomal recessive neurological syndrome infrequently associated with late-onset ichthyosis that is characterized by an excessive accumulation of phytanic acid in tissues and body fluids. Due to deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase, patients are unable to degrade phytanic acid, a 20-carbon, saturated, branched-chain fatty acid exclusively derived from dietary chlorophyll.200 The clinical hallmarks are anosmia and early-onset retinitis pigmentosa with variable combinations of neuropathy, deafness, ataxia, and ichthyosis. The age of onset of symptoms ranges widely from early childhood to the 6th decade of life.201 The disorder usually leads to insidious

195. Sillen A, Holmgren G, Wadelius C. First prenatal diagnosis by mutation analysis in a family with Sjögren–Larsson syndrome. Prenat Diagn. 1997; 17:1147–1149. 196. Rizzo WB, Craft DA, Kelson TL, et al. Prenatal diagnosis of Sjögren–Larsson syndrome using enzymatic methods. Prenat Diagn. 1994;14:577–581. 197. Taube B, Billeaud C, Labreze C, et al. Sjögren–Larsson syndrome: early diagnosis, dietary management and biochemical studies in two cases. Dermatology. 1999;198:340–345. 198. Willemsen MA, Rotteveel JJ, Steijlen PM, et al. 5-Lipoxygenase inhibition: a new treatment strategy for Sjögren–Larsson syndrome. Neuropediatrics. 2000;31:1–3. 199. Haug S, Braun-Falco M. Restoration of fatty aldehyde dehydrogenase deficiency in Sjögren–Larsson syndrome, Gene Ther. 2006;13:1021–1026. 200. Wanders RJA, Jacobs C, Skjedal OH. Refsum disease. In: Scriver CR, Beaud, Sly WS, et al, eds. Refsum disease. New York: McGraw-Hill; 2001:3303– 3317. 201. Wierzbicki AS, Lloyd MD, Schofield CJ, et al. Refsum’s disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J Neurochem. 2002;80:727–735.

neurological symptoms such as muscle weakness, difficulty walking, and failing night vision during childhood. The progressive but undulating course of the disorder with periods of acute exacerbation and remission may delay diagnosis and result in gradual neurological deterioration. Cardinal features of Refsum disease are cerebellar ataxia, atypical retinitis pigmentosa, peripheral polyneuropathy, and elevated protein content in the cerebrospinal fluid. In addition, these may be accompanied by other symptoms, including cranial nerve dysfunction (anosmia, sensorineural deafness), renal tubular dysfunction, and skeletal hyperostosis. Cardiac arrhythmia and cardiomyopathy ensuing heart failure are not uncommon and may be fatal. Cutaneous symptoms (ichthyosis) tend to develop in adulthood in some but not all patients. The associated ichthyosis is mild to moderate with small white scales covering extremities and trunk, often resembling ichthyosis vulgaris. Larger and dark scales or palmoplantar keratoderma have been also reported.202 Lipid-containing vacuoles in basal keratinocytes may be the only diagnostic finding on histopathologic skin examination.202 The diagnosis can be confirmed by detecting severely increased phytanic acid levels in the plasma (>200 µmol/L) or an increased phytanic acid/pristanic acid ratio using liquid gas chromatography/proton nuclear magnetic resonance spectroscopy.203–205 The vast majority of patients have a severely decreased phytanic acid oxidase activity and phytanoyl-CoA hydroxylase deficiency in cultured fibroblasts.206 The CSF protein concentration is elevated, as is the pipecolic acid concentration in approximately 20% of affected individuals.205 Heterozygous carriers of Refsum disease usually have normal plasma levels of phytanic acid, although the enzyme activity of phytanoyl-CoA hydroxylase is decreased in cultured fibroblasts. On a molecular level, two genes have been implicated in the pathogenesis of Refsum disease. More than 90% of affected individuals have inactivating mutations in the PHYH gene on chromosome 10p13, which encodes the peroxisomal enzyme phytanoyl-CoA hydroxylase.207,208 More than 50% of the observed mutations are missense changes, while frameshift mutations (insertions, deletions) and splice-site mutations are less common.208,205 The remainder of patients have mutations in the PEX7 gene on chromosome 6q23.3 encoding the peroxisomal biogenesis factor 7, also known as the peroxisomal type 2 targeting signal receptor. This enzyme contains a type-2 peroxisomal targeting signal207 and catalyzes the first step of phytanic acid metabolism by generating pristanic acid. The enzymatic block

REFSUM DISEASE

world, including missense (38%), splice site (16%) and nonsense (5%) mutations, as well as deletions, insertions and complex mutations (>33%).194 Although the majority of mutations are private, there are a few common mutations with a higher allele frequency in the northern European and MiddleEastern population, which may facilitate DNA-based molecular diagnosis. Prenatal diagnosis is available using molecular genetic as well as enzymatic methods from chorionic villus sampling or amniocentesis material.190,195,196 The management of Sjögren–Larsson syndrome patients requires a multidisciplinary approach, including dermatologic, neurologic, ophthalmologic, orthopedic, and social collaboration. Aggressive physiotherapy, followed by appropriate surgical intervention, has been shown to drastically improve the mobility of children.184 Various forms of a fat-reduced diet have not yet provided consistent and reproducible results, although early dietary intervention during infancy was beneficial in one case.197 5-Lipoxygenase inhibitors that block the synthesis of leukotriene B4 might be a promising class of therapeutics to diminish pruritus, but a beneficial effect on CNS symptoms has not been proven.198 In a pilot study, viral-mediated transfection of normal FALDH cDNA into cultured SLS keratinocytes achieved resistance to the fatty aldehyde-induced toxicity.199 Nevertheless, many technical and application problems have to be overcome before a clinical use of gene therapeutic approaches is feasible in SLS.

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202. Davies MG, Marks R, Dykes PJ, et al. Epidermal abnormalities in Refsum’s disease. Br J Dermatol. 1977;97:401–406. 203. Cingolani L. Rapid gas chromatographic determination of phytanic acid from serum of a patient suffering from Refsum’s disease. J Chromatogr. 1987;419:475–478. 204. Oostendorp M, Engelke UF, Willemsen MA, et al. Diagnosing inborn errors of lipid metabolism with proton nuclear magnetic resonance spectroscopy. Clin Chem. 2006;52:1395–1405. 205. Wanders RJA, Waterham HR, Leroy BP. Refsum disease. GeneReviews 2006, www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=refsum 206. Poulos A, Pollard AC, Mitchell JD, et al. Patterns of Refsum’s disease. Phytanic acid oxidase deficiency. Arch Dis Child. 1984;59:222–229. 207. Mihalik SJ, Morrell JC, Kim D, et al. Identification of PAHX, a Refsum disease gene. Nat Genet. 1997;17:185–189. 208. Jansen GA, Ferdinandusse S, Hogenhout EM, et al. Phytanoyl-CoA hydroxylase deficiency. Enzymological and molecular basis of classical Refsum disease. Adv Exp Med Biol. 1999;466:371–376.

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leads to subsequent accumulation of phytanic acid in plasma and various tissues where it replaces up to 50% of normal fatty acid constituents, thus explaining skin, liver, heart, adipose, and peripheral nervous tissue involvement.207 In contrast, little phytanic acid is stored in the brain. Preliminary data suggest that a disturbed interaction of PAHX with its associated protein number 1 might lead to the development of cranial nerve symptoms.207 The peroxisomal biogenesis factor 7 is required for the import of phytanoyl-CoA hydroxylase and other proteins with a type 2 peroxisomal targeting signal into peroxisomes. Hence, mutations in PEX7 are associated with a broad spectrum of clinical phenotypes depending on the enzymes involved, including rhizomelic chondrodysplasia punctata and adult Refsum disease.209 Molecular genetic testing of the PHYH and PEX7 genes detects mutations in more than 95% of affected individuals but is available on a clinical basis only in Europe.204 Prenatal diagnosis can be performed by targeted molecular testing in families with known mutations or alternatively by measuring phytanic acid oxidation in cultured cells obtained by CVS or amniocentesis. Abnormalities in catabolism of phytanic acid and its accumulation also occur in other peroxisomal deficiency syndromes including rhizomelic chondrodysplasia punctata, Zellweger syndrome, infantile Refsum disease, and neonatal adrenal lipodystrophy. The combination of neurological symptoms and late-onset ichthyosis, however, is characteristic of Refsum disease. The treatment of adult Refsum disease includes a restricted dietary intake of phytanic acid of 50% of patients) and in one study, 100% developed lesions within the first year of life.346 The disorder is characterized by the independent occurrence of two morphologic features: circumscribed migrating and figurate erythematous lesions and sharply demarcated, hyperk-

338. Richard G, Smith LG, Bailey RA, et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet. 1998;20: 366–369. 339. Richard G, Brown N, Rouan F, et al. Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30. 3) and genotype-phenotype correlations. J Invest Dermatol. 2003;120:601–609. 340. Richard G, White TW, Smith LE, et al. Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma. Hum Genet. 1998;103:393–399. 341. Lamartine J, Munhoz Essenfelder G, Kibar Z, et al. Mutations in GJB6 cause hidrotic ectodermal dysplasia. Nature Genet. 2000;26:142–144. 342. Ishida-Yamamoto A, McGrath JA, Lam H, et al. The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope. Am J Hum Genet. 1997;61:581–589. 343. Van Steensel MAM, Oranje AP, Van der Schroeff JG, et al. The missense mutation G12D in connexin 30.3 can cause both erythrokeratodermia

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Ichthyosis and disorders of other cornification

Figure 8.42  Brownish hyperkeratotic lesions with geographic, sharply demarcated borders. In this patient a mutation in connexin has been documented (personal communication, G. Richard).

eratotic, brownish plaques (Fig. 8.42).347 The brownish hyperkeratotic and well-demarcated plaques are relatively fixed in site at the extensor surfaces, although extension and regression occur. Erythema may change in extent and shape within hours but also remain for more than one week.346 Erythematous lesions may be surrounded by an anemic halo (Fig. 8.43).346 The erythema can easily be provoked by external factors such as trauma to the skin, changes of temperature and emotional stress. Subjective complaints include itching and burning sensations. Often focal hyperkeratotic plaques are present on palms and soles but diffuse keratoderma may occur.348 Some patients have a characteristic superficial peeling of the palms and soles (Fig. 8.44).346 Lesions preferentially affect the face, buttocks, and extensor surfaces of the limbs. It is important to realize that cutaneous lesions in EKV are often distributed in an asymmetrical way. In 1957, Sommacal and Schnyder reported on a family with 14 affected members. We have re-examined this pedigree, which comprised 77 members with 29 affected persons over five generations (45 females, 31 males).346 In all patients, EKV presented in the first year of life, and several mothers noted the erythematous lesions at birth of their children. The hyper­ keratotic lesions appeared later. In all but two of the patients

variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia Gottron. Am J Med Genet A. 2009;149A:657–661. 344. Gottfried I, Landau M, Glaser F, et al. A mutation in GIB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein. Hum Mol Genet. 2002;11:1311–1316. 345. Akman A, Masse M, Mihci E, et al. Progressive symmetrical erythrokeratoderma: report of a Turkish family and evaluation for loricrin and connexin gene mutations. Clin Exp Dermatol. 2008;33:582–584. 346. Itin P, Levy CA, Sommacal-Schopf D, et al. Family study of erythrokeratodermia figurata variabilis. Hautarzt. 1992;43:500–504. 347. Rogers M. Erythrokeratodermas: a classification in a state of flux? Australas J Dermatol. 2005;46:127–141. 348. Itin PH, Schaub NA. Keratodermies palmoplantaires héréditaires et syndromes associés. In: Saurat JH, Grosshans E, Laugier P, et al, eds. Dermatologie et maladies sexuellement transmissibles. 3rd ed. Paris: Masson; 1999.

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Figure 8.44  Keratoderma with superficial peeling of palms and soles. A

Erythrokeratoderma progressiva symmetrica of Darier–Gottron This group is less homogeneous in the clinical manifestations than in patients with EKV. Patients develop symmetrical erythematous and hyperkeratotic plaques on the extremities and face within the first year of life but the skin is usually normal at birth. Often, cheeks, buttocks, and shoulders are affected, as well as wrists and ankles. Itching is only mild or absent. In general, progression of the disease with involvement of large parts of the skin occurs. Some regression may start around puberty, especially in sporadic cases. Transgenic mice expressing a mutant form of loricrin revealed clinically erythrokeratoderma, and this indicated the molecular basis of some cases of progressive symmetric erythrokeratoderma.349 It has been shown recently that this variant is allelic with erythrokeratoderma figurata variabilis.343 B

Figure 8.43  (A) Brownish hyperkeratotic lesions with geographic borders. (B) Symmetric erythematous, irregularly shaped lesions (Courtesy Dr A. Torrelo).

erythema was prominent and in the others hyperkeratotic lesions were more severe. Most patients had a burning sensation in their red areas. Teeth, hairs and nails are normal and no associated changes in mucous membranes are found. Differential diagnosis includes erythrokeratolysis hiemalis, Netherton syndrome, and some types of ichthyosis. Histopathological features, as in all erythrokeratodermas, are not diagnostic.

349. Suga Y, Janik M, Attar PS, et al. Transgenic mice expressing a mutant form of loricrin reveal the molecular basis of the skin disease, Vohwinkel

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Erythrokeratoderma en cocardes Erythrokeratoderma en cocardes is also known as genodermatose en cocardes or Degos’ syndrome. The condition is characterized by large round plaques with concentric erythema and scaling. The target-like configuration comes and goes.333 Lesions are present at birth and superficial scaling on palms and soles may occur resembling erythrokeratolysis hiemalis.

Erythrokeratoderma with erythema gyratum repens-like lesions A recently described subtype of erythrokeratoderma with erythema gyratum repens-like lesions is most likely the same

syndrome and progressive symmetric erythrokeratoderma. J Cell Biol. 2000;151:401–412.

Ichthyosis and disorders of other cornification

THERAPEUTICS AND PROGNOSIS Moisturizing agents, topical retinoids and standard keratolytics result in minor improvement. Systemic treatment with retinoids may result in improvement even with very low dosage and some patients show a total clearing as long the treatment is continued.350

PALMOPLANTAR KERATODERMA Daniel Hohl and Stephanie Christen-Zaech

INTRODUCTION CLASSIFICATION The palmoplantar keratodermas (PPK) are a heterogeneous group of dermatosis characterized by thickening of the palms and soles. They can be subdivided into acquired and inherited PPK. Inherited forms may be part of generalized skin disorders or mainly isolated. PPKs can be further classified according to their mode of inheritance, clinical distribution of hyperkeratosis (diffuse, focal or punctuate), and whether ectodermal or nonectodermal involvement is present. The classification of PPK may be difficult due to the variability of the morphology, the variation of the clinical appearance during the lifetime as well as within and between families, and the use of different nomenclatures. The identification of underlying gene defects may allow a more precise classification.

DIAGNOSTIC APPROACH

diograms, histology, biochemical studies or molecular genetic analyses help to distinguish clinical phenotypes. For example, elevated tyrosine levels will confirm hereditary tyrosinemia type 2, for which an early dietary restriction is essential. Histopathologic evaluation may also be useful, such as in diagnosing PPK of Vörner, characterized by epidermolytic hyperkeratosis. However, biopsies from patients with epidermolytic PPK may not show the epidermolysis, sometimes requiring more than one biopsy. In addition, epidermolytic hyperkeratosis can be found focally in other PPKs, such as in pachyonychia congenita (with or without nail changes). Loricrin keratoderma (PPK of Camisa) is characterized by parakeratosis with retention of a round nucleus until the most superficial stratum corneum. Acrokeratoelastoidosis of Costa is characterized by the fragmentation of elastic dermal fibers. Huriez syndrome reveals dermal fibrosis and sclerosis with augmentation of vascular structures and atrophic epithelial structures, e.g., eccrine glands. Ultrastructure analysis has little importance in the diagnostic approach of PPK, except in the Richner Hanhart syndrome in which tyrosine crystals can be detected (although not the way to diagnose the disorder). Molecular analysis of PPK is widely used and allows confirmation of the diagnosis by identifying mutations in the genes encoding for keratins, connexins, loricrin, SLURP and many more. Some of these analyses are easy to perform; others are more time consuming and expensive and are usually reserved for research.

DIFFUSE PALMOPLANTAR KERATODERMAS

disease which was formerly called erythrokeratoderma anularis migrans.336

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DIFFUSE PALMOPLANTAR KERATODERMAS The group of PPK with diffuse pattern is heterogeneous. Within the first year of life diffuse keratoderma may start with a focal pattern that can progressively develop into a confluent hyper­ keratotic pattern.

Clinical presentation The family and personal history will help to distinguish acquired from inherited PPK. Inherited PPKs often first manifest during infancy when children start walking. Environmental or hostrelated factors, on the other hand, may explain an acquired PPK. Symmetrically distributed PPKs may occur in PPK that is inherited or acquired, especially if the latter results from mechanical trauma to both hands. However, inherited PPK is usually symmetrical with a diffuse, focal, or punctate distribution, whereas asymmetrical PPK is mostly acquired. Evaluation of the entire integument, mucous membranes, teeth, periodontal tissues, nails and hair is critical in patients with PPK to distinguish among forms of PPK.

Laboratory findings Additional examinations are often necessary to confirm a clinical diagnosis. Investigations, such as audiometry, electro- or echocar-

350. Van de Kerkhof PCM, Steijlen PM, van Dooren-Greebe RJ, et al. Acitretin in the treatment of erythrokeratodermia variabilis. Dermatologica. 1990;181:330–333. 351. Kuster W, Becker A. Indication for the identity of palmoplantar keratoderma type Unna–Thost with type Vorner. Thost’s family revisited 110 years later. Acta Derm Venereol. 1992;72:120–122.

ISOLATED DIFFUSE PALMOPLANTAR KERATODERMAS Autosomal dominant Diffuse non-epidermolytic (Unna) and epidermolytic (Vörner) keratodermas Unna and Vörner are clinically indistinguishable diffuse types of PPK, characterized by non-transgrediens, sharply marginated, yellowish hyperkeratosis with surrounding erythema. Nonepidermolytic palmoplantar keratoderma (NEPPK) was originally described by Unna and Thost, and thus termed ‘Unna–Thost PPK’. Re-evaluation of the original family described by Thost showed that epidermolytic forms existed within the family351 and that several family members of the original family had keratin 9 mutations.352 Epidermolytic palmoplantar keratoderma (EPPK) of Vörner may be able to be differentiated

352. Kuster W, Reis A, Hennies HC. Epidermolytic palmoplantar keratoderma of Vorner: re-evaluation of Vorner’s original family and identification of a novel keratin 9 mutation. Arch Dermatol Res. 2002;294:268–272.

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histologically from the non-epidermolytic types by the presence of epidermolysis; however, more than one sample may be required to demonstrate evidence of the epidermolysis. NEPPK may also be a morphologically heterogeneous group with epidermolysis variably present in one type and absent in another.

Epidemiology EPPK and NEPPK are the most common forms of diffuse PPK. The incidence of EPPK in Northern Ireland is 1 in 23 000,353 and of NEPPK in Northern Sweden 3–5.5 in 1000.354 They are of autosomal dominant inheritance with complete penetrance.

A

Clinical presentation DIFFUSE PALMOPLANTAR KERATODERMAS

Initial involvement in early infancy may be patchy, but within the first few years of life, palms and soles are covered by a thick, diffuse, yellowish hyperkeratosis (Fig. 8.45). The keratoderma is sharply outlined at the lateral margins of the hands and feet, and is often surrounded by an erythematous border. PPK of Voerner shows minor transgrediens extension on to the dorsal surface of fingers and toes. In PPK of Unna occasional thickening of the skin over the metacarpo- and interphalangeal joints (knuckle pads) can be observed.355,356 Although the abnormality is largely confined to the hands and feet, mild hyperkeratosis of umbilicus, areolae, elbows and knees may rarely occur.357 In 50% of cases, nails show a watch glass-like curvature. Hyperhidrosis is often present, and may lead to maceration, and fissuring. Moreover, pruritus and odor, which are often associated with fine scaling and erythema, may be a sign of secondary fungal or bacterial infections. Unlike bullous ichthyosiform erythroderma, EPPK does not usually blister despite histological epidermolysis (Fig. 8.46). However, there is a decreased threshold to mechanically induced friction blisters, a symptom exacerbated by treatment with oral synthetic retinoids. Mutations in keratin KRT9 (PPK of Voerner) have been shown to lead to more severe clinical manifestations than mutations in keratin KRT1 (Unna’s PPK).

Laboratory findings Histology of EPPK is marked by hyperorthokeratosis, acanthosis, papillomatosis and epidermolysis. The granular cell layer may be increased, diminished or absent. The suprabasal epidermolysis358 or dyskeratosis78 is associated with ultrastructurally abnormal keratin aggregates and cytolysis of spinous and granular

353. Covello SP, Irvine AD, McKenna KE, et al. Mutations in keratin K9 in kindreds with epidermolytic palmoplantar keratoderma and epidemiology in Northern Ireland. J Invest Dermatol. 1998;111:1207–1209. 354. Lind L, Lundstrom A, Hofer PA, et al. The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13. Hum Mol Genet. 1994;3:1789–1793. 355. Nogita T, Furue M, Nakagawa H, et al. Keratosis palmoplantaris nummularis. J Am Acad Dermatol. 1991;25:113–114. 356. Kimonis V, DiGiovanna JJ, Yang JM, et al. A mutation in the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma. J Invest Dermatol. 1994;103:764–769. 357. Reis A, Hennies HC, Langbein L, et al. Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma (EPPK). Nat Genet. 1994;6: 174–179.

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B

Figure 8.45  (A) Plantar (Courtesy Dr A. Torrelo). (B) Palmoplantar keratoderma of the hand in a 3-year-old girl (Courtesy Dr A Lucky).

cells. Since epidermolysis is easily missed a careful search of several biopsy specimens is often required. Immunostaining of EPPK359 shows increased expression of both cornified envelope proteins (transglutaminase-1, involucrin and loricrin) and profilaggrin, the major protein of keratohyaline granules. In general, KRT9 mutations are associated with epidermolytic histology. However, in a Japanese family with the common R162W mutation, the epidermolysis was very mild, with rounded, dissociated mid-epidermal cells rather than frank epidermolysis.360 In KRT1 EPPK, there is minimal cytolysis with tonofilament clumping in occasional cells.361 The histology of NEPPK shows some acanthosis and hyperorthokeratosis and is distinguished from EPPK by the absence of epidermolysis.

358. Navsaria HA, Swensson O, Ratnavel RC, et al. Ultrastructural changes resulting from keratin-9 gene mutations in two families with epidermolytic palmoplantar keratoderma. J Invest Dermatol. 1995;104: 425–429. 359. Hashimoto K, Mizuguchi R, Tanaka K, et al. Palmoplantar keratoderma (Voerner) with composite keratohyalin granules: studies on keratinization parameters and ultrastructures. J Dermatol. 2000;27:1–9. 360. Mayuzumi N, Shigihara T, Ikeda S, et al. R162W mutation of keratin 9 in a family with autosomal dominant palmoplantar keratoderma with unique histologic features. J Invest Dermatol Symp Proc. 1999;4:150–152. 361. Hatsell SJ, Eady RA, Wennerstrand L, et al. Novel splice site mutation in keratin 1 underlies mild epidermolytic palmoplantar keratoderma in three kindreds. J Invest Dermatol. 2001;116:606–609.

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Figure 8.46  Palmar (A) and dorsal surface (B)

A

DIFFUSE PALMOPLANTAR KERATODERMAS

involvement in Voerner PPK due to a keratin 9 mutation. Note the extension to the dorsal aspects of the fingers and knuckles.

B

Pathogenesis The specificity of keratin KRT9 to palmar and plantar skin makes KRT9 an obvious candidate gene. Reis et al. mapped EPPK to the type I (acidic) keratin gene cluster on 17q, and subsequently identified mutations in the keratin KRT9 gene in EPPK families.357 Mutant KRT9 disrupts keratin filaments in vitro in cell transfection experiments362 and in vivo when injected into mouse skin.363 Thus, the phenotype is due to a dominant negative effect of the mutant keratin. Haplo-insufficiency was considered in one case with a KRT9 stop codon mutation predicting a markedly truncated and rapidly degraded mRNA.364 However, in all keratin disorders only recessive loss of function mutations have been reported to date. Most KRT9 mutations in EPPK affect amino acid residues 156–171, which correspond to the highly conserved 1A helix initiation region of the alpha-helical domain crucial for keratin filament assembly. The commonest KRT9 mutation causing EPPK is R162W: a similar mutation also occurs in KRT14 in epidermolysis bullosa simplex and in KTR10 in BIE (bullous ichthyosiform erythroderma). A mutation affecting the KRT9 2B helix termination motif (1362ins3) was described in sporadic EPPK.365 By analogy with other keratin disorders, the same phenotype should be produced by mutations in the corresponding type II keratin. However, no neutral-basic keratin is expressed specifically in palmoplantar epidermis such that KRT1 forms het-

362. Kobayashi S, Tanaka T, Matsuyoshi N, et al. Keratin 9 point mutation in the pedigree of epidermolytic hereditary palmoplantar keratoderma perturbs keratin intermediate filament network formation. FEBS Lett. 1996;386:149–155. 363. Kobayashi S, Kore-eda S, Tanaka T. Demonstration of the pathogenic effect of point mutated keratin 9 in vivo. FEBS Lett. 1999;447:39–43. 364. Szalai S, Szalai C, Becker K, et al. Keratin 9 mutations in the coil 1A region in epidermolytic palmoplantar keratoderma. Pediatr Dermatol. 1999;16:430–435. 365. Coleman CM, Munro CS, Smith FJ, et al. Epidermolytic palmoplantar keratoderma due to a novel type of keratin mutation, a 3-bp insertion in the keratin 9 helix termination motif. Br J Dermatol. 1999;140:486–490.

erodimers with KRT9. Indeed, Lind et al. mapped NEPPK to the type II keratin gene cluster in 1994,354 and mutations have been identified in KRT1 in both NEPPK356 and EPPK.361 The fact that keratin 1 pairs with keratin 9 in palmoplantar skin, and with keratin 10 elsewhere is consistent with the notion that BIE due to KRT1 mutations involves the palms and soles while BIE due to KRT10 mutations leads to mild palmoplantar keratoderma, if any.366 In contrast to the highly disruptive KRT1 mutations of generalized BIE that affect the important helix boundary motifs, those underlying keratoderma limited to palms and soles involve the central part of the helix in EPPK.361 In the diffuse NEPPK of Unna patient, the KRT1 mutation involves loss of a highly conserved lysine residue within the amino-terminal variable end domain of keratin KRT1 which normally attaches to the cornified envelope by transglutaminase cross-linking.356,367 It results not in transgrediens lesions, but in PPK and callosities on the dorsal surfaces of toes and fingers in response to friction. The extent of involvement in individuals with KRT1 mutations may range from generalized bullous ichthyosis to NEPPK associated with hyperkeratosis of the areola, umbilicus and knuckles356 to minor involvement of the palms and soles. NEPPK is probably heterogeneous. In three British families, NEPPK mapped proximal to the type II keratin gene cluster, excluding KRT9 and KRT1 as candidates.368 Keratin 6 and 16 mutations also result in NEPPK.

366. Yang JM, Nam K, Kim SW, et al. Arginine in the beginning of the 1A rod domain of the keratin 10 gene is the hot spot for the mutation in epidermolytic hyperkeratosis. J Dermatol Sci. 1999;19:126–133. 367. Candi E, Tarcsa E, Digiovanna JJ, et al. A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases. Proc Natl Acad Sci U S A. 1998;95:2067–2072. 368. Kelsell DP, Stevens HP, Purkis PE, et al. Fine genetic mapping of diffuse non-epidermolytic palmoplantar keratoderma to chromosome 12q11-q13: exclusion of the mapped type II keratins. Exp Dermatol. 1999;8:388–391.

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Table 8.7  Inherited palmoplantar keratodermas TYPE

SYNONYMS

INHERITANCE GENE DEFECT (PROTEIN)

Diffuse PPK – isolated   Unna–Thost Non-epidermolytic AD PPK PPK

DIFFUSE PALMOPLANTAR KERATODERMAS

ONSET

ECTODERMAL FEATURES

KRT1

Early infancy

Sharply localized to palms and soles (knuckle pads) Hyperhidrosis Sharply localized to palms and soles (knuckle pads) Hyperhidrosis Transgredient Extensor keratosis (pseudoainhum) Hyperhidrosis Transgredient Extensor keratosis Mutilating hyperhidrosis Nail dystrophy Transgredient Knuckle pads Mutilating Hyperhidrosis

NONECTODERMAL FEATURES

OMIM

144200 139350

  Vörner PPK

Epidermolytic PPK, degeneration

AD

KRT9 KRT1

Early infancy

  Greiter and Sybert PPK

Transgrediens and progrediens PPK Nagashima PPK, Recessive Norbotten PPK

AD

KRT1

Infancy

AR

ARS B (SLURP-1)

Birth or early infancy

Recessive Norbotten PPK

AR

Unknown

Unknown

AD

Unknown

Birth or early infancy

AD

GJB2

Infancy

124500

AD

GJB2

Infancy

124500

AD AR

Unknown CSTC

AR

JUP Infancy (Plakoglobin)

  Mal de Meleda

  Gamborg– Nielsen PPK

Diffuse PPK with associated features   Olmsted PPK with syndrome periorificial plaques

  Vohwinkel syndrome   Loricrin keratoderma

Camisa PPK, Variant Vohwinkel PPK   Huriez syndrome Sclerotylosis   Papillon–Lefèvre PPK with syndrome periodontitis Haim–Munk syndrome   Naxos disease PPK with woolly hair and cardiomyopathy

144200

133200

248300

244850

Transgredient Mutilating Hyper- or hypohidrosis Nail dystrophy

Birth or early infancy

Periodontitis

Wooly hair

181600 245010

Right ventricular 601214 cardiomyopathy

Continued

Differential diagnosis Distinctive features of the inherited PPKs (Table 8.7), such as transgrediens spread, distant keratoses, periodontosis and ainhum, are not apparent in infants. Family history and examination of first degree relatives are therefore critical for the diagnosis. If the affected child is a sporadic case it is often impossible to make a precise diagnosis until later. As PPK may be associated with deafness in connexin disorders (such as in Vohwinkel syndrome), hearing should be tested in all infants with PPK. Acquired PPK of infectious origin needs to be confirmed by adequate paraclinical tests. Finally, histopathologic analysis is 620

often helpful and allows to characterize inflammatory PPK, such as eczema with spongiosis, psoriasis with Kogoj pustules, and infectious PPK such as evidence of hyphae suggesting fungal infection by PAS staining.

Transgrediens and progrediens palmoplantar keratoderma (Greither and Sybert) PPK of Greither and Sybert is a severe non-epidermolytic form, characterized by diffuse and transgredient hyperkeratosis in a glove-and-socks distribution and involving the elbows and knees. It may be considered a subset of Unna’s.

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Table 8.7  Inherited palmoplantar keratodermas (continued) SYNONYMS

INHERITANCE GENE DEFECT (PROTEIN)

Focal PPK – isolated   Striate PPK Focal nonAD epidermolytic PPK, Brünauer– Fuhs–Siemens type   Areata

Focal epidermolytic PPK Hereditary painful callosities Wachter type

Focal PPK with associated features   Howel–Evans Tylosis with syndrome esophageal carcinoma   Pachonychia Jadassohn– congenita Lewandowsky type 1 type   Pachonychia Jackson–Lawler congenita type type 2   Richner–Hanhart Tyrosinemia type syndrome II Oculocutaneous tyrosinemia   Carvajal Striate PPK with syndrome wooly hair and cardiomyopathy Punctate PPK – isolated   Keratosis Buschke–Fischer– palmoplantaris Brauer, papulosa punctate PPK type 1   AcrokeratoCosta syndrome, elastosis Punctate PPK type 3   Focal acral hyperkeratosis   Spiny PPK Porokeratosis punctata palmoplantaris, punctate PPK type 2

AD

Type 1: DSG1 Type 2: DSP Type 3: KRT1 KRT16

AD

ONSET

ECTODERMAL FEATURES

4–10 years

KRT6/16

AD

KRT6/17

AR

TAT

AR

DSP

OMIM

148700 125647 139350

600962

Late infancy to adolescence

AD

NONECTODERMAL FEATURES

Esophageal cancer

Infancy to early childhood Infancy to early childhood Infancy to adolescence

Infancy

DIFFUSE PALMOPLANTAR KERATODERMAS

TYPE

148500

167200

167210

276600

Wooly hair

Left ventricular 605676 cardiomyopathy

AD

148600

AD

101850

AD

101850

AD

175860

K, keratin; TAT, tyrosine amino-transferase.

Epidemiology

Clinical presentation

Transgrediens and progrediens PPK keratoderma is extremely rare. Its inheritance is autosomal dominant with variable penetrance and a significant phenotypic heterogeneity.369

This keratoderma is first noted in infancy, worsens during childhood, and tends to improve in the fifth decade. The palmoplantar hyperkeratosis is diffuse, has erythematous borders and

369. Sybert VP, Dale BA, Holbrook KA. Palmar-plantar keratoderma. A clinical, ultrastructural, and biochemical study. J Am Acad Dermatol. 1988;18:75–86.

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pattern distinguishes it from Mal de Meleda, and its transgredient pattern from NEPPK (Table 8.7). Finally, the course of the disease and/or genetic analysis will help guide diagnosis.

Autosomal recessive Mal de Meleda From the late 14th to the early 19th century, the small island of Mljet (then called Meleda) off the Dalmatian coast was used to quarantine people with the plague and leprosy. Isolation led to inbreeding and the emergence of recessive traits including this disease from (‘mal de’) Meleda, in which PPK is associated with keratoses on the extensor surfaces. DIFFUSE PALMOPLANTAR KERATODERMAS

Epidemiology Figure 8.47  Greither’s PPK: note the extension over the Achilles tendon.

the lesions tend to extend to the dorsal aspects of the hands and feet (transgrediens) and to the Achilles tendons (Fig. 8.47). This PPK may be mild or severe, and is usually accompanied by hyperhidrosis. Pseudoainhum formation with amputation of the digits has been reported.369 Hyperkeratotic plaques also develop on elbows, knees and sometimes on the skin flexures. Whereas palmoplantar symptoms may be discrete, the involvement of other body sites is rather pronounced.

Laboratory findings Histologically, acanthosis, hyperorthokeratosis and hypergranulosis, with prominent and irregular keratohyaline granules are seen.

Pathogenesis Linkage to the erythrokeratodermia variabilis locus on 1p by Gedde–Dahl could not be confirmed in a family with both erythrokeratodermia variabilis and Greither syndrome.370 Two large families with Greiter type of PPK and a history of neonatal blistering were shown to have a missense mutation in their KRT1 gene,371 emphasizing the variability of the clinical phenotype seen in patients with KRT1 mutations.

Differential diagnosis The differentiation of Greither type PPK from erythrokeratodermia variabilis of Mendes da Costa may be challenging. Histopathology allows to identify epidermolytic hyperkeratosis in cases due to KRT1 mutations.371 Its autosomal dominant inheritance

370. Richard G, Lin JP, Smith L, et al. Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes. J Invest Dermatol. 1997;109:666–671. 371. Gach JE, Munro CS, Lane EB, et al. Two families with Greither’s syndrome caused by a keratin 1 mutation. J Am Acad Dermatol. 2005;53: S225–S230. 372. Fischer J, Bouadjar B, Heilig R, et al. Genetic linkage of Meleda disease to chromosome 8qter. Eur J Hum Genet. 1998;6:542–547. 373. Franceschetti AT, Reinhart V, Schnyder UW. Meleda disease. J Genet Hum. 1972;20:267–296.

622

Mal de Meleda is a rare, autosomal recessive genodermatosis with an estimated prevalence in Mediterranean countries of 1 in 100 000.372 Cases have been seen in Northern Europe, North Africa, the Middle East, the USA and the Far East.

Clinical presentation Present at birth or developing in early infancy, this progressive keratoderma starts as palmoplantar erythema that is transgredient by 12 months of age. Hyperkeratosis increases markedly in the first 4 years of life. The keratoderma changes progressively into thick, yellow-brown-red, diffuse hyperkeratotic plaques with erythematous borders that extend to the dorsal surfaces of the hands and feet, up to the Achilles tendon (Fig. 8.48).373,374 Knuckle pads may be seen on the finger joints. Flexion contractures of the hands and pseudoainhum (digital constriction bands) may develop. By the second decade, severe hyperhydrosis leading to a characteristic maceration, fissures and malodor, secondary to fungal and bacterial infections are often present. Lichenoid plaques on the elbows and knees are sharply demarcated and often erythematous with a cobblestone appearance.373,375 A transient perioral erythema may occur. Nail changes such as subungual keratosis, koilonychia, and onychogryphosis are frequently observed.375,376

Laboratory findings Histology of affected areas reveals hyperorthokeratosis, acanthosis, hypergranulosis and a mild inflammatory infiltrate of the upper dermis.

Pathogenesis Fischer et al. mapped Mal de Meleda to 8qter372 in two large consanguineous Algerian families. Focusing on the gene encoding SLURP-1 (secreted Ly-6/uPAR related protein 1) at this locus,

374. Salamon T, Cezarovic B, Nardelli-Kovacici M, et al. Meleda disease – akroerythrokeratoderma. Z Hautkr. 1982;57:580–586. 375. Bakija-Konsuo A, Basta-Juzbasic A, Rudan I, et al. Mal de Meleda: genetic haplotype analysis and clinicopathological findings in cases originating from the island of Mljet (Meleda), Croatia. Dermatology. 2002;205:32–39. 376. Bouadjar B, Benmazouzia S, Prud’homme J, et al. Clinical and genetic studies of 3 large, consanguineous, Algerian families with Mal de Meleda. Arch Dermatol. 2000;136:1247–1252.

Ichthyosis and disorders of other cornification

8

Gamborg–Nielson palmoplantar keratodermas This is a severe, mutilating, recessive PPK found in Norbotten, a province of Northern Sweden. It differs from Mal de Meleda by its less severe phenotype of the PPK and absence of nail changes and distant keratoses. The term Norbotten PPK has, confusingly, been used for both this severe recessive type, and the dominant Unna–Thost NEPPK found in the same area. The two are genetically distinct.379 The recessive type may be genetically allelic with Mal de Meleda.

DIFFUSE PALMOPLANTAR KERATODERMAS WITH ASSOCIATED FEATURES

A

DIFFUSE PALMOPLANTAR KERATODERMAS

Autosomal dominant Vohwinkel keratoderma (keratoderma mutilans with deafness, Vohwinkel syndrome) Vohwinkel keratoderma, or keratoderma hereditaria mutilans, was first described by Vohwinkel in 1929. More recently, two types have been differentiated:327 classical Vohwinkel PPK, which is typically characterized by deafness caused by connexin 26 mutations, and Loricrin keratoderma with ichthyosis caused by loricrin mutations.328

Epidemiology B

Figure 8.48  Mal de Meleda on (A) hands and (B) feet, with progressive extension to the dorsal side. Note the characteristic macerated yellowish red aspect.

Vohwinkel keratoderma is inherited as a fully penetrant autosomal dominant trait, with occasional sporadic cases presumably representing new mutations.

Clinical presentation

they identified three different homozygous mutations in 19 affected families of Algerian and Croatian origin.377 Secreted and receptor proteins of the Ly-6/uPAR superfamily have been implicated in transmembrane signal transduction, cell activation and cell adhesion. SLURP-1 may be essential for both epidermal homeostasis and inhibition of TNF-alpha release by macrophages during wound healing, and thus explain both the hyperproliferative as well as the inflammatory clinical phenotype of Mal de Meleda.378

There is a diffuse PPK with an abrupt margin particularly over the wrist (Fig. 8.49). The PPK is described as ‘honeycombed,’ meaning that there is a fine and clearly discernible superficial pattern which completely replaces the normal dermatoglyphs. Starfish-shaped keratoses occur over the elbows and knees and sometimes over the dorsum of hands and feet. With time, pseudoainhum develops, in which fingers or toes become constricted, sometimes to the point of autoamputation. Patients with Vohwinkel keratoderma with deafness suffer from a moderate to severe sensorineural deafness. However, they do not present ichthyosis as observed in loricrin keratoderma (see below).

Differential diagnosis

Laboratory findings

Papillon–Lefevre is another autosomal recessive and transgrediens form of PPK, which can be distinguished by the characteristic periodontosis developing after 1 year of age (Table 8.7). Sporadic cases of Mal de Meleda and Greither or Vohwinkel PPK may be confused clinically and only the disease course or genetic analysis will reveal the diagnosis.

Histology of affected skin shows acanthosis, hypergranulosis, and hyperkeratosis with retention of round nuclei. Abnormal loricrin distribution, with sparse labeling of the abnormally thin cornified envelopes and strongly labeled intranuclear granules in the granular and cornified layers, can be seen on immunoelectronmicroscopy.

377. Fischer J, Bouadjar B, Heilig R, et al. Mutations in the gene encoding SLURP-1 in Mal de Meleda. Hum Mol Genet. 2001;10:875–880. 378. Chimienti F, Hogg RC, Plantard L, et al. Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda. Hum Mol Genet. 2003;12:3017–3024.

379. Gamborg Nielsen P. Two different clinical and genetic forms of hereditary palmoplantar keratoderma in the northernmost county of Sweden. Clin Genet. 1985;28:361–366.

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types of PPK. This phenotype resembles the maternally inherited sensorineural deafness with NEPPK, associated with a point mutation A7745G in the mitochondrial genome (see below). See Table 8.7 for differentiation from other PPKs.

Loricrin keratoderma (keratoderma mutilans with ichthyosis, keratoderma of Camisa) Epidemiology Loricrin keratoderma is inherited as a fully penetrant autosomal dominant trait, with occasional sporadic cases presumably representing new mutations (see Chapter 7).

Clinical presentation DIFFUSE PALMOPLANTAR KERATODERMAS

Figure 8.49  Vohwinkel keratoderma due to connexin 26 mutation with the typical honeycomb pattern, pseudoainhum and extension over the wrist.

Pathogenesis Following the identification of mutations in a gap-junction protein (GJB2, or connexin 26,CX26) in autosomal recessive nonsyndromic deafness, Richard et al. identified a heterozygous missense mutation (R75W) in a family with autosomal dominant deafness and Vohwinkel PPK.340 Maestrini et al. found a further missense mutation (D66H) in CX26 in British, Spanish and Italian families with Vohwinkel keratoderma and deafness.380 Gap junctions are specialized structures on plasma membranes between cells, consisting of cell-to-cell channels. Connexins are proteins extracted from enriched gap junctions. They are tissue specific and designated by their molecular mass. Connexin subunits assemble as hexamers into connexons. Unlike the loss-of-function mutation that causes autosomal recessive deafness, the R75W mutation has a deleterious dominant negative effect on gap channel function in vitro. The common D66H mutation is located at a highly conserved residue in the first extracellular domain of the CX26 molecule, and interferes with epidermal differentiation as well as inner ear function.381 Connexin mutations are responsible not only for deafness and PPK but also Charcot–Marie–Tooth syndrome.381 PPK has been reported in a family with Charcot–Marie–Tooth syndrome.382 As more connexin mutations emerge, the PPK deafness phenotype is proving more variable than originally thought.

Differential diagnosis Even before the development of pseudoainhum, the honeycomb nature of the keratoderma, and the abnormal skin on the flexor and extensor aspects of joints differentiate Vohwinkel from other

380. Maestrini E, Korge BP, Ocana-Sierra J, et al. A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel’s syndrome) in three unrelated families. Hum Mol Genet. 1999;8:1237–1243. 381. Kelsell DP, Di WL, Houseman MJ. Connexin mutations in skin disease and hearing loss. Am J Hum Genet. 2001;68:559–568.

624

Loricrin keratoderma patients are sometimes born as collodion babies and suffer from non-erythrodermic ichthyosis. The PPK is evident within a few weeks of birth. The onset of digital constricting bands is variable and is often delayed until adolescence or adulthood. However, patients with loricrin keratoderma do not show the starfish shaped lesions as observed typically in Vohwinkel’s keratoderma.328 Digital constricting bands sometimes lead to autoamputation (pseudoainhum), particularly of the fifth finger. Osteoporotic changes may occur distal to constricting bands. There is a mild, non-erythrodermic generalized ichthyosis with flexural accentuation and linear hyperkeratotic streaks or a more diffuse, verrucous lichenification. Alopecia occasionally occurs but nails, teeth, and mucous membranes are normal.

Laboratory findings Palmoplantar skin shows acanthosis, hypergranulosis, and hyperkeratosis with retention of rounded nuclei. Immunoelectron microscopy shows abnormal loricrin distribution, with sparse labeling of the abnormally thin cornified envelopes and strongly labeled intranuclear granules in the granular and cornified layers327 and mutant loricrin also localizes to the nuclear granules.383

Pathogenesis Loricrin keratoderma is due to mutations in the loricrin gene. Frame-shift insertion mutations (730 insG, 709 insC, 662 insT, 578 insG) in the loricrin gene change the terminal amino acids to missense and add residues to the mutant protein which encode for basic nuclear localization signals. This leads to import and accumulation of defective loricrin in the nucleus where it becomes cross-linked. Thus, nuclei remain round and resistant to degradation throughout the stratum corneum. Transgenic experiments reveal a massive effect of mutant loricrin even in the absence of endogenous normal loricrin in loricrin knockout animals.349 Thus, the deposition of mutant protein in the nucleus interferes by itself with late stages of epidermal differentiation.

382. Rabbiosi G, Borroni G, Pinelli P, et al. Palmoplantar keratoderma and Charcot–Marie–Tooth disease. Arch Dermatol. 1980;116:789–790. 383. Ishida-Yamamoto A, Kato H, Kiyama H, et al. Mutant loricrin is not crosslinked into the cornified cell envelope but is translocated into the nucleus in loricrin keratoderma. J Invest Dermatol. 2000;115:1088–1094.

Ichthyosis and disorders of other cornification

Before the development of pseudoainhum, this can be differentiated from other forms of PPK by the honeycomb nature of the keratoderma and by the non-erythrodermic generalized ichthyosis. Hearing should be tested to exclude Vohwinkel PPK with deafness. See Table 8.7 for differentiation from other PPKs.

Olmsted syndrome Olmsted syndrome is characterized by non-diffuse, transgredient, sharply circumscribed, mutilating PPK, and symmetrical periorificial (mouth, nose, genital, and anal) keratoderma.384

Epidemiology This condition is exceedingly rare with only 40 reported cases in the literature. As two-thirds of patients are males, an X-linked recessive form has also been proposed. All cases are sporadic except from monozygotic twin boys385 and two families with autosomal dominant inheritance.386,387

Clinical presentation The hyperkeratotic periorificial plaques may be detectable around the mouth and anogenital area at birth as localized erythema, which becomes yellow–brown and sharply demarcated.388 In the first few months of life, patients develop initially focal, then diffuse, thick PPK with sharp margins that continuously spread to the dorsal aspects of the hands and feet. Keratoderma increases when a toddler starts walking and painful fissures can make this learning process difficult. With time, this keratoderma becomes mutilating with flexion con­tractures, constrictions (pseudoainhum), and autoamputation of digits. Hyperkeratotic plaques may also affect the intertriginous folds (axillae, neck, and groins). These flexural lesions appear as streak-like linear or follicular keratoses. Over 20% of patients suffer from eye lesions, sometimes with severe corneal defects. In addition, keratosis pilaris, palmoplantar hyper- or hypohidrosis, oral leukokeratosis, tooth anomalies, nail dystrophy, alopecia, joint laxity, and high-tone loss or neurosensory deafness have all been described. In two cases, squamous cell cancer has been observed within the keratoderma. In some patients the condition is slowly progressive; in others it waxes and wanes in severity.

increased vascularity with mononuclear infiltrate.388 Kress et al. found suprabasilar staining with a keratin antibody that normally only stains the basal layer.389 Scanning electron micro­ scopy of hair revealed twisting, trichorrhexis nodosa fractures and cuticle changes.385,390

Pathogenesis Pathogenesis remains unknown. Although immunoreactivity in one case suggested abnormal expression of keratin 5 and 14,391 recent investigations of a single patient failed to detect mutations in any of the coding regions of the genes for K1, Cx26, loricrin and SLURP-1.390

Differential diagnosis In infancy, the periorificial keratoses may be mistaken for acrodermatitis enteropathica and, in childhood, the flexor plaques for flexural psoriasis. Later, the mutilating PPK may resemble Vohwinkel and Mal de Meleda. The formation of linear or starshaped distant keratoses is reminiscent of Vohwinkel’s keratoderma. A family with autosomal dominant PPK reported by Rivers as Vohwinkel was clinically more like Olmsted, with periorificial involvement.390 The other variable features may lead to confusion with ectodermal dysplasia and pachyonychia congenita.

Huriez syndrome The characteristic features of this distinctive condition are mild PPK, diffuse scleroatrophy of hands and feet, ridging or hypoplasia of nails, and an increased risk of developing squamous carcinoma in atrophic zones of the hands.

Epidemiology Huriez syndrome is a very rare, autosomal dominant condition that has been described in about 12 families from France, Germany, Tunisia, India and the UK.

Clinical presentation

Histologic findings show ortho- or parakeratotic hyperkeratosis, acanthosis, papillomatosis and in the papillary dermis an

Huriez syndrome presents from birth or in early infancy with diffuse, erythematous, mildly hyperkeratotic keratoderma, which is more marked on palms than soles and shows focally accentuated keratoses.392,393 The keratoderma is not transgredient; however dorsal aspects of hands and feet may be covered by a reticulate erythema and thickened patches over the knuckles. Accentuated palmar creases, punctate pits over thenar and

384. Poulin Y, Perry HO, Muller SA. Olmsted syndrome – congenital palmoplantar and periorificial keratoderma. J Am Acad Dermatol. 1984;10: 600–610. 385. Cambiaghi S, Tadini G, Barbareschi M, et al. Olmsted syndrome in twins. Arch Dermatol. 1995;131:738–739. 386. Rivers JK, Duke EE, Justus DW. Etretinate: management of keratoma hereditaria mutilans in four family members. J Am Acad Dermatol. 1985;13:43–49. 387. Atherton DJ, Sutton C, Jones BM. Mutilating palmoplantar keratoderma with periorificial keratotic plaques (Olmsted’s syndrome). Br J Dermatol. 1990;122:245–252. 388. Frias-Iniesta J, Sanchez-Pedreno P, Martinez-Escribano JA, et al. Olmsted syndrome: report of a new case. Br J Dermatol. 1997;136:935–938.

389. Kress DW, Seraly MP, Falo L, et al. Olmsted syndrome. Case report and identification of a keratin abnormality. Arch Dermatol. 1996;132: 797–800. 390. Mevorah B, Goldberg I, Sprecher E, et al. Olmsted syndrome: mutilating palmoplantar keratoderma with periorificial keratotic plaques. J Am Acad Dermatol. 2005;53: S266–S272. 391. Fonseca E, Pena C, Del Pozo J et al. Olmsted syndrome. J Cutan Pathol. 2001;28:271–275. 392. Delaporte E, N’Guyen-Mailfer C, Janin A, et al. Keratoderma with scleroatrophy of the extremities or sclerotylosis (Huriez syndrome): a reappraisal. Br J Dermatol. 1995;133:409–416. 393. Downs AM, Kennedy CT. Scleroatrophic syndrome of Huriez in an infant. Pediatr Dermatol. 1998;15:207–209.

Laboratory findings

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Differential diagnosis

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hypothenar eminences, absence of dermatoglyphics and hypohidrosis may be observed. Tapering and flexion contractures of the fingers may develop during early childhood. Despite the sclerotic appearance, Raynaud phenomenon does not occur. Focal PPK develops over pressure points on the soles in adulthood.394 Nail changes such as hypoplasia or aplasia, onychorrhexis, longitudinal ridging, leuconychia or koilonychia are frequently observed. Hair and teeth are normal. Squamous cell carcinomas may arise in the scleroatrophic skin in the third to fourth decade. They may be multiple, and fatal metastases have been reported, emphasizing the importance of patient education and regular surveillance. Some individuals have poikiloderma-like changes on the nose and lips.395 Associated carcinomas of the gastrointestinal tract have been reported, but the risk may not be greater than for the general population.392

Laboratory findings Histologically, affected skin shows hyperorthokeratosis, acanthosis, hypergranulosis and scleroatrophy of the dermis with fibrosis, increased vascularity and reduced sweat glands and elastic fibers.394 Ultrastructurally392 the desmosomes appear normal, tonofilaments are grouped in dense bundles and keratohyalin is abundant and clumped in the granular layer. There is a characteristic, almost complete absence of Langerhans cells. This defect of immune surveillance involving the presentation of tumor-associated antigens by Langerhans cells could explain the increased risk of squamous cell carcinoma on the hands.392

Pathogenesis The gene responsible has been mapped to 4q23.396 Linkage to the MN blood group at 4q28–q31, reported in 1967, was subsequently excluded.392 Because of the association with skin cancer, DNA repair was studied in one patient and was normal.392

Differential diagnosis The intact microvasculature and the lack of Raynaud phenom­ enon help to differentiate Huriez syndrome from systemic sclerosis. Atrophic changes of the hands and poikiloderma-like changes of the face may remind of progeria and Rothmund– Thomson syndrome, but a thorough clinical exam will allow differentiation. Acrogeria shows similar skin changes and dis­ tribution but less marked nail changes, and is autosomal recessive.

394. Hamm H, Traupe H, Brocker E, et al. The scleroatrophic syndrome of Huriez: a cancer-prone genodermatosis. Br J Dermatol. 1996;134: 512–518. 395. Kavanagh GM, Jardine PE, Peachey R, et al. The scleroatrophic syndrome of Huriez. Br J Dermatol. 1997;137:114–118. 396. Lee YA, Stevens HP, Delaporte E, et al. A gene for an autosomal dominant scleroatrophic syndrome predisposing to skin cancer (Huriez syndrome) maps to chromosome 4q23. Am J Hum Genet. 2000;66:326–330. 397. Toomes C, James J, Wood AJ, et al. Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet. 1999;23:421–424. 398. Lefevre C, Blanchet-Bardon C, Jobard F, et al. Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families

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Autosomal recessive Papillon–Lefèvre/Haim–Munk syndrome Papillon–Lefèvre syndrome is characterized by PPK associated with rapidly progressive periodontitis. This syndrome is due to cathepsin C deficiency,397,398 which leads to a severe reduction in the activity and stability of neutrophil-derived serine proteases. Even although the gene responsible has been identified, the link between the epidermal and gingival abnormalities remains unclear.399

Epidemiology Papillon–Lefèvre syndrome has been identified throughout the world, while the Haim–Munk variant has been observed only among descendents of an isolated population from Cochin, India. The prevalence of this autosomal recessive condition is estimated to be 1–4 per million.399 There is a variable penetrance, with occasional cases of isolated PPK or isolated periodontosis.400

Clinical presentation Moderate diffuse PPK with well-defined and intensely erythematous margins may be evident at birth or develop during infancy. The keratoderma may be punctate or striate rather than diffuse. Transgredient extension to the dorsa of the hands and feet is characteristic. The severity of the keratoderma is variable, and the soles are usually worse than the palms. Hyperhidrosis, maceration and superinfection occur frequently, thus causing distinct malodor. Keratotic lesions may be found on the elbows, knees and the metacarpo- and interphalangeal joints.401 Nonspecific nail changes (ridging or horizontal depressions, discoloration, koilonychia, increased brittleness and dystrophy) are often present.401 Severe periodontitis is the diagnostic sign of Papillon–Lefèvre syndrome. It appears between 1 and 5 years of age and causes premature and inevitable loss of both deciduous and permanent teeth. The teeth are not carious, and oral inflammation is limited to periodontal tissues but may lead to extensive alveolar bone resorption. Gingival inflammation destroys the periodontal ligaments loosening the teeth and ends in shedding. The deciduous teeth are lost by 4 years, after which the mouth becomes normal until the secondary teeth erupt. The process is repeated with eruption and loss of the permanent teeth by mid-teens. The periodontitis and the skin lesions improve after all teeth are shed. Although both Papillon–Lefèvre syndrome and its Haim–Munk variant show the periodontitis and PPK, ectopic calcification of the falx cerebri,401 susceptibility for bacterial infections401,402 has

from Europe and North Africa with Papillon-Lefevre syndrome. J Invest Dermatol. 2001;117:1657–1661. 399. Gorlin RJ. Of palms, soles, and gums. J Med Genet. 2000;37:81–82. 400. Soskolne WA, Stabholz A, van Dyke TE et al. Partial expression of the Papillon-Lefevre syndrome in 2 unrelated families. J Clin Periodontol. 1996;23:764–769. 401. Haneke E. The Papillon-Lefevre syndrome: keratosis palmoplantaris with periodontopathy. Report of a case and review of the cases in the literature. Hum Genet. 1979;51:1–35. 402. Djawari D. Deficient phagocytic function in Papillon-Lefevre syndrome. Dermatologica. 1978;156:189–192.

Ichthyosis and disorders of other cornification

Laboratory findings Skin biopsy shows hyperkeratosis, acanthosis, with psoriasiform parakeratosis and discrete inflammatory infiltrate in the dermis.

Pathogenesis Papillon–Lefèvre syndrome was mapped to 11q13–q14,405 and is due to mutations in the cathepsin C gene.397 A functional assay showed almost total loss of cathepsin C activity in patients and reduced activity in obligate carriers. Hart et al. found several different mutations in an ethnically diverse group of patients, and listed all the mutations to date.406 The same group identified mutations in cathepsin C in Haim–Munk syndrome, confirming that these two conditions are allelic variants.407 Most mutations in Papillon–Lefèvre syndrome reside within the mature enzyme domain and presumably impair or abolish catalytic activity.408 Cathepsin C activates serine proteinases expressed in leukocyte granules and implicated in a variety of immune responses, and its deficiency could thus explain the severe periodontitis of Papillon–Lefèvre syndrome. The hyperkeratosis is less easy to explain.399

Differential diagnosis Isolated periodontosis associated with diffuse PPK is pathognomonic for this condition. This association can also be found in Micali syndrome, which however has numerous other features (see below).

Naxos disease Diffuse PPK associated with wooly hair and right ventricular cardiomyopathy was first reported in 1986 in four families on the Greek island of Naxos.409,410 Carvajal described a striate PPK with wooly hair and dilated cardiomyopathy (see below).

Epidemiology Diffuse PPK with wooly hair and arrhythmogenic cardiomyopathy is extremely rare and is transmitted as an autosomal recessive trait.

403. Haim S, Munk J. Keratosis palmo-plantaris congenita, with periodontosis, arachnodactyly and a peculiar deformity of the terminal phalanges. Br J Dermatol. 1965;77:42–54. 404. Puliyel JM, Sridharan Iyer KS. A syndrome of keratosis palmo-plantaris congenita, pes planus, onychogryphosis, periodontosis, arachnodactyly and a peculiar acro-osteolysis. Br J Dermatol. 1986;115:243–248. 405. Fischer J, Blanchet-Bardon C, Prud’homme JF, et al. Weissenbach. Mapping of Papillon-Lefevre syndrome to the chromosome 11q14 region. Eur J Hum Genet. 1997;5:156–160. 406. Hart PS, Pallos D, Zhang Y, et al. Identification of a novel cathepsin C mutation (pW185X) in a Brazilian kindred with Papillon-Lefevre syndrome. Mol Genet Metab. 2002;76:145–147. 407. Hart TC, Hart PS, Michalec MD, et al. Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet. 2000;37:88–94. 408. Nakano A, Nomura K, Nakano H, et al. Papillon-Lefevre syndrome: mutations and polymorphisms in the cathepsin C gene. J Invest Dermatol. 2001;116:339–343.

Clinical presentation The PPK, which is indistinguishable from NEPPK, and wooly hair are present from infancy.411 The hair is tightly curled, dense, rough and wiry. The classic cardiac anomalies are right ventricular enlargement and right ventricular band, associated with ventricular arrhythmias. Ebstein anomaly with additional right ventricular myocardial dysplasia has also been reported. The cardiac condition may be asymptomatic, but can cause arrhythmia, heart failure and sudden death. It is not clinically apparent before the age of 15 years and usually presents first as palpitations and syncope.

Laboratory findings The PPK of Naxos disease shows compact hyperkeratosis, hypergranulosis, and acanthosis, as in NEPPK.411

DIFFUSE PALMOPLANTAR KERATODERMAS

only been described in Papillon–Lefèvre syndrome, while the Haim–Munk syndrome typically shows arachnodactyly, acro­ osteolysis, and onychogryphosis.403,404

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Pathogenesis Naxos disease was mapped to 17q21 in 21 patients from nine families in Naxos, and KRT9 was initially the obvious candidate gene.412 Subsequently, the same group found mutations in the plakoglobin gene at the same locus.413 Nineteen affected individuals were homozygous, and 29 clinically unaffected family members were heterozygous for a 2bp deletion which caused a frameshift and premature termination of plakoglobin, a key component of desmosomes and adherens junctions in heart and skin.

Differential diagnosis Naxos disease can be distinguished from NEPPK only by the associated features of wooly hair and cardiomyopathy. Cavarjal disease differs from Naxos disease by striate PPK and left ventricular cardiomyopathy.

DIFFUSE PPK IN GENERALIZED SKIN DISORDERS (see Chapter 7) Diffuse PPK also occurs in the following generalized disorders, which are discussed in more detail elsewhere. Broadly, they can be divided into epidermal fragility disorders, ichthyoses, erythrokeratoderma, ectodermal dysplasia syndromes in which other ectodermal derivatives are affected, or complex syndromes with

409. Protonotarios N, Tsatsopoulou A, Patsourakos P, et al. Cardiac abnormalities in familial palmoplantar keratosis. Br Heart J. 1986;56:321–326. 410. Protonotarios N, Tsatsopoulou A. Naxos disease: cardiocutaneous syndrome due to cell adhesion defect. Orphanet J Rare Dis. 2006;1:4. 411. Tosti A, Misciali C, Piraccini BA, et al. Woolly hair, palmoplantar keratoderma, and cardiac abnormalities: report of a family. Arch Dermatol. 1994;130:522–524. 412. Coonar AS, Protonotarios N, Tsatsopoulou A, et al. Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation. 1998;97:2049–2058. 413. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000;355:2119–2124.

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PPK including non-ectodermal symptoms. PPK can be prominent in individuals with epidermolysis bullosa simplex, particularly on the soles.414,415 Diffuse PPK has also been reported in association with congenital poikiloderma and traumatic blister formation in patients with Kindler syndrome, an autosomal recessive disorder due to deficiency of kindlin (fermitin family homologue 1) and now considered a subset of epidermolysis bullosa.416 Poikiloderma, PPK, and acrokeratotic papules, but no blistering, are seen in the dominantly inherited Weary syndrome. Marked palmoplantar creases are a hallmark finding in the common semidominant disorder ichthyosis vulgaris resulting from profilaggrin deficiency.417 Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) is a rare, autosomal recessive disorder potentially due to abnormal kerato­ hyaline formation. There are characteristic bizarre striate hyperkeratoses in the flexures.418–420 Diverse autosomal recessive congenital ichthyoses including autosomal recessive congenital ichthyosis (ARCI; lamellar ichthyosis, nonbullous congenital ichthyosiform erythroderma and harlequin ichthyosis), bullous ichthyosis, ichthyosis hystrix, and complex congenital ichthyoses such as trichothiodystrophy and Chanarin–Dorfman syndrome are all associated with diffuse PPK.421 Diffuse or punctate PPK may be one of the manifestations of Naegeli–Franceschetti–Jadassohn syndrome, an autosomal dominant ectodermal dysplasia syndrome caused by keratin 14 mutations.422 Other manifestations include acquired, progressive reticulate pigmentation, and hypohidrosis. Nail abnormalities include onycholysis and subungual hyperkeratosis. Yellow discoloration of tooth enamel occurs. Familial pityriasis rubra pilaris (PRP) is very rare, but several autosomal dominant pedigrees have been reported.423,424 PPK is characterized by intense erythema with scales or discrete keratosis with an orange hue and painful cracks. The PPK is associated with partly confluent keratotic follicular papules primarily located on the trunk, the scalp and the extensor surfaces of the limbs. Erythrokeratodermia variabilis (EKV) is due to autosomal dominant mutations of connexin genes GJB3 and 4. In EKV skin lesions are often present by 1 year of age, but may rarely first occur later in childhood or early adulthood. Palmoplantar keratoderma can be associated, but often takes the form of a fine erythematous scaling rather than frank hyperkeratosis, similar to the one observed in keratolytic winter erythema.346 Progressive symmetric erythrokeratodermia (PSEK, Darier–Gottron syndrome) is a heterogeneous disease. Some cases may be indis-

414. Shirakata Y, Tamai K, Nakaoka H, et al. Severe palmo-plantar hyperkeratosis in Koebner epidermolysis bullosa simplex. J Dermatol. 2003;30:135–140. 415. Shemanko CS, Mellerio JE, Tidman MJ, et al. Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in the keratin 14 gene (KRT14). J Invest Dermatol. 1998;111:893–895. 416. Lai-Cheong JE, Tanaka A, Hawche G, et al. Kindler syndrome: a focal adhesion genodermatosis. Br J Dermatol. 2009;160:233–242. 417. Sandilands A, O’Regan GM, Liao H, et al. Prevalent and rare mutations in the gene encoding filaggrin cause ichthyosis vulgaris and predispose individuals to atopic dermatitis. J Invest Dermatol. 2006;126: 1770–1775. 418. Chaves AJ, Merchan-Garcia R, Fernandez-Recio JM, et al. Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK syndrome). Actas Dermosifiliogr. 2006;97:342–344. 419. Pujol RM, Alomar A, De Moragas JM. A new type of erythrokeratoderma, or KLICK syndrome? Br J Dermatol. 2005;153:461; author reply 462.

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Figure 8.50  PPK in keratitis-ichthyosis-deafness syndrome with marked keratoderma characterized by symmetric erythematous verrucous plaques with a grainy surface.

tinguishable clinically from loricrin keratoderma, lamellar ichthyosis of the ichthyin type, or EKV Mendes da Costa in elderly patients. Furthermore, a novel PSEK locus has been described on chromosome 21q11. Erythematous palmoplantar keratoderma is seen in about 50% of cases. PSEK appears in childhood, often in the first year of life. It is characterized by fixed, large, welldefined, hyperkeratotic plaques. They are symmetrical with a reddish-orange or brownish color and erythema at the periphery of lesions. They commonly occur on the limbs, buttocks, shoulders and fingers and may also involve the face. The chest and abdomen are usually spared, unlike the involvement of EKV. Keratitis ichthyosis deafness (KID) syndrome is autosomal dominant and can result from GJB2 or GJB6 connexin mutations, similar to Vohwinkel syndrome and Clouston ectodermal dysplasia. Patients show keratotic, symmetric erythematous verrucous plaques with a grainy or spiny surface, a characteristic that is also found on the thickened palms and soles (Fig. 8.50). Affected individuals may have follicular keratoses, nail dystrophy and recurrent skin infections. Patients develop photophobia due to blepharitis, conjunctivitis and progressive proliferating vascular keratitis and congenital sensorineural hearing defects.425 Clouston syndrome is an autosomal dominant hidrotic ectodermal dysplasia characterized by thickened nails, variable alopecia, and a diffuse or focal PPK. Plantar surfaces are more severely involved, and keratoses may be limited to weight-bearing surfaces. Deafness occasionally occurs. Missense mutations in GJB6 encoding

420. Vahlquist A, Ponten F, Pettersson A. Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK-syndrome): a rare, autosomal recessive disorder of keratohyaline formation? Acta Derm Venereol. 1997;77:225–227. 421. Math A, Frank J, Handisurya A, et al. Identification of a de novo keratin 1 mutation in epidermolytic hyperkeratosis with palmoplantar involvement. Eur J Dermatol. 2006;16:507–510. 422. Lugassy J, Itin P, Ishida-Yamamoto A, et al. Naegeli-FranceschettiJadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14. Am J Hum Genet. 2006;79:724–730. 423. Parish LC, Woo TH. Pityriasis rubra pilaris in Korea. Treatment with methotrexate. Dermatologica. 1969;139:399–403. 424. Vanderhooft SL, Francis JS, Holbrook KA, et al. Familial pityriasis rubra pilaris. Arch Dermatol. 1995;131:448–453. 425. Messmer EM, Kenyon KR, Rittinger O, et al. Ocular manifestations of keratitis-ichthyosis-deafness (KID) syndrome. Ophthalmology. 2005;112:e1–e6.

Ichthyosis and disorders of other cornification

connexin 30 lead to non-synonymous amino acid substitutions: e.g., G11R, V37E, D50N or A88V.426,427 Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder due to mutations of the connexin 43 gene, GJA1. It is characterized by microphthalmia, hypotelorism, nasal hypo­ plasia, hypotrichosis, dental anomalies and digital anomalies including type III syndactyly. Diffuse orange colored keratoderma is rarely observed on palmar more than on plantar surfaces and appears to be due to mutations involving particularly the C-terminal tail of connexin 43.428 In Bureau–Barriere–Thomas syndrome, diffuse PPK with hyperhidrosis is associated with giant arched nails on massive drumstick fingers and toes and with elongated, cortical atrophic bones in this very rare autosomal recessive syndrome of unknown origin.429 CEDNIK syndrome (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) is a very rare autosomal recessive disease that results from strongly decreased expression of SNAP29, a SNARE protein involved in vesicle fusion. Palmoplantar keratoderma and lamellar ichthyosis appear between 5 and 11 months of age, with progressive worsening during the 2nd year of life. Microcephaly, eye anomalies, sensorineural deafness and facial dysmorphism are associated with major psychomotor retardation in the 1st year. Brain magnetic resonance imaging reveals corpus callosum abnormalities and cortical dysplasia.430 PPK is an occasional feature of the group of ectodermal dysplasias that results form mutations in the p63 protein (p73-like protein, TP73L). These autosomal dominant ectodermal dysplasias with clefting431 include Rapp–Hodgkin syndrome, Hay–Wells or ankyloblepharon-ectodermal dysplasia-clefting syndrome, and EEC (ectrodactyly, ectodermal dysplasia and cleft lip/palate) syndrome.432 In the autosomal recessive ectodermal dysplasia Schopf– Schultz–Passarge syndrome,433 diffuse PPK accompanies cysts of the eyelid margins, nail fragility, hypodontia, and alopecia. Atrophic PPK and absent dermatoglyphics are sometimes found in dyskeratosis congenita, a heterogeneous degenerative disorder of skin, nails, mucosal epithelium, and bone marrow. It is caused by alterations of the telomerase complex or shelterins which elongate or protect telomers. It is transmitted as rare X-linked recessive (due to dyskerin mutations) or autosomal dominant trait (TERC, TERT, NOP10, NHP2 or TINF2 mutations).434

Micali syndrome is a rare autosomal recessive PPK due to R-SPONDIN 1 mutations with 46 XX sex-reversal leading to hypospadia, hypogenitalism, gynecomastia, high FSH and low testosterone levels.435 R-spondins are secreted by fibroblasts and stabilize β-catenin in epithelial cells. Diffuse non-epidermolytic PPK accompanies scleroatrophy, hyperhidrosis and chronic periodontal disease with loss of teeth. Squamous cell cancer may be a complication.436

426. Patel RR, Bixler D, Norins AL. Clouston syndrome: a rare autosomal dominant trait with palmoplantar hyperkeratosis and alopecia. J Craniofac Genet Dev Biol. 1991;11:176–179. 427. Baris HN, Zlotogorski A, Peretz-Amit G, et al. A novel GJB6 missense mutation in hidrotic ectodermal dysplasia 2 (Clouston syndrome) broadens its genotypic basis. Br J Dermatol. 2008;159:1373–1376. 428. Vreeburg M, de Zwart-Storm EA, Schouten MI, et al. Skin changes in oculo-dento-digital dysplasia are correlated with C-terminal truncations of connexin 43. Am J Med Genet A. 2007;143:360–363. 429. Bureau Y, Horeau M, Barriere H, et al. Two cases of drumstick fingers with palmoplantar hyperkeratosis and bone lesions. Bull Soc Fr Dermatol Syphiligr. 1958;65:328–330. 430. Sprecher E, Ishida-Yamamoto A, Mizrahi-Koren M, et al. A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am J Hum Genet. 2005;77:242–251. 431. Kantaputra PN, Pruksachatkunakorn C, Vanittanakom P. Rapp-Hodgkin syndrome with palmoplantar keratoderma, glossy tongue, congenital

absence of lingual frenum and of sublingual caruncles: newly recognized findings. Am J Med Genet. 1998;79:343–346. 432. Macias E, de Carlos F, Cobo J. Hay-Wells syndrome (AEC): a case report. Oral Dis. 2006;12:506–508. 433. Castori M, Ruggieri S, Giannetti L, et al. Schopf-Schulz-Passarge syndrome: further delineation of the phenotype and genetic considerations. Acta Derm Venereol. 2008;88:607–612. 434. Walne AJ, Dokal I. Advances in the understanding of dyskeratosis congenita. Br J Haematol. 2009;145:164–172. 435. Parma P, Radi O, Vidal V, et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet. 2006;38:1304–1309. 436. Micali G, Nasca MR, Innocenzi D, et al. Association of palmoplantar keratoderma, cutaneous squamous cell carcinoma, dental anomalies, and hypogenitalism in four siblings with 46, XX karyotype: a new syndrome. J Am Acad Dermatol. 2005;53: S234–S239. 437. Whittock NV, Ashton GH, Dopping-Hepenstal PJ, et al. Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency. J Invest Dermatol. 1999;113:940–946.

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FOCAL PALMOPLANTAR KERATODERMAS FOCAL PALMOPLANTAR KERATODERMAS

ISOLATED FOCAL PALMOPLANTAR KERATODERMAS Focal PPK appear at sites of mechanical pressure. Therefore they are more likely to affect the soles and to develop later than diffuse PPK. In addition to the conditions discussed in this section, it should be recalled that disorders classified as diffuse PPK may in some patients present initially with focal involvement, often localized over pressure points.

Autosomal dominant Palmoplantar keratoderma striata type (Siemens–Brünauer–Fuhs) Epidemiology Striate PPK is an autosomal dominant disorder with consider­ able inter- and intrafamilial variability. This variability can, at least in part, be explained by variable exposure to mechanical stress, which is an important triggering factor.

Clinical presentation Striate PPK manifests itself in infancy, adolescence or adulthood, and is precipitated by mechanical trauma.437 Linear keratotic streaks extend in stripes along the flexor aspects of the fingers and on to the palm. The striate pattern may be restricted to the fingers while the palms show a diffuse hyperkeratosis. Plantar involvement tends to be nummular rather than linear callosities at the pressure points. Sometimes striate PPK is associated with subungual or eponychial keratosis or curly hair.

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Striate PPK associated with abnormal teeth, pili torti, sparse hair and eyelashes, hypohidrosis, and sensorineural hearing loss has been described.438 Four brothers with striate keratoderma of the palms and diffuse hyperkeratosis of soles with mental retardation, spastic paraplegia, and pes cavus have also been described; their mother and sisters were not affected.439

Laboratory findings Histologically there is massive hyperorthokeratosis, hypergranulosis, acanthosis, papillomatosis and widening of intercellular spaces throughout the spinous layer. Ultrastructurally, desmosomes are reduced in size and number. Keratin filaments show disruption of their attachment to the plasma membrane, and are compacted in a perinuclear distribution. FOCAL PALMOPLANTAR KERATODERMAS

Pathogenesis Mutations in desmoglein I and in desmoplakin are the cause of striate PPK.437,440–442 Desmoplakin mutations result in a null allele, suggesting that autosomal dominant striate PPK may be due to haploinsufficiency of desmoplakin in these families. Such a dosage effect might explain the strong influence of mechanical factors, and the variability between family members, and between sites within individuals.

Differential diagnosis An association with wooly hair should prompt cardiac evaluation to exclude arrhythmogenic left cardiomyopathy. Occasionally striate PPK can mimic Dupuytren’s contractures.

Insulated focal palmoplantar keratoderma (Wachter) Wachter introduced the term ‘keratosis palmoplantaris varians’, reflecting the considerable inter- and intrafamilial variability. This autosomal dominant condition is sometimes termed hereditary painful callosities, non-epidermolytic palmoplantar keratoderma (NEEPK), or PPK areata of Wachter.

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Orogenital and follicular keratoses may be associated with this condition as well as subtle nail changes (sub- or periungual hyperkeratoses),443 which are distinctly less severe than those found in patients with a complete phenotype of pachyonychia congenita I.

Laboratory findings Histology of affected areas shows hyperorthokeratosis, hypergranulosis, acanthosis, and papillomatosis. Sometimes there is localized epidermolytic hyperkeratosis. Ultrastructurally the keratin filament bundles are condensed, but do not form the dense aggregates seen in more severe forms that are typical of PPK or in more severe keratin disorders. This is consistent with the milder phenotype from a keratin disorder, as is the case with EB simplex of the localized form.

Pathogenesis Keratin 16 mutations have been identified both in pachyonychia congenita type 1, which features focal NEPPK, and in isolated focal NEPPK.443,444 The milder phenotype of focal NEPPK is probably due to less deleterious mutations in the keratin 16 protein.445

Differential diagnosis Children with focal NEPPK and their relatives should be examined for other features of pachyonychia congenita type 1 (oral leukokeratosis and nail dystrophy; see below). Focal insulated PPK may rarely be due to desmoglein 1 mutations. Focal NEPPK looks like the PPK of Howel–Evans syndrome, but the onset is much earlier in childhood.

FOCAL PALMOPLANTAR KERATODERMAS WITH ASSOCIATED FEATURES Autosomal dominant

Clinical presentation

Pachonychia congenita type I (Jadassohn–Lewandowsky)

Plantar keratoses are apparent as hard yellow hyperkeratoses over the pressure points on the sole as soon as children begin to walk. Palmar focal keratoses appear only in response to mechanical stress. Disease severity varies within the members of an affected family.

This autosomal dominant disorder is caused by heterozygous mutations in keratins 6a or 16, and is characterized by thickened, tubular nails, focal PPK, and oral leukokeratosis. Mosaicism for a keratin 16 mutation has been described in a patient with linear PKK along the lines of Blaschko.

438. Egelund E, Frentz G. A case of hyperkeratosis palmoplantaris striata combined with pili torti, hypohidrosis, hypodontia and hypacusis. Acta Otolaryngol. 1982;94:571–573. 439. Fitzsimmons JS, Fitzsimmons EM, McLachlan JI, et al. Four brothers with mental retardation, spastic paraplegia and palmoplantar hyperkeratosis. A new syndrome? Clin Genet. 1983;23:329–335. 440. Rickman L, Simrak D, Stevens HP, et al. N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum Mol Genet. 1999;8:971–976. 441. Armstrong DK, McKenna KE, Purkis PE, et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum Mol Genet. 1999;8:143–148.

442. Hunt DM, Rickman L, Whittock NV, et al. Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. Eur J Hum Genet. 2001;9:197–203. 443. Shamsher MK, Navsaria HA, Stevens HP, et al. Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families. Hum Mol Genet. 1995;4:1875–1881. 444. Smith FJ, McKusick VA, Nielsen K, et al. Cloning of multiple keratin 16 genes facilitates prenatal diagnosis of pachyonychia congenita type 1. Prenat Diagn. 1999;19:941–946. 445. Smith FJ, Liao H, Cassidy AJ, et al. The genetic basis of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10:21–30.

Ichthyosis and disorders of other cornification

Pachonychia congenita type I is a rare autosomal dominant disease. It is allelic with PPK Wachter (form of NEPPK, see above), which can be considered an oligosymptomatic mild form of pachonychia congenita type I. Usually appears early after birth, but late onset in adulthood occurs.446,447

Clinical presentation Pachonychia congenita type I shows the prominent nail dystrophy with thickening of the nail plate, dyschromia and subungual hyperkeratosis. Focal, insulated PPK is enhanced by the mechanical pressure, develops rapidly after children start walking and may be associated by hyperhidrosis. Keratoderma is more prominent on plantar surfaces. Marked follicular keratosis with helicotrichia and oral leukokeratosis, sometimes extending on the nasal, laryngeal, esophageal or tympanal mucosa, are present.448 Angular cheilitis446 and verrucous hyperkeratotic lesions are often found on elbows and knees. Hyperpigmentation and amyloidosis as in Naegeli–Franceschetti–Jadassohn syndrome have been reported.449 Bullous lesions may develop upon treatment with retinoids.

which can be considered an oligosymptomatic mild form of pachyonychia congenita type II.

Clinical presentation The PPK and the nail dystrophy of pachonychia congenita type II are similar to pachyonychia congenita type I but usually less severe and often are influenced by the mechanical stress to which an individual patient is exposed. Usually follicular keratosis is absent but many sebaceous cysts are present with a distribution identical to familial sebocystoma and may be characterized by recurrent acneiform inflammation.451 Helicotrichia and natal teeth are sometimes present and oligosymptomatic variants have been reported.452

Laboratory findings Histology reveals acanthosis, hyperkeratosis with rare foci of epidermolytic hyperkeratosis.

Pathogenesis

Histology presents acanthosis, hyperkeratosis with focal epidermolytic hyperkeratosis.

Mutations of the genes KRT6B (chromosome 12q11) and KRT17 (chromosome 17q12) have been identified.450 They are located within the helix initiation peptides of the 1A domain of these keratins.445 Keratin 6B and keratin 17 form heterodimers and are expressed suprabasally in nail, palmoplantar skin, outer hair root sheet and sebaceous ducts.

Pathogenesis

Differential diagnosis

Mutations of the genes KRT6A (chromosome 12q11) and KRT16 (chromosome 17q12) have been identified.450 They are located mostly within the helix initiation peptides of the 1A domain of these keratins but may occur in the helix termination peptide of the 2B domain of KRT6A.445 KRT6A and KRT16 form heterodimers and are expressed suprabasally in nail, palmoplantar skin, outer hair root sheet and mucosal stratified epithelia.

Distinguishing the multiple sebaceous cysts from those of other diseases such as Gardner syndrome requires careful clinical examination.

Laboratory findings

Pachonychia congenita type II (Jackson–Sertoli) Pachonychia congenita type II has originally been reported by the Italian dermatologist Sertoli and was rediscovered by Jackson. The disorder combines focal palmoplantar keratoderma, mild follicular keratosis, angular cheilitis, oral leukokeratosis and sebaceous cysts.

FOCAL PALMOPLANTAR KERATODERMAS

Epidemiology

8

Linear PPK (epidermal nevus) Linear verrucous epidermal nevus on the palm or sole can be regarded as a form of localized PPK (see Mosaicism). In general, this phenomenon is due to mosaicism for an autosomal dominant gene expressed in palmoplantar epidermis. Terrinoni et al. reported a unilateral palmoplantar verrucous nevus due to a mosaic mutation in KRT16.453 The continuous morphology and epidermolytic histology of Terrinoni’s mosaic case contrast interestingly with the focal NEPPK produced by germline KRT16 mutations.

Epidemiology

Howel–Evans syndrome (tylosis with esophageal carcinoma)

Pachyonychia congenita type II is a rare autosomal dominant disease. It is allelic with steatocystoma multiplex of Günter

Howel–Evans syndrome was described as the association of focal NEPPK with esophageal carcinoma. It was originally described

446. Su WP, Chun SI, Hammond DE, et al. Pachyonychia congenita: a clinical study of 12 cases and review of the literature. Pediatr Dermatol. 1990;7:33–38. 447. Paller AS, Moore JA, Scher R. Pachyonychia congenita tarda. A late-onset form of pachyonychia congenita. Arch Dermatol. 1991;127:701–703. 448. Dahl PR, Daoud MS, Su WP. Jadassohn-Lewandowski syndrome (pachyonychia congenita). Semin Dermatol. 1995;14:129–134. 449. Tidman MJ, Wells RS, MacDonald DM. Pachyonychia congenita with cutaneous amyloidosis and hyperpigmentation – a distinct variant. J Am Acad Dermatol. 1987;16:935–940.

450. McLean WH, Rugg EL, Lunny DP, et al. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet. 1995;9: 273–278. 451. Hodes ME, Norins AL. Pachyonychia congenita and steatocystoma multiplex. Clin Genet. 1977;11:359–364. 452. Hohl D. Steatocystoma multiplex and oligosymptomatic pachyonychia congenita of the Jackson-Sertoli type. Dermatology. 1997;195: 86–88. 453. Terrinoni A, Puddu P, Didona B, et al. A mutation in the V1 domain of K16 is responsible for unilateral palmoplantar verrucous nevus. J Invest Dermatol. 2000;114:1136–1140.

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in two kindreds from Liverpool, UK, in 1958. Six generations of the original family were reviewed in 1994.454

Epidemiology Further families with this rare autosomal dominant PPK have been reported from the UK, the USA, and Germany.

Clinical presentation

FOCAL PALMOPLANTAR KERATODERMAS

The onset of this PPK is in late infancy or during adolescence.455 The hyperkeratotic skin is focal, it develops on zones exposed to friction, thus rather on the soles than on the palms, and regresses on bed-rest. Follicular keratoses and oral leukokeratoses precede the plantar lesions. In the original Liverpool family, esophageal carcinoma occurred in 18 of 48 affected and in one of 87 non-affected family members. Esophageal carcinoma was diagnosed at an average age of 43 years. Development of esophageal carcinoma after the third decade is a virtual certainty in family members with PPK, with an estimated risk at 95% by age 65.

Laboratory findings Histologic findings are hyperorthokeratosis, acanthosis and hypergranulosis without epidermolysis.

Pathogenesis The syndrome was mapped to 17q, suggesting the keratin type 1 genes and the breast cancer gene BRCA1 as candidates or contiguous genes.456 Linkage to the gene for envoplakin, a component of desmosomes expressed in epidermal and esophageal keratinocytes, was suggested first but excluded later.457 The Howel–Evans locus, known as TOC (tylosis and oesophageal cancer) shows loss of heterozygosity in 69% of sporadic esophageal cancers, and DMC1 is a specific gene within the TOC region that shows loss of expression in a variety of cancers.458 However, recent efforts by sequencing of the minimal linkage area did not identify causative mutations.459 Also, critical analysis of both the original455 and the US460 pedigree of Howel–Evans syndrome reveals that autosomal dominance can only be attributed to PPK. Normally in tumor syndromes, at least one tumor is also clinically transmitted as a dominant trait. Thus, the linked trans­ mission of esophageal cancer and keratoderma (tylosis) as suggested for Howel–Evans syndrome may not exist or at least awaits further molecular confirmation and explanation.

454. Ellis A, Field JK, Field EA, et al. Tylosis associated with carcinoma of the oesophagus and oral leukoplakia in a large Liverpool family – a review of six generations. Eur J Cancer B Oral Oncol. 1994;30B:102–112. 455. Howel-Evans W, McConnell RB, Clarke CA, et al. Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis): a study of two families. Q J Med. 1958;27:413–429. 456. Rogaev EI, Rogaeva EA, Ginter EK, et al. Identification of the genetic locus for keratosis palmaris et plantaris on chromosome 17 near the RARA and keratin type I genes. Nat Genet. 1993;5:158–162. 457. Risk JM, Evans KE, Jones J, et al. Characterization of a 500 kb region on 17q25 and the exclusion of candidate genes as the familial Tylosis Oesophageal Cancer (TOC) locus. Oncogene. 2002;21:6395–6402. 458. Harada H, Nagai H, Tsuneizumi M, et al. Identification of DMC1, a novel gene in the TOC region on 17q25. 1 that shows loss of expression in multiple human cancers. J Hum Genet. 2001;46:90–95.

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Differential diagnosis The phenotype is similar to type 1 pachyonychia congenita, with oral leukokeratosis and focal PPK and PPK of Wachter.

Pseudo-dominant maternally inherited Mitochondrial NEPPK with deafness Just as for connexin mutations, a mitochondrial mutation was first identified in familial deafness461 and then in patients with inherited deafness plus PPK.462,463

Epidemiology This has been reported in Scottish, French, New Zealand, and Japanese pedigrees. The condition is transmitted only by females because mitochondria are exclusively inherited from the oocyte. Penetrance is variable, and is higher for hearing loss (60%) than for PPK (37%).463

Clinical presentation Focal plantar hyperkeratosis appears on pressure points during childhood sparing typically plantar arches. Palmar involvement develops later and sometimes not at all. Sensorineural deafness starts in infancy or childhood and is slowly progressive, sometimes becoming total. The plantar keratoderma is sharply delimited and not transgredient. It predominantly affects the weight-bearing area, but may extend to the instep and Achilles tendon, and keratotic plaques may be found on the dorsum of the foot. Palmar involvement is more common in manual workers. Pseudoainhum has not been reported. Hair, nails, teeth, and mucous membranes are normal. The hearing impairment is variable and progressive. High-tone loss predominates. Both the PPK and deafness are slowly progressive.

Laboratory findings There is acanthosis, hypergranulosis, and ortho- and parakeratosis, but no epidermolysis at histological analysis. Ultrastructurally there are large keratohyaline granules in the granular layer, and perinuclear bundles of tonofilaments.

Pathogenesis There is a mutation designated A7445G in the mitochondrial DNA.462,463 The mitochondrial genome consists of double-

459. Langan JE, Cole CG, Huckle EJ, et al. Novel microsatellite markers and single nucleotide polymorphisms refine the tylosis with oesophageal cancer (TOC) minimal region on 17q25 to 42. 5 kb: sequencing does not identify the causative gene. Hum Genet. 2004;114:534–540. 460. Marger RS, Marger D. Carcinoma of the esophagus and tylosis. A lethal genetic combination. Cancer. 1993;72:17–19. 461. Reid FM, Vernham GA, Jacobs HT. A novel mitochondrial point mutation in a maternal pedigree with sensorineural deafness. Hum Mutat. 1994;3: 243–247. 462. Sevior KB, Hatamochi A, Stewart IA, et al. Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness. Am J Med Genet. 1998;75:179–185. 463. Martin L, Toutain A, Guillen C, et al. Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome. Br J Dermatol. 2000;143:876–883.

Ichthyosis and disorders of other cornification

Differential diagnosis See Table 8.7 for differentiation from other types of PPK.

Autosomal recessive Carvajal syndrome This extremely rare autosomal recessive condition is characterized by striate keratoderma, wooly hair and dilated left cardiomyopathy and has been described first in families from Ecuador.464

Clinical presentation The tightly curled (wooly) hair is present at birth and the striate PPK develops at around 10 months of age. Striated lichenoid keratoses in major flexural areas and follicular keratoses of elbows and knees may arise progressively. Left ventricular dilatation can be asymptomatic at first and may only be revealed by cardiological investigation including electrocardiographic and echocardiographic examinations. Electrocardiogram abnormalities have been documented in children as young as 8 years of age, resulting in heart failure during adolescence464 or sudden death.465

Laboratory findings Histology of affected palmoplantar epidermis shows acantholytic hyperkeratosis with large intercellular spaces between the suprabasal keratinocytes. At immunohistochemistry suprabasal keratinocytes desmoplakin and plakoglobin appeared mainly at points of cell–cell contact and perinuclear localization of keratin in suprabasal keratinocytes suggests a collapsed intermediate filament network.466

Pathogenesis Affected individuals from three families were homozygous for a deletion in the desmoplakin gene. This produces a premature stop codon leading to a truncated desmoplakin protein missing

464. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol. 1998;39:418–421. 465. Kolar AJ, Milroy CM, Day PF, et al. Dilated cardiomyopathy and sudden death in a teenager with palmar-plantar keratosis (occult Carvajal syndrome). J Forensic Leg Med. 2008;15:185–188. 466. Norgett EE, Hatsell SJ, Carvajal-Huerta L, et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum Mol Genet. 2000;9:2761–2766. 467. Viglizzo GM, Occella C, Bleidl D, et al. Richner-Hanhart syndrome (tyrosinemia II): early diagnosis of an incomplete presentation with unusual findings. Pediatr Dermatol. 2006;23:259–261.

the C domain of the tail region.466 Desmoplakin is the most abundant protein in desmosomes, which are particularly prominent in epidermis and cardiac muscle, and may account for the resistance of these tissues to mechanical forces.

Differential diagnosis The wooly hair and cardiac defects distinguish this condition from striate PPK. Naxos disease can be differentiated from Carvajal syndrome, both clinically by diffuse PPK and right ventricular cardiomyopathy and at the molecular level by plakoglobin mutations.

Richner–Hanhart syndrome Richner–Hanhart syndrome (tyrosinemia type II; oculocutaneous tyrosinemia) is an autosomal dominant disorder of tyrosine metabolism characterized by corneal ulcerations, painful focal PPK and progressive neurological changes if untreated. The condition is lifelong, and a diet restricted in tyrosine and phenylalanine can result in complete remission of symptoms.

FOCAL PALMOPLANTAR KERATODERMAS

stranded DNA and contains 37 genes that encode 13 respiratory chain polypeptides, two types of ribosomal RNA and 22 transfer RNAs. The A7445G mutation on one DNA strand results in a silent change to the cytochrome oxidase 1 gene, and on the other strand a substitution adjacent to the 3 prime end of the serine tRNA gene. The consequences of these rearrangements remain unclear.

8

Epidemiology There are about 100 cases in the literature. Although cases have been reported from around the world, many patients are of Italian ancestry.

Clinical presentation The earliest presenting complaint, in the first few months of life, is dendritic keratitis with photophobia. Corneal erosions may progress to corneal ulcerations, and left untreated, to glaucoma, neovascularization and blindness. Many patients are erroneously treated for presumed herpes keratitis. A split-lamp exam allows visualization of the tyrosine crystals. Vesicles on the fingertips is another heralding sign.467 Occasionally leukokeratosis of the oral mucosa is found.468 Painful circumscribed callosities, developing on pressure points of the palms (fingertips, hypothenar, and thenar eminences) and weight-bearing surfaces of the soles as well as occasionally on elbow and knees, can appear in early childhood or may be delayed to the second decade.469 Palmoplantar hyperhidrosis and blistering can be associated with this condition. The palmoplantar keratoses are characteristically painful and may lead to refusal to walk.470 The keratoderma is episodic, and the clinical characteristics may be quite variable. Mental retardation, which varies in severity, develops if there is no restrictive diet.

468. Larregue M, de Giacomoni P, Bressieux JM, et al. Richner-Hanhart’s syndrome or oculo-cutaneous tyrosinosis (about one case) (author’s transl.). Ann Dermatol Venereol. 1979;106:53–62. 469. Rabinowitz LG, Williams LR, Anderson CE, et al. Kaplan. Painful keratoderma and photophobia: hallmarks of tyrosinemia type II. J Pediatr. 1995;126:266–269. 470. Jaeger W, Gallasch G, Schnyder UW, et al. Tyrosinemia and Richner– Hanhart syndrome (an autosomal recessive hereditary metabolic disease of childhood with bilateral dendritic pseudokeratitis, keratosis palmaris et plantaris and mental deficiency. Ber Zusammenkunft Dtsch Ophthalmol Ges. 1978;649–654.

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Laboratory findings

Spiny palmoplantar keratoderma

The disease can be detected early by expanded newborn screening using tandem mass spectometry.471 Histology of affected skin will show ortho- and parakeratotic hyperkeratosis, hypergranulosis, multinuclear keratinocytes and dyskeratosis. The corneocytes contain lipid droplets within the cytoplasm.472 Electron microscopy shows aggregations of tonofilaments and minute tyrosine crystals within the cytoplasm of keratinocytes.473 Tyrosine crystals are also deposited in the cornea.474 Serum and urinary tyrosine levels are elevated.

This autosomal dominant disorder is characterized by numerous asymptomatic 1–3 mm spiny or acuminated or spike keratoses on the plantar aspects of both feet and on the palms of both hands. These are most commonly located within creases. The disorder is synonymous with punctate palmoplantar porokeratosis.477

Pathogenesis

FOCAL PALMOPLANTAR KERATODERMAS

Tyrosinemia type II is due to deficiency of the hepatic cytosolic enzyme, tyrosine aminotransferase, leading to accumulation of tyrosine in affected tissues. Plasma tyrosine levels and urinary tyrosine metabolites, p-hydroxyphenylacetic acid, Nacetyltyrosine, and p-tyramine, are increased. Many different mutations have been identified in the hepatic tyrosine aminotransferase gene (TAT) on 16q.

Differential diagnosis Ocular problems ulceration.

are

often

misdiagnosed

as

herpetic

Punctate palmoplantar keratodermas As phenotypic expression of punctate PPK has considerable inter- and intrafamilial variation, classification is difficult. Only the most clearly defined disorders are mentioned here.

ISOLATED PUNCTATE PALMOPLANTAR KERATODERMAS Autosomal dominant Punctate palmoplantar keratoderma (Brauer–Buschke–Fischer) Punctate PPK, also known as keratosis palmoplantaris papulosa, was originally described by Brauer, Buschke and Fischer and by Davies and Colley. This autosomal dominant disorder is linked to chromosomes 8q24,475 and 15q22.476 It is characterized by small, hard keratotic papules which can be picked out, leaving a depression. Onset is usually after the first decade.

471. Meissner T, Betz RC, Pasternack SM, et al. Richner-Hanhart syndrome detected by expanded newborn screening. Pediatr Dermatol. 2008;25:378–380. 472. el-Shoura SM, Tallab TM. Richner-Hanhart’s syndrome: new ultrastructural observations on skin lesions of two cases. Ultrastruct Pathol. 1997;21:51–56. 473. Shimizu N, Ito M, Ito K, et al. Richner-Hanhart’s syndrome. Electron microscopic study of the skin lesion. Arch Dermatol. 1990;126:1342–1346. 474. al-Hemidan AI, al-Hazzaa SA. Richner-Hanhart syndrome (tyrosinemia type II). Case report and literature review. Ophthalmic Genet. 1995;16: 21–26. 475. Zhang XJ, Li M, Gao TW, et al. Identification of a locus for punctate palmoplantar keratodermas at chromosome 8q24. 13–8q24. 21. J Invest Dermatol. 2004;122:1121–1125.

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Acrokeratoelastoidosis Acrokeratoelastoidosis, also known as Costa syndrome, is of autosomal dominant inheritance. Skin lesions develop before the age of 20 and are characterized by hyperkeratotic, ovalshaped to polygonal papules with a yellowish translucent color (Fig. 8.51). They are 1–3 mm in diameter, may show a central depression and are mainly confined to the margins of the palms and soles. Focally, they may coalesce to produce a more diffuse pattern. Palmoplantar hyperhidrosis is a regularly associated feature. Hyperkeratotic lesions may be present on the dorsa of the metacarpophalangeal and interphalangeal joints. Histology shows hyperorthokeratosis, acanthosis and fragmentation of elastic fibers in the dermis, which is called elastorrhexis and was claimed to be a specific feature of this type of PPK.478 However, own experience indicates that it is identical to focal acral hyperkeratosis (see below). Pedigrees with both maintained elastic fibers and elastorrhexis were reported.

Focal acral hyperkeratosis Punctate hyperkeratoses located particularly on the lateral palmoplantar borders are probably inherited as an autosomal dominant trait. More common in blacks, the disorder affects 2–4% of adults. The keratoses may be painful and may be provoked by manual labor. Histologically, elastorrhexis is lacking.479

PUNCTATE PALMOPLANTAR KERATODERMAS IN GENERALIZED SKIN DISORDERS Punctate or papular PPK may be observed in generalized skin disorders.477 Palmoplantar papules, many of which are keratotic or keratin filled depressions, are almost invariably found in Darier disease.480 Subtle palmoplantar changes can be detected with the interruption of the dermatoglyphic pattern. Acrokeratosis verruciformis, reported originally by Hopf, is now considered a mild form of Darier disease and is also characterized by palmoplantar keratotic papules, flat wart-like papules on the dorsal

476. Martinez-Mir A, Zlotogorski A, Londono D, et al. Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22q24. J Med Genet. 2003;40:872–878. 477. Sakas EL, Gentry RH. Porokeratosis punctata palmaris et plantaris (punctate porokeratosis). Case report and literature review. J Am Acad Dermatol. 1985;13:908–912. 478. Costa OG. Acrokeratoelastoidosis. AMA Arch Derm Syphilol. 1954;70:228–231. 479. Rongioletti F, Betti R, Crosti C. Marginal papular acrokeratodermas: a unified nosography for focal acral hyperkeratosis, acrokeratoelastoidosis and related disorders. Dermatology. 1994;188:28–31. 480. Kim C, Fangman W. Keratosis follicularis (Darier–White disease), with an unusual palmoplantar keratoderma. Dermatol Online J. 2007;13:7.

Ichthyosis and disorders of other cornification

8

POROKERATOSIS PALMOPLANTARIS ET DISSEMINATA Palmoplantar and disseminated porokeratosis is a rare autosomal dominant keratinization disorder characterized histologically by peripheral ‘cornoid lamellae’. They first develop on the palmoplantar surfaces at several years of age and later extend on to extremities, trunk and neck, forming small papules with the typical elevated keratotic border.486 There is a small risk of developing squamous cell cancer within porokeratotic lesions.487 The disorder has been linked to chromosome 12q23,488 and needs to be differentiated from disseminated superficial actinic porokeratosis and disseminated superficial porokeratosis, which do not involve palmoplantar surfaces.

A

FOCAL PALMOPLANTAR KERATODERMAS

ACQUIRED PALMOPLANTAR KERATODERMA Although beyond the scope of this chapter to review acquired palmoplantar keratoderma, it should be emphasized that most palmoplantar keratodermas of childhood are acquired. The list of triggers is long, and includes mechanical, infectious, druginduced, hormonal, paraneoplastic and zinc deficiency. Inflammatory disorders such as atopic dermatitis, psoriasis and lichen planus may involve palmoplantar skin. Infectious disorders are often asymmetric and may be due to fungal infection, warts or scabies.

MANAGEMENT OF INHERITED PALMOPLANTAR KERATODERMAS B

Figure 8.51  (A, B) Acrokeratoelastoidosis. Note the hyperkeratotic, round or

As keratoderma persists throughout life and treatment is not curative, therapy must not be more burdensome than the condition itself.

oval-shaped confluent papules with a yellowish translucent color.

Topical therapy

aspect of the extremities, and nail changes.481 Punctate PPK, often with central depressions, are present in about half of the patients with Cowden disease.482 PPK is present in 80–90% of patients with basal cell nevus syndrome (Gorlin syndrome) and characterized by multiple punctate depressions.483 Histologically, they reveal basaloid proliferations reminiscent of superficial basal cell cancer. The PPK in epidermodysplasia verruciformis (of Lewandowsky–Lutz), an autosomal recessive disorder due to inactivating mutations in EVER1 and EVER2, is classically papular and can evolve into squamous cell carcinoma.484 The disease is characterized by a particular susceptibility to develop flat warts on the shoulders, face and limbs due to HPV infection, including oncogenic HPV5.485

The choice of local treatment will be guided by the child’s age, the degree of hyperkeratosis and the associated symptoms. Anti­ cipatory guidance may suffice in asymptomatic young children. Twice daily application of keratolytic and moisturizing creams or ointments, as well as mechanical paring, represent the basis of topical treatment of PPKs. Salicylic acid (to be used with caution in children) or lactic acid in a rich moisturizing base leads to keratolysis. The appropriate concentration can be found by increasing gradually from 5% to 20%. Urea (10%) and propylene glycol (20–60%) have both keratolytic and moisturizing properties. The use of such prescriptions under occlusive dressings at night considerably accelerates the softening of the lesions. Topical tazarotene therapy can also be considered. Maceration and irritation of adjacent normal skin can be prevented by the application of petrolatum. Application of topical 5-fluorouracil may be useful,

481. Hovnanian A. SERCA pumps and human diseases. Subcell Biochem. 2007;45:337–363. 482. Lee HR, Moon YS, Yeom CH, et al. Cowden’s disease – a report on the first case in Korea and literature review. J Korean Med Sci. 1997;12:570–575. 483. Nassab R, Rayatt S, Peart F. Infected palmar pits: a rare presentation of Gorlin’s syndrome. J Hand Surg [Br]. 2005;30:459–460. 484. Lutz W. Epidermodysplasia verruciformis. Dermatologica. 1957;115:309–314. 485. Orth G. Host defenses against human papillomaviruses: lessons from epidermodysplasia verruciformis. Curr Top Microbiol Immunol. 2008;321: 59–83.

486. Marschalko M, Somlai B. Porokeratosis plantaris, palmaris, et disseminata. Arch Dermatol. 1986;122:890–891. 487. Beers B, Jaszcz W, Sheetz K, et al. Porokeratosis palmaris et plantaris disseminata. Report of a case with abnormal DNA ploidy in lesional epidermis. Arch Dermatol. 1992;128:236–239. 488. Wei SC, Yang S, Li M, et al. Identification of a locus for porokeratosis palmaris et plantaris disseminata to a 6. 9-cM region at chromosome 12q24. 1–24. 2. Br J Dermatol. 2003;149:261–267.

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DARIER DISEASE (DARIER–WHITE DISEASE)

as it is in warts.489 Calcipotriol alone is ineffective490 but may be useful in combination with systemic retinoids.489 Topical treatment of loricrin keratoderma is similar to that for other PPKs, but the results are generally unsatisfactory. Painful fissures may be sealed with silver nitrate, super glue, Elastoplast (adhesive tape) or glycerin under occlusion. Manual paring of keratoses instantly relieves pain caused by plantar hyperkeratosis491 and can be carried out by parents; some patients with extensive palmoplantar thickening have pared with a Dremel drill. A chiropodist can advise on equipment and technique. Dermabrasion has also been used successfully.492 Injection of botulinum toxin is a highly efficient alternative in treating pain in verrucous plantar lesions, e.g., in pachyonychia congenita.493 Prevention of friction may considerably improve PPKs, for hyperkeratosis represents a protective response of the skin caused by an increased susceptibility to mechanical stress. Poor gait due to pain on walking can be helped by customized in-soles. Treatment of hyperhidrosis can be achieved by potassium permanganate soaks, aluminum chloride hexahydrate lotion, iontophoresis or botulinum injections.

Systemic treatments Oral retinoids such as acitretin (0.1 to 0.5 mg/kg per day) and, to a lesser extent, isotretinoin (0.5–1 mg/kg per day) may improve the hyperkeratosis but increase skin fragility, especially in patients with K1 mutations.494 Retinoids improve pseudoainhum, keratoderma, lichenoid plaques and contractures, but peeling of the palms limits the dose.495 Considering their sideeffects, especially in long-term use (such as premature epiphyseal closure or myopathy), these drugs should only be used in severe forms of PPK. Intermittent therapy, e.g., 4 months ‘on’ and 2 months ‘off,’ is a useful alternative. Discontinuation of retinoids is usually followed by a rapid relapse. Treatment of secondary fungal infection with terbinafine or azole derivatives is indicated. Full-thickness excision and grafting of the palmar skin may be necessary and useful in some severe disorders, such as Olmsted syndrome.387 Pseudoainhum may be treated either with retinoids or surgery to release the constriction. In Papillon–Lefèvre syndrome the management of the periodontitis is difficult. Compulsive oral hygiene and vigorous plaque removal may slow disease progression, but this is difficult to achieve in young children. Extractions are frequently required for relief of pain. Early loss of dentition leads to significant dis-

489. Horikoshi M, Kuroda K, Tajima S. Punctate palmoplantar keratoderma with pigmentary lesions on the dorsa of feet and ankles: successful treatment with a combination of low-dose oral etretinate and topical calcipotriol. J Dermatol. 2004;31:469–472. 490. Kragballe K, Steijlen PM, Ibsen HH, et al. Efficacy, tolerability, and safety of calcipotriol ointment in disorders of keratinization. Results of a randomized, double-blind, vehicle-controlled, right/left comparative study. Arch Dermatol. 1995;131:556–560. 491. Redmond A, Allen N, Vernon W. Effect of scalpel debridement on the pain associated with plantar hyperkeratosis. J Am Podiatr Med Assoc. 1999;89: 515–519. 492. Daoud MS, Randle HW, Yarborough JM. Dermabrasion of the hyperkeratotic foot. Dermatol Surg. 1995;21:243–244. 493. Swartling C, Vahlquist A. Treatment of pachyonychia congenita with plantar injections of botulinum toxin. Br J Dermatol. 2006;154:763–765. 494. Virtanen M, Gedde-Dahl T Jr, Mork NJ, et al. Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression. Acta Derm Venereol. 2001;81:163–170.

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tortion of maxillary and mandibular growth but once all teeth have been shed dentures are usually well tolerated. It has been suggested that early treatment with oral retinoids will preserve dentition and improve keratoderma.496 In Howel–Evans syndrome, esophageal dysplasia may precede the development of an invasive carcinoma; endoscopic surveillance and treatment of premalignant lesions are recommended. Systemic retinoids may improve the PPK but do not prevent the development of esophageal dysplasia.497 In Carvajal syndrome, cardiomyopathy can cause early death and may be delayed by implantation of a cardiac defibrillator.498 In Richner–Hanhart syndrome, a diet restricted in tyrosine and phenylalanine will clear the keratitis and the skin lesions, and may delay or prevent cognitive impairment.469,499

Pediatric aspects of PPK Pain from hyperkeratosis with or without fissures may affect motor development, particularly the gait. Likewise, thick palmar keratoderma and hyperhidrosis may impair manual activities. Ideally, treatment is directed at relief of functional impairment, thus allowing children to participate fully in all activities. Some children develop a habit of removing loose flakes of skin. Older children dislike grease but may accept an oily preparation overnight and a lighter cream during the day. Adolescent people with PPK should be advised to choose a job that minimizes trauma to the palms and soles.

OTHER KERATOSES Peter Itin

DARIER DISEASE (DARIER–WHITE DISEASE) INTRODUCTION AND HISTORICAL NOTE This disorder was described independently by Darier and White more than 100 years ago.500 Darier first described the dyskeratotic features of the epidermis but he incorrectly interpreted these as forms of an epidermal parasite. His term ‘keratosis follicularis’ is a misnomer because the lesions are not follicular. White recognized the genetic nature of the disease. The disease is characterized by altered keratinization of the epidermis which leads clinically to multiple keratotic papules.

495. Peris K, Salvati EF, Torlone G, et al. Chimenti. Keratoderma hereditarium mutilans (Vohwinkel’s syndrome) associated with congenital deaf-mutism. Br J Dermatol. 1995;132:617–620. 496. Siragusa M, Romano C, Batticane N, et al. A new family with PapillonLefevre syndrome: effectiveness of etretinate treatment. Cutis. 2000;65: 151–155. 497. Ashworth MT, Nash JR, Ellis A, et al. Abnormalities of differentiation and maturation in the oesophageal squamous epithelium of patients with tylosis: morphological features. Histopathology. 1991;19:303–310. 498. Norgett EE, Lucke TW, Bowers B, et al. Early death from cardiomyopathy in a family with autosomal dominant striate palmoplantar keratoderma and woolly hair associated with a novel insertion mutation in desmoplakin. J Invest Dermatol. 2006;126:1651–1654. 499. Benoldi D, Orsoni JB, Allegra F. Tyrosinemia type II: a challenge for ophthalmologists and dermatologists. Pediatr Dermatol. 1997;14: 110–112. 500. Sehgal VN, Srivastava G. Darier’s (Darier-White) disease/keratosis follicularis. Int J Dermatol. 2005;44:184–192.

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DARIER DISEASE (DARIER–WHITE DISEASE)

Figure 8.52  Darier disease. Flesh-colored or brown keratotic, generally non-follicular papules (Courtesy Dr A. Torrelo).

EPIDEMIOLOGY Darier disease (OMIM 124200) is an autosomal dominant skin disorder occurring worldwide. The prevalence ranges between 1 : 30 000 and 1 : 100 000. It has been shown that de novo mutations occur and penetrance is high. It affects males and females equally. Munro noted that in general women show a milder disorder than men.501 Marked intrafamilial clinical heterogeneity is common.502

PRESENTING HISTORY AND PHYSICAL EXAMINATION Patients usually present with skin-colored or brownish papules in a characteristic distribution. The lesions tend to develop between the ages of 5 and 20 with a peak incidence during puberty.503 However, congenital appearance has been reported.504 Sometimes the condition is misdiagnosed as acne, seborrheic dermatitis, or genital warts.505 The primary lesions are firm, rough-textured and greasy, flesh-colored or brown, keratotic, mostly non-follicular papules that may be covered by a scaly crust (Fig. 8.52). The clinical spectrum is rather wide. It includes discrete keratotic papules and tumor-like, malodorous vegetations in intertriginous areas with maceration. Rarely, guttate leukodermatous macules and hemorrhagic vesicles in an acral distribution may occur. Coalescence of papules produces plaques that may become papillomatous (Fig. 8.53). The disorder is often aggravated by sun, heat, and sweating; therefore, the disease often manifests in summer for the first time. In general the distribution is symmetrical. Darier disease may occur anywhere on the body surface but predilection sites are the ‘sebor-

501. Munro CS. The phenotype of Darier’s disease: penetrance and expressivity in adults and children. Br J Dermatol. 1992;127:126–130. 502. Tavadia S, Mortimer E, Munro CS. Genetic epidemiology of Darier’s disease: a population study in the west of Scotland. Br J Dermatol. 2002;146:107–109. 503. Burge SM, Wilkinson JD. Darier–White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27:40–50. 504. Fong G, Capaldi L, Sweeney SM, et al. Congenital Darier disease. J Am Acad Dermatol. 2008;59:S50–S51.

Figure 8.53  Darier disease. Papillomatous vegetations, especially in intertriginous areas.

rheic areas’ such as the face, ears, neck, chest, shoulders, and supraclavicular fossae, or the midline of the back. In addition, the flexures such as the anogenital region, the groin, and the gluteal fold are often involved. Flat wart-like papules may occur on the dorsal aspects of the hands and feet. Hand involvement occurs in almost 100% with pits and punctate keratotic plaques (Fig. 8.54). Ten percent of patients develop hyperkeratosis on the palms and soles, and circumscribed keratoderma may occur.506 Acrokeratosis verruciformis of Hopf is today considered as an acral variant of Darier disease with wart-like lesions on the dorsum of the hands and feet, although genetic heterogeneity seems to exist.507 Nails are affected in 60% of patients and show diagnostic longitudinal red and white lines (Fig. 8.55).501 Increased brittleness with fragility, splintering and fissuring associated with V-shaped notches on the distal part of the nail plate are typical findings. Subungual hyperkeratosis may be found. Children may present with nail involvement only. Almost 90% complain of marked pruritus, and pain was reported in 17% in a large study.503 Secondary eczematization is a prominent feature. The odor, particularly in hypertrophic flexural areas, is mainly due to bacterial overgrowth. Skin fragility and fissuring with painful erosions may occur.

505. Salopek TG, Krol A, Jimbow K. Case report of Darier disease localized to the vulva in a 5-year-old girl. Pediatr Dermatol. 1993;10:146–148. 506. Thappa DM, Garg BR. Darier’s disease with circumscribed plantar keratoderma. J Dermatol. 1996;23:139–140. 507. Wang PG, Gao M, Lin GS, et al. Genetic heterogeneity in acrokeratosis verruciformis of Hopf. Clin Exp Dermatol. 2006;31:558–563.

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DARIER DISEASE (DARIER–WHITE DISEASE)

Oral involvement occurs in 13–50% of patients and palate, gingiva, buccal mucosa, and the tongue are most commonly affected,508 often with a cobblestone appearance. In addition, the hypopharyngeal, laryngeal, vaginal, or rectal mucosa may be affected. Duct obstruction due to salivary stones is an uncommon complication. The external auditory canal may be blocked

by accumulated keratotic debris. Retinitis pigmentosa associated with keratosis follicularis has been observed in two affected brothers.509 Extensive involvement of the scalp has been documented510 and alopecia may result. Increased susceptibility to bacterial and viral infections is known in such patients, and a defect in cell-mediated immunity has been suspected. The defective skin barrier may increase skin infection rate. Patients with Darier disease are prone to Kaposi’s varicelliform eruption due to herpes simplex.511 The differential diagnosis of skin lesions includes Hailey– Hailey disease, seborrheic dermatitis, and keratosis pilaris. It has been suggested that Darier disease is associated with mild neuropsychiatric features, including mental handicap, schizophrenia, and bipolar disorder. Linkage analysis showed that bipolar susceptibility co-segregates with the chromosome region of Darier’s disease.512 In neuropsychiatric cases there was a nonrandom clustering of mutations in the 3′ end of the ATP2A2 gene, and a predominance of the missense type.513 Ocular involvement leads to focal keratinization of the limbal conjunctiva, a regional increase in conjunctival goblet cells and a diffuse thickening of the basement membrane of the corneal epithelium.514 In 1906, Kreibich reported a localized form of Darier disease.515 Since this time more than 50 cases of localized Darier disease have been reported.516 Such phenotypes have been called zosteriform, linear, segmental or unilateral. Segmental Darier disease follows the lines of Blaschko, and results from postzygotic mutations (see type I mosaicism in Mosaicism).516–519 Gonadal mosaicism may lead to generalized Darier disease in the following generation. Rarely, patients may have diffuse disease (heterozygous mutation) but, in addition, a mosaic form with localized increased severity of disease (type 2 mosaicism, Fig. 8.56) (see Hailey–Hailey disease, below). The absence of the corresponding wild-type allele results in a marked increase of severity in the linear arrangement as compared with the common phenotype of the disorder. Type 2 originates from an individual with a heterozygous germline mutation and, in addition, a postzygotic mutation occurred, such as mitotic recombination, nondisjunction, or deletion. These mechanisms led to a population of cells either homozygous or hemizygous for the underlying mutation.520,521 Type 2 mosaic Darier disease has been associated with an adjacent band-like area of healthy skin in a patient with Darier disease, providing support for the concept of twin spotting.522

508. Frezzini C, Cedro M, Leao JC, et al. Darier disease affecting the gingival and oral mucosal surfaces. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102:e29–e33. 509. Itin P, Büchner SA, Gloor B. Darier’s disease and retinitis pigmentosa; is there a pathogenetic relationship? Br J Dermatol. 1988;119:397–402. 510. Mailänder W, Stieler W, Stadler R. Ausgedehnte Kopfhautbeteiligung bei Morbus Darier. Akt Dermatol. 1991;17:284–286. 511. Pantazi V, Potouridou I, Ratsarou A, et al. Darier’s disease complicated by Kaposi’s varicelliform eruption due to herpes simplex virus. J Eur Acad Dermatol Venereol. 2000;14:209–211. 512. Green E, Elvidge G, Jacobsen N, et al. Localization of bipolar susceptibility locus by molecular genetic analysis of the chromosome 12q23-q24 region in two pedigrees with bipolar disorder and Darier’s disease. Am J Psychiatry. 2005;162:35–42. 513. Jacobsen NJ, Lyons I, Hoogendoorn B, et al. ATP2A2 mutations in Darier’s disease and their relationship to neuropsychiatric phenotypes. Hum Mol Genet. 1999;8:1631–1636. 514. Daicker B. Ocular involvement in keratosis follicularis associated with retinitis pigmentosa. Clinicopathological case report. Ophthalmologica. 1995;209:47–51.

515. Kreibich K. Zum wesen der psorospermosis Darier. Arch Dermatol Syphilol (Wien). 1906;80:367. 516. O’Malley MP, Haake A, Goldsmith L, et al. Localized Darier disease. Implications for genetic studies. Arch Dermatol. 1997;133:1134–1138. 517. Plantin P, Le Noac’h E, Leroy JP, et al. Maladie de Darier, localisée, récidivante et photo-induite suivant les lignes de Blaschko. Ann Dermatol Venereol. 1994;121:393–395. 518. Papadavid E, Dawber RPR. Linear Darier’s disease in a patient with recurrent carcinoma of the bladder reflects cutaneous mosaicism. J Europ Acad Dermatol Venereol. 1997;9:249–252. 519. Sakuntabhai A, Dhitavat J, Burge S, et al. Mosaicism for ATP2A2 mutations causes segmental Darier’s disease. J Invest Dermatol. 2000;115:1144–1147. 520. Happle R, Itin PH, Brun AM. Type 2 segmental Darier disease. Eur J Dermatol. 1999;9:449–451. 521. Itin PH, Büchner SA, Happle R. Segmental manifestation of Darier disease. What is the genetic background in type 1 and type 2 mosaic phenotypes? Dermatology. 2000;200:254–257. 522. Itin PH, Happle R. Darier disease with paired segmental manifestation of either excessive or absent involvement: A further step in the concept of twin spotting. Dermatology. 2002;205:344–347.

Figure 8.54  Darier disease. Pits.

Figure 8.55  Darier nail disease. V-shaped notches with longitudinal white and reddish lines.

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8

especially N767S substitution in the M5 transmembrane domain.527

THERAPEUTICS AND PROGNOSIS

superimposed on the ordinary phenotype.

PATHOPHYSIOLOGY AND HISTOGENESIS Histological hallmarks are focal suprabasal clefting (lacunae) due to acantholysis and subsequent degeneration of keratino­ cytes (dyskeratosis) with overlying parakeratosis. These dyskeratotic cells are called grains and corps ronds. Corps ronds are cells showing premature partial keratinization in the spinous layer. They give rise to the grains that are small cells with shrunken cytoplasm in the upper layers of the epidermis. Additional histopathological findings include mild non-specific perivascular dermal infiltration, dermal villi protruding into the epidermis, hyperkeratosis, and acanthosis. The causative gene maps to a 2-cM region on chromosome 12q23–24.1.523–525 Sakuntabhai et  al.526 described causative mutations in ATP2A2, encoding a calcium pump in the endoplasmatic reticulum. Alteration of the protein product SERCA2 leads to acantholysis and apoptosis. In 47 European pedigrees, 40 distinct mutations within the ATP2A2 gene have been found that lead to classic and variant forms of Darier disease.527 Families with hemorrhagic variants show a missense mutation,

523. Craddock N, Dawson E, Burge S, et al. The gene for Darier’s disease maps to chromosome 12q23–q24. 1. Hum Mol Genet. 1993;2:1941–1943. 524. Bashir R, Munro CS, Masons, et al. Localisation of a gene for Darier’s disease. Hum Mol Genet. 1993;2:1937–1939. 525. Foggia L, Aronchik I, Aberg K, et al. Activity of the hSPCA1 Golgi Ca2+ pump is essential for Ca2+-mediated Ca2+ response and cell viability in Darier disease. J Cell Sci. 2006;119:671–679. 526. Sakuntabhai A, Ruiz-Perez VL, Carter S, et al. Mutations in ATP2A2, encoding a Ca21 pump, cause Darier disease. Nat Genet. 1999;21:271–277. 527. Ruiz-Perez VL, Carter SA, Healey E, et al. ATP2A2 mutations in Darier’s disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class. Hum Mol Genet. 1999;8:1621–1630. 528. Micali G, Nasca MR. Tazarotene gel in childhood Darier disease. Pediatr Dermatol. 1999;16:243–244. 529. Santiago-et-Sánchez-Mateos JL, Beà S, Fernández M. Botulinum toxin type A for the preventive treatment of intertrigo in a patient with Darier’s disease and inguinal hyperhidrosis. Dermatol Surg. 2008;34: 1733–1737.

HAILEY–HAILEY DISEASE

Figure 8.56  Type 2 segmental Darier disease. Pronounced linear lesions are

The waxing and waning natural course of Darier disease makes an evaluation of therapeutic regimens difficult. Keratolytic topical agents that contain urea, salicylic acid or retinoic acid are beneficial. Treatment of childhood Darier disease with tazarotene has been described,528 but irritancy is often limiting, especially in patients with inflammatory disease. In such cases a moderate-potency topical steroid may control inflammation. Topical vitamin D preparations may lead to improvement as well.490 Some children benefit from systemic administration of retinoids, but then require monitoring of skeletal and biochemical changes. If retinoids are used, the lowest possible dose to control the disease should be used. Procedural intervention, such as dermabrasion, laser treatment and photodynamic therapy, have been applied with success. Botulinum toxin type A decreased hyperhidrosis and prevented the intertrigo in a patient.529 Frequent cleansing with antibacterial soaps is important and intermittent courses of oral antibiotics are sometimes necessary to treat widespread secondary bacterial infections. The intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes was shown to cause antibiotic treatment failure in a patient with Darier disease.530 Herpetic infections should be treated systemically. An important preventive regimen is avoidance of direct sun exposure and regular application of sunscreen. Clothing should be cool cotton and not too tight.531

HAILEY–HAILEY DISEASE Hailey–Hailey disease (familial benign chronic pemphigus) (OMIM 169600) is a relatively common autosomal dominant skin disorder characterized by vesicles, erosions, hemorrhagic crusts and eczematous changes that occur predominantly in the body folds. In advanced stages, severe involvement of the axillary or inguinal regions may even lead to immobility of limbs.532,533 Rarely, disseminated spread in Hailey–Hailey disease may occur and resemble the keratotic papules of Darier disease.534 Histopathologically, suprabasal clefting with acantholysis is observed. These changes usually do not affect the hair follicles and sweat glands, presumably because these adnexal structures do not express the intrinsic defect of cell adhesion535 and perhaps

530. von Eiff C, Becker K, Metze D, et al. Intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with Darier’s disease. Clin Infect Dis. 2001;32:1643–1647. 531. Burge S. Management of Darier’s disease. Clin Exp Dermatol. 1999;24: 53–56. 532. Burge SM. Hailey–Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126:275–282. 533. Zhang F, Yan X, Jiang D, et al. Eight novel mutations of ATP2C1 identified in 17 Chinese families with Hailey-Hailey disease. Dermatology. 2007;215: 277–283. 534. Ikeda S, Shigihara T, Mayuzumi N, et al. Mutations of ATP2C1 in Japanese patients with Hailey-Hailey disease: intrafamilial and interfamilial phenotype variations and lack of correlation with mutation patterns. J Invest Dermatol. 2001;117:1654–1656. 535. Metze D, Hamm H, Schorat A, et al. Involvement of the adherens junction-actin filament system in acantholytic dyskeratosis of Hailey– Hailey disease: a histological, ultrastructural, and histochemical study of lesional and non-lesional skin. J Cutan Pathol. 1996;23:211–222.

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Table 8.8 Classification of porokeratosis TYPE

ABBREVIATION

MCKUSICK’S CATALOG

Plaque-type porokeratosis of Mibelli

PM

175800

Disseminated actinic superficial porokeratosis

DSAP

175900

Linear porokeratosis as a mirror of LOH

175900

POROKERATOSIS

Porokeratosis palmaris, plantaris et disseminata

PPPD

175850

Porokeratosis punctata palmaris et plantaris

PPPP

175860

CAP-syndrome

603116

Porokeratosis ptychotropica Craniosynostosis, anal anomalies, and porokeratosis

Figure 8.57  Type 2 segmental manifestation of Hailey–Hailey disease in a 5-year-old girl. Pronounced unilateral lesions characterized by blistering and eczematous changes following the lines of Blaschko (Courtesy of Dr F. Vakilzadeh, Hildesheim, Germany).

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Linear porokeratosisa a

Most cases probably mosaic manifestation of DSAP. (From Happle R. Somatic recombination may explain linear porokeratosis associated with disseminated superficial actinic porokeratosis. Am J Med Genet 1991;39:237.)

contributing to the beneficial effect of dermabrasion in this disorder. The underlying genetic defect involves the gene ATP2C1 at 3q21–q24, encoding a calcium pump.536 In general, this phenotype cannot be classified as a pediatric condition because it does not become manifest before adulthood. However, Vakilzadeh and Kolde537 reported a 5-year-old girl with unilateral manifestation of a ‘relapsing linear acantholytic dermatosis.’ A follow-up report of this case revealed that this patient had a family history of Hailey–Hailey disease comprising four generations.538 Since the age of 3 months, the girl had severe lesions of erythema and blistering arranged in a unilateral pattern following the lines of Blaschko (Fig. 8.57). At the age of 24 years, additional scattered symmetrical lesions involving the axillary and inguinal folds were noted. This case can be best explained by type 2 mosaicism (see Mosaicism) in autosomal dominant skin disorders.539 Unlike the ordinary heterozygous phenotype, this type 2 mosaic manifestation is characterized by pronounced acantholytic involvement of adnexal structures as well, reflecting the greater severity of involvement caused by loss of the corresponding wild-type allele within the segmental areas, and explaining the failure to respond to dermabrasion.538

POROKERATOSIS

536. Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey–Hailey disease. Nat Genet. 2000;24: 61–65. 537. Vakilzadeh F, Kolde G. Relapsing linear acantholytic dermatosis. Br J Dermatol. 1985;112:349–355. 538. Poblete-Gutiérrez P, Wiederholt T, König A, et al. Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept. J Clin Invest. 2004;114:1467–1474. 539. Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol. 1999;41:143.

540. Happle R. Cancer proneness of linear porokeratosis may be explained by allelic loss. Dermatology. 1997;195:20–25. 541. Liu P, Zhang S, Yao Q, et al. Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31. 3-p31. 1. Hum Genet. 2008;123:507–513. 542. Zhang ZH, Niu ZM, Yuan WT, et al. A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis. Br J Dermatol. 2005;152:658–663.

INTRODUCTION AND HISTORICAL NOTE Porokeratosis is a genetic disorder of keratinization with circular lesions showing central atrophy and a raised horny border that corresponds histopathologically to a column of parakeratotic cells overlying a thinned or absent granular layer, the so-called cornoid lamella.540 Six clinical variants are recognized (Table 8.8).

EPIDEMIOLOGY AND GENETICS Porokeratoses are rather common genodermatoses, especially the disseminated actinic type. In general, porokeratoses are inherited as an autosomal dominant trait. Several gene loci and candidate genes have been described in recent years.541 The candidate gene, SART3, is expressed in skin and works as a tumor rejection antigen. SART3 also associates transiently with small nuclear ribonuclear proteins involved in the regulation of mRNA splicing.542

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POROKERATOSIS

Ichthyosis and disorders of other cornification

Figure 8.58  Porokeratosis of Mibelli. Central atrophic lesion with raised margin on the border.

Figure 8.60  Disseminated actinic superficial porokeratosis occurs symmetrically over sun-exposed areas (Courtesy Dr A. Torrelo).

Figure 8.59  Giant lesion of porokeratosis of Mibelli.

PRESENTING HISTORY AND PHYSICAL FINDINGS Porokeratosis of Mibelli is rare and has an early onset with a male predominance. Lesions gradually enlarge centrifugally from a few millimeters to several centimeters with a hyperkeratotic border (Fig. 8.58). Giant lesions rarely occur (Fig. 8.59).543 Lesions are dry, brownish papules with a very distinct rimmed border. The onset is usually in childhood or adolescence but a later onset has been observed. The distribution is symmetric and lesions may be single or numerous. Sites of predilection are the face, trunk, and extremities. In general hair, nails, and mucous

543. Thappa DM, Garg BR, Ratnakar C. Giant porokeratosis. J Dermatol. 1995;22:964–965. 544. Kanzaki T, Miwa N, Kobayashi T, et al. Eruptive pruritic papular porokeratosis. J Dermatol. 1992;19:109–112. 545. Watanabe T, Murakami T, Okochi H, et al. Ulcerative porokeratosis. Dermatology. 1998;196:256–259. 546. Ricci C, Rosset A, Panizzon RG. Bullous and pruritic variant of disseminated superficial actinic porokeratosis: successful treatment with Grenz Rays. Dermatology. 1999;199:328–331. 547. Freyschmidt-Paul P, Holfman R, Konig A, et al. Linear porokeratosis superimposed on disseminated superficial actinic porokeratosis: report of two cases exemplifying the concept of type 2 segmental manifestation of

membranes are spared. Subtypes associated with reticular erythema exist. Disseminated actinic superficial porokeratosis is the most common form and occurs symmetrically over sun-exposed areas, particularly on the lower extremities. Lesions are often asymptomatic lesions, but may become pruritic (Fig. 8.60).544 Erosive or bullous variants may occur.545,546 The dermatosis typically appears in the third or fourth decade of life. Lesions are smaller than in the Mibelli type and often hundreds are present. The disorder may show amyloid deposition.547 Malignant degeneration in longstanding lesions may occur. Linear porokeratosis develops at least in some cases from loss of heterozygosity, and co-existence of linear porokeratosis and disseminated superficial actinic porokeratosis has been documented in a large number of patients (Fig. 8.61).540,547 Congenital linear porokeratosis has been described in patients who develop disseminated superficial actinic porokeratosis during childhood or early adulthood.548 Porokeratosis palmaris, plantaris et disseminata is characterized by numerous symmetric lesions with a clearly raised hyperkeratotic margin. The lesions initially erupt on the palms and soles and later on sun-exposed and covered body sites (Fig. 8.62). Oral lesions have been noted. Filiform keratoses on the trunk and extremities have been observed in this type, and dystrophic nails from porokeratotic lesions may result (Fig. 8.63).549 Porokeratosis punctata palmaris et plantaris is a rare variant of porokeratosis with discrete punctate keratotic or spine-like lesions confined to palms and soles.550 The keratotic papules may be tender and histology shows the columnar parakeratosis.

autosomal dominant skin disorders. J Am Acad Dermatol. 1999;41:644–647. 548. Suh DH, Lee HS, Kim SD, et al. Coexistence of disseminated superficial porokeratosis in childhood with congenital linear porokeratosis. Pediatr Dermatol. 2000;17:466–468. 549. Itin PH. Porokeratosis plantaris, palmaris et disseminata mit multiplen filiformen Hyperkeratosen und Nageldystrophie. Hautarzt. 1995;46: 869–872. 550. Friedman SJ, Herman PS, Pittelkow MR, et al. Punctate porokeratotic keratoderma. Arch Dermatol. 1988;124:1678–1682.

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Figure 8.61  (A,

B) Linear porokeratosis (Courtesy Dr A. Torrelo).

POROKERATOSIS

A

B

Figure 8.62  Plantar porokeratotic lesions.

Figure 8.63  Nail dystrophy induced by porokeratotic lesions.

Flanagan et al.551 reported the occurrence of coronal craniosynostosis, anal anomalies, and porokeratosis in two male sibs. The pedigree suggested an autosomal or X-linked recessive inheritance.

suggested to produce a Köbner phenomenon. Nelson et al.553 have shown p53 to be upregulated, together with dysregulated cell cycle control. It has been suggested that a mutant clone of epidermal cells expands peripherally, seen histologically as the cornoid lamella. The development of abnormal clones is certainly genetically predisposed but additional factors seem to be important for the clinical manifestations of porokeratoses. Immunosuppression is a well-documented predisposing factor in disseminated porokeratosis. In several cases the course of porokeratosis paralleled the degree of immunosuppression. Immunosuppression seems to reduce the capability of immunosurveillance and facilitates expansion of abnormal keratinocytic clones with possible malignant degeneration. Also, loss of

PATHOPHYSIOLOGY AND HISTOGENESIS The pathogenesis of porokeratosis is still unclear.552 Genetic factors are invariably involved in all forms of porokeratosis. In addition, ultraviolet light has at least an impact in disseminated superficial actinic porokeratosis. Remarkably, electron beam radiation seems to be another triggering factor. Trauma such as burning or application of needles for hemodialysis has been

551. Flanagan N, Boyadjiev SA, Harper J, et al. Familial craniosynostosis, anal anomalies, and porokeratosis: CAP syndrome. J Med Genet. 1998;35: 763–766. 552. Kanitakis J, Euvrard S, Fawe M, et al. Porokeratosis and immunosuppression. Eur J Dermatol. 1998;8:459–465.

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553. Nelson C, Cowper S, Morgan M. p53, mdm-2, and p21 waf-1 in the porokeratoses. Am J Dermatopathol. 1999;21:420–425.

Ichthyosis and disorders of other cornification

THERAPEUTICS AND PROGNOSIS Treatment of porokeratosis is usually unsatisfactory. Surgical excision has been performed in small lesions. Electrocautery, liquid nitrogen, keratolytics, 5-fluorouracil, and intralesional steroids have been tried with variable results. Topical and systemic retinoids, dermabrasion, CO2-laser, photodynamic therapy or Grenz rays have produced satisfactory results but rapid recurrence may occur.546,556–558 The course is chronic and recurrences have been observed.559

POROKERATOSIS

HLA-DR antigen expression by epidermal Langerhans cells in disseminated superficial porokeratosis has been found and may be associated with clonal expansion of abnormal lesional keratinocytes.554 Of the various forms of porokeratosis, the linear type is particularly susceptible to malignant degeneration,540 suggesting that the allelic loss giving rise to linear porokeratosis may represent an initial step in the development of cancer. Biopsy sections show a parakeratotic columnar keratosis known as the cornoid lamella. This is a sharply delineated area of altered keratinization. In addition, a moderate chronic inflammatory infiltrate is present in the dermis, consisting mainly of helper T cells intermingled with Langerhans cells.555

8

554. Abe M, Ishikawa O, Miyachi Y. The loss of HLA-DR antigen expression by epidermal Langerhans cell in disseminated superficial porokeratosis. Eur J Dermatol. 1997;7:303–304. 555. Jurecka W, Neumann RA, Knobler RM. Porokeratoses: immunohistochemical, light and electron microscopic evaluation. J Am Acad Dermatol. 1991;24:96–101. 556. Bhushan M, Craven NM, Beck MN, et al. Linear porokeratosis of Mibelli: successful treatment with cryotherapy. Br J Dermatol. 1999;141:389.

557. Liu HT. Treatment of lichen amyloidosis (LA) and disseminated superficial porokeratosis (DSP) with frequency-doubled Q-switched Nd: YAG laser. Dermatol Surg. 2000;26:958–962. 558. McCullough TL, Lesher JL Jr. Porokeratosis of Mibelli: rapid recurrence of a large lesion after carbon dioxide laser treatment. Pediatr Dermatol. 1994;11:267–270. 559. Adriaans B, Salisbury JR. Recurrent porokeratosis. Br J Dermatol. 1991;124: 383–386.

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DISEASES OF MUCOUS MEMBRANES AND APPENDAGEAL STRUCTURES

Mucous membrane disorders Adelaide A. Hebert DISORDERS OF THE OCULAR MUCOUS MEMBRANES

INTRODUCTION



Blepharitis is an inflammatory condition of the eyelid margins. It is most often chronic and typically begins in childhood. The most common causes are seborrheic dermatitis and infection with Staphylococcus aureus, although occasionally secondary infection with other organisms may supervene.1 Seborrheic blepharitis usually occurs in association with dermatitis of the scalp and sometimes of the skin of the face and trunk. The lid margins are erythematous and scaly with accumulation of debris at the base of the lashes. The blepharitis seems

to fluctuate in severity, depending on the extent of the dermatitis. Rarely, with severe involvement, there is an accompanying superficial marginal keratitis. This is most commonly seen in fair-skinned, red-haired children. Staphylococcal blepharitis is also characterized by erythema and scaling of the lid margins; however, tenacious firm yellow crusts are usually present as well. Removal of the crusts may disclose small ulcers along the lid margin. The contiguous skin of the lids may be eczematized, fissured, and scaly. This type of blepharitis represents a suppurative inflammatory process of the lash follicles and the glands of Zeis and Moll. When acute and severe, conjunctivitis and keratitis may be associated. Ultimately, if the infection becomes chronic and persistent, recurrent styes and chalazions, loss of lashes, and thickening of the lid margins may result. The diagnosis of blepharitis is usually made on clinical grounds. If moist exudate, crusts, or ulcers are present, a bacterial culture for identification of the organism and antibiotic sensitivities should be obtained. Seborrheic blepharitis can be controlled by mechanical removal of the scales by scrubbing the lid margins with an isotonic shampoo. A soft toothbrush or cotton-tipped applicator is most effective. Topical antifungal shampoo, cream or lotions containing selenium sulfide and zinc pyrithione have also been used with some improvement.2 This procedure should be performed daily until the blepharitis has subsided. A low-potency non-fluorinated corticosteroid (hydrocortisone) ointment can be gently massaged into the lid margin. The use of an ophthalmic preparation (Decadron ointment) will avoid burning and irritation of the conjunctivae. Other treatment options include topical calcineurin inhibitors, although use in children younger than 2 years of age is controversial.2 The crusts of staphylococcal blepharitis can be softened by compressing with tap water or saline or Burow’s solution several times daily and ophthalmic petrolatum overnight. Once softened, they should be gently removed with a cotton-tipped applicator and an antibiotic ointment (such as bacitracin or erythromycin) massaged into the lash follicles. This treatment should be continued for several weeks, as the condition tends to chronicity.

1.

2.

Disorders of the mucous membranes can occur as isolated findings or may be a reflection of a more generalized process involving the integument or the entire organism. Although lesions of the oropharynx are the most numerous and varied, certain dermatologic problems affect the ocular and anogenital mucous membranes as well. Mucous membrane lesions are grouped for organizational purposes into those that affect the ocular tissues, the anogenital area, and oropharyngeal mucous membranes. Consideration of these conditions as a cohesive group is problematic for a number of reasons. Many of these entities fall within the purview of ophthalmology, gynecology, otolaryngology, dentistry, or infectious disease and are routinely diagnosed and treated by specialists in those areas rather than by dermatologists. Most such disorders have been omitted from this chapter. Certain mucous membrane lesions are a transient or insignificant feature of a more generalized process that also involves the skin; many of these lesions are discussed elsewhere in this book.

DISORDERS OF THE OCULAR MUCOUS MEMBRANES ANATOMY (See Fig. 9.1.) BLEPHARITIS

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Nelson LB. Pediatric ophthalmology. Philadelphia: WB Saunders; 1984.

Peralejo B, Beltrani V, Bielory L. Dermatologic and allergic conditions of the eyelid. Immunol Allergy Clin N Am. 2008;28:137–168.

Mucous membrane disorders

Lacrimal caruncle Lateral ocular angle Tarsal fold (inferior)

Medial ocular angle Semilunar fold

Figure 9.1  Anatomy of the ocular mucous membranes.

pyrethrin, permethrin (Elimite or Acticin), crotamiton, and malathion are too irritating to be used near the eye. Appropriate pediculocidal therapy has to be employed concomitantly for other affected sites. Known human contacts should be examined and treated if evidence of infestation is found. General measures for environmental control must also be instituted.

CONJUNCTIVITIS Inflammation of the ocular mucous membranes is a common affliction of children and most often represents an infectious process. Although usually a relatively banal rather than a serious problem, certain types of conjunctivitis have the potential to cause significant sequelae. The various types of conjunctivitis are best considered on an age-related basis. DISORDERS OF THE OCULAR MUCOUS MEMBRANES

Orbitopalpebral sulcus (superior) (tarsal fold)

9

Conjunctivitis in the infant Chemical conjunctivitis

PEDICULOSIS OF THE EYELASHES (PHTHIRIASIS PALPEBRARUM) Infestation of the lashes with lice is usually caused by the pubic louse (Pthirus pubis), although in instances of florid scalp involvement, the head louse may populate the eyelashes as well.3 Signs and symptoms range from simple pruritus of the lid margins to blepharitis with inflammation of the conjunctivae and preauricular lymphadenopathy. Maculae ceruleae and marginal keratitis have been noted in rare instances.3 Examination of the lids will disclose small gray or black concretions (nits) attached to the lashes. Reddish-brown granular material (feces) may also be deposited at the base of the lashes. A hand magnifying lens and small tweezers are helpful for discerning nits and capturing live lice for identification. Discovery of pediculosis of the lashes should prompt a thorough examination of the scalp for head lice and nits. In the adolescent patient, examination of pubic, axillary, and body hair is also mandatory. Identification of public lice in the lashes of prepubertal children raises the possibility of sexual abuse,4 should be further investigated, and not be lightly dismissed as acquisition by innocent contact with an infested relative.5 Treatment consists of eradication of lice and nits by thickly coating the lid margins and lashes with petrolatum four times daily for several days.6 Probably, the lice suffocate. Physostigmine 0.25 (Eserine) ointment can be used as an alternative agent but must be continued for 14 days to span the entire life cycle of the louse, as it is not effective against nits.3 Although this drug is a cholinesterase inhibitor, side effects are apparently few. Fluorescein eye drops 20% are also reported to have a toxic effect on lice if applied to the lids and lashes,7 but staining of the skin is an annoying problem. Yellow oxide of mercury and ammoniated mercury ointments are outmoded therapies, and lindane,

3. 4. 5.

Couch JM, Green WR, Hirst LW, et al. Diagnosis and treating Phthirus pubis palpebrum. Surv Ophthalmol. 1982;26:219. Scott MJ, Esterly NB. Eyelash infestation by Phthirus pubis as a manifestation of child abuse, letter. Pediatr Dermatol. 1983;1:179. Alexander JO. Phthirus pubis infestation of the eyelashes. JAMA. 1983;250: 32.

This type of conjunctivitis is the result of prophylaxis used to prevent gonococcal infection (ophthalmia neonatorum) in the newborn. The most widely employed preparation, in use since its introduction by Credé in 1881, is 1% silver nitrate solution instilled into the conjunctival sac immediately after birth. The resultant mild conjunctivitis, which usually persists for 24–36 h, occurs in up to 100% of newborns so treated.1,8 Antibiotics, including erythromycin or tetracycline ophthalmic ointment, may be used as a substitute for silver nitrate. Silver nitrate produces its effect both via its antibacterial activity and by irritation of the conjunctiva, resulting in an influx of neutrophils that directly cause death of the organisms. Saline washes should not be used, because precipitation of the silver by chloride ions reduces the germicidal activity.8 This type of prophylaxis is ineffective against chlamydial or viral infections.3 Chemical conjunctivitis from silver nitrate requires no treatment. The rare occurrence of corneal damage due to accidental application of a more concentrated silver nitrate solution is the only deterrent. The topical application of any one of these agents is not useful in treating established gonococcal infections in the neonate, but the smaller inoculum of organisms received during birth is felt to be eliminated.

Bacterial conjunctivitis This type of conjunctivitis, in contrast to chemical conjunctivitis, occurs after the third day of life and is most often due to infection from staphylococci, streptococci, or pneumococci, although Gram-negative organisms occasionally are implicated. The lids are edematous, with chemosis and a purulent discharge. A Gram stain of the pus will usually disclose the etiologic agent, which can also be identified by culture. Although bacterial conjunctivitis in the newborn is self-limited, local instillation of antibiotics (erythromycin for Gram-positive

6. 7. 8.

Rasmussen JE. Pediculosis and the pediatrician. Pediatr Dermatol. 1984;2:74. Matthew M, DiSouza P, Mehta DK. A new treatment of phthirus palpebrum. Ann Ophthalmol. 1982;14:439. Moore RA, Schmitt BD. Conjunctivitis in children. Clin Pediatr. 1979;18:26.

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organisms, gentamicin for Gram-negative organisms) will hasten resolution. When staphylococci are isolated as the causative agent, culture and sensitivity studies are helpful to identify erythromycin-resistant strains.

Gonococcal conjunctivitis

DISORDERS OF THE OCULAR MUCOUS MEMBRANES

This organism causes the most destructive type of conjunctivitis and can be transmitted during delivery or afterwards, via the hands of the individuals caring for the infant. Gonococcal infection presents after a 1- to 3-day incubation period as an acute mucopurulent infection with lid edema, chemosis, and copious drainage, at times discolored by hemorrhage. Corneal ulceration and perforation may ensue. Systemic involvement may also complicate the course. Gram-stained smears of pus demonstrating the intracellular Gram-negative diplococci are diagnostic. If the gonococcal infection is localized, ceftriaxone 25–50 mg/kg per day should be given intravenously or intramuscularly once daily. Alternatively, cefotaxime, 25 mg/kg per day, intravenously or intramuscularly, may be given in either two or three daily doses depending on the age of the infant. The duration of therapy is 7 days. Ceftriaxone should not be given to hyperbilirubinemic infants, especially premature infants, as this drug is reversibly bound to plasma proteins and can displace bilirubin from serum albumin. Aqueous crystalline penicillin G, in a dosage of 100 000 units/ kg per day in divided doses intravenously (IV) every 12 h and every 6 h thereafter for 7 days, is recommended if the gonococcal isolate is proven susceptible to penicillin. A local antibiotic such as tetracycline, chloramphenicol, or sulfonamide is also advisable until the infection is controlled. (In many European countries, even the use of chloramphenicol in an ointment is banned.)

Chlamydial conjunctivitis Also known as trachoma inclusion conjunctivitis (TRIC), this type of conjunctivitis has become quite common in the newborn, since approximately 13% of pregnant women shed chlamydia from the cervix during the third trimester.9 Onset is usually 5–15 days postpartum. The infection is typically mild and evidenced by erythema, chemosis, lid edema, and a mucopurulent exudate. The conjunctivitis is more typically a papillary palpebral one rather than a bulbar type. A Giemsa stain of conjunctival scrapings will demonstrate basophilic intracytoplasmic inclusions in the epithelial cells. Topical prophylaxis is ineffective and prompt culture of the organism is recommended. Treatment consists of oral erythromycin syrup: 50 mg/kg body weight per day in four divided doses for 14 days. If inclusion conjunctivitis recurs after this treatment, erythromycin should be reinstituted for an additional 7–14 days.10 Conjunctival scarring and pannus formation can complicate the course and mandate precise diagnosis and early treatment.8 Concomitant infection involving the respiratory tract may occur, requiring systemic therapy with erythromycin.

9.

Chandler JW, Alexander ER, Pheiffer TA, et al. Ophthalmia neonatorum associated with maternal chlamydial infections. Trans Am Acad Ophthalmol Otolaryngol. 1977;83:302. 10. Schachter J, Sweet RL, Grossman M, et al. Experience with the routine use of erythromycin for chlamydial infections in pregnancy. N Engl J Med. 1986;314:276.

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Conjunctivitis in the child Viral conjunctivitis The most common type of conjunctivitis in children is viral in origin and usually occurs in association with a respiratory infection. Erythema, edema, and a watery discharge, as well as preauricular lymphadenopathy, are characteristic. Most commonly adenovirus, echovirus type 11, and coxsackievirus B2 are the responsible agents.8 Rubella is no longer considered a common cause of childhood conjunctivitis. Saline compresses are all that is required; antibiotics are to be avoided. TRIC is the exception to this rule and should be treated vigorously with topical sulfonamide or tetracycline. Unlike in the newborn, TRIC in the older child is characterized by marked follicular hypertrophy of the lower eyelids.

Bacterial conjunctivitis Severe inflammation with lid edema and purulent discharge is highly suggestive of bacterial infection, although a milder presentation can occur. The most common causative agents are S. aureus, Haemophilus spp., and Pneumococcus. A Gram stain or culture of the exudate will confirm the diagnosis and identify the etiologic agent. Treatment should consist of gentle cleansing and removal of exudates with saline solution and the use of a broad-spectrum topical antibiotic for up to 1 week. This is effective in most cases of bacterial conjunctivitis because of the extremely high antibiotic concentrations that can be achieved at the ocular surface. Most cases of bacterial conjunctivitis will respond to these ophthalmic preparations even when in vitro tests indicate bacterial resistance. Sodium sulfacetamide drops, bacitracin, chlortetracycline, and erythromycin ointments used four times a day are effective. Alternative combination products such as trimethoprim-polymyxin B eye drops, bacitracin-polymyxin B ointment, or gramicidin-neomycin-polymyxin B eye drops can be prescribed. Drops should be instilled in the eyes every two hours initially if the infection is severe. The interval can be extended to every four hours while the patient is awake when the infection is under better control. Ointments may be more useful in younger patients because tearing may rapidly wash away eye drop solutions. Any ointment preparation should be instilled at bedtime as interference with vision is not a contraindication at that time. Conjunctivitis is a constant symptom of Kawasaki’s disease, which is characterized by fever of over 5 days, lymph node enlargement, changes of the oral mucosa, erythema multiformelike skin alterations, palm and sole lesions, and frequent coronary complications.11

Foreign body Conjunctivitis, particularly when unilateral, may be a manifestation of a foreign body in the eye. Referral to an ophthalmologist

11. Blorn US, Zeller B, Perminow KV, Fjærli H-O. Kawasaki’s syndrome. Tidsskr Nor Lægeforen. 2000;120:3540–3543.

Mucous membrane disorders

Allergic conjunctivitis Allergic conjunctivitis is usually seen in the setting of other allergic conditions such as allergic rhinitis. It is characterized by watery discharge, conjunctival injection, itching, tearing, swelling of the lids, and chemosis. Smears of the discharge from the conjunctival sac will demonstrate numerous eosinophils. Treatment consists of elimination of the allergen, if possible, as well as cool compresses, oral antihistamines, and a topical corticosteroid.1

Vernal conjunctivitis Vernal conjunctivitis is a recurrent form of allergic conjunctivitis that is more common in children, particularly in boys, and occurs mainly in spring and summer. A family history of atopic disorders is usual. Salient features are itching, tearing, photophobia, a thick ropy discharge, cobblestone papillae observed most easily on the inner aspect of the upper lid, and conjunctival nodules at the corneal limbus. Topical vasoconstrictors and corticosteroids are the treatment of choice.1,8 Topical cromolyn sodium and lodoxamine 0.1%, have also been used with reasonable success in palliating symptoms.1

OCULAR HERPES SIMPLEX INFECTION Herpes simplex virus (HSV) infection in infants and children may involve the eyelid and ocular tissues rather than the mouth and is almost always due to HSV type 1 (HSV-1). When it develops on the lid or lid margin, the eruption resembles herpes infection elsewhere on the skin and consists of grouped vesicopustules on an erythematous base, usually in a unilateral distribution. These lesions erode, crust, and, if uncomplicated, heal within 7–10 days without scarring.1 Primary ocular HSV infection may also present as an acute follicular conjunctivitis or keratoconjunctivitis with or without lid involvement. Accompanying systemic manifestations include rhinitis, pharyngitis, fever, malaise, and irritability. Ipsilateral preauricular adenitis is found in more than one-half of cases.12 Ocular infection is most often unilateral but may become bilateral after a unilateral onset. These infections can last for up to 5 weeks and, in a small percentage of cases, may persist as a chronic blepharoconjunctivitis. Ocular and periocular involvement can develop in patients with atopic dermatitis who become infected with HSV (eczema herpeticum). Patients with ocular HSV infection most commonly complain of erythema, tearing, itching, irritation, and lid swelling. Pain, photophobia, and blurred vision occur less often. In addition to the characteristic cutaneous lesions, common signs of HSV

12. Darougar S, Wishart MS, Viswalingam ND. Epidermiological and clinical features of primary herpes simplex virus ocular infection. Br J Ophthalmol. 1985;69:2. 13. Dawson CR. Ocular herpes simplex virus infections. Clin Dermatol. 1984;2:56. 14. Sudesh S, Laibson PR. The impact of the herpetic eye disease studies on the management of herpes simplex virus ocular infections. Curr Opin Ophthalmol. 1999;10:230–233. 15. Panda A, Das GK, Khokhar S, et al. Efficacy of four antiviral agents in the treatment of uncomplicated herpetic keratitis. Can J Ophthalmol. 1995;30:256–258.

infection include hyperemia and edema of the conjunctivae, follicular hypertrophy (mainly on the conjunctiva of the lower lid) and, rarely, punctate keratitis, erosions, dendritic ulcers, or stromal keratitis.12 Because corneal involvement is unusual in a primary childhood HSV infection, the course is generally benign. However, recurrent ocular HSV infection is more often associated with corneal involvement and severe stromal reactions, resulting in scarring and visual loss. Untreated infection can lead to herpes simplex keratitis, regarded as the leading cause of infectious blindness in the USA.2 About 26% of children with primary ocular HSV infection develop a recurrence within 2 years of the initial episode. Almost 50% of those with a history of more than one attack will have three or more recurrences within 2 years.1,12 Any child with suspected HSV infection of the eye should have an immediate ophthalmologic consultation. Corneal evaluation by slit lamp or biomicroscopy is critical for optimal care.1,13 Mild infections are usually treated with topical antiviral agents, such as trifluridine and acyclovir applied 2–4 times daily.14,15 However, too long an application of trifluridine has to be avoided.16 Complicated and severe infections may require de­ bridement and corticosteroid therapy, particularly for stromal keratitis and iridocyclitis. Serious side-effects and permanent ocular damage may result from injudicious use of corticosteroids in patients with HSV infection of the eye. In such a setting, steroids should be prescribed only by an ophthalmologist, with careful frequent evaluation of the patient for the development of increased ocular pressure, cataracts, and deterioration of stromal keratitis or iritis.17 Newborn infants can also develop ocular HSV infection in association with widespread systemic disease or as a limited infection. Typical cutaneous lesions may develop on the lids; however, corneal involvement may also occur as a primary infection. Recurrent corneal HSV infection may follow. In contrast to older infants and children, neonatal infections are most often contracted during delivery and are therefore due to HSV-2.18

DISORDERS OF THE OCULAR MUCOUS MEMBRANES

is indicated for corneal examination, removal of the material, and appropriate therapy.

9

OCULAR VARICELLA-ZOSTER VIRUS INFECTION Although ocular herpes zoster (HZ) is a well-known entity, eye involvement in varicella is rarely discussed, probably because of its relatively infrequent occurrence as compared with zoster ophthalmicus. In one series of 125 unselected patients with chickenpox, the incidence of ocular lesions was found to be 4%.19 Common complaints among a group of children referred for ocular involvement included photophobia, redness, soreness, tearing, and lid swelling.19,20 Physical findings included typical vesicles on the lid margins, conjunctival perilimbal vesicles, palpebral conjunctivitis with prominent follicles, anterior uveitis, and punctate keratitis without frank dendrites that healed

16. Maudgal PC, Van Damme B, Missotten L. Corneal epithelial dysplasia after trifluridine use. Graefes Arch Clin Exp Ophthalmol. 1983;220:6–12. 17. Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic eye disease study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994;101:1883–1895. 18. Nahmias AJ, Visitine AM, Caldwell DR, et al. Eye infections with herpes simplex virus in neonates. Surv Ophthalmol. 1976;21:100. 19. Jordan DR, Noel L-P, Clarke WN. Ocular involvement in varicella. Clin Pediatr. 1984;23:434. 20. de Freitas D, Sato EH, Kelly LD, et al. Delayed onset of varicella keratitis. Cornea. 1992;11:471–474.

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External urethral orifice

Clitoris Frenulum of clitoris Urethral meatus Fossa navicularis Fourchette

Prepuce of clitoris

Corona glandis

Glans penis

Pubis Frenulum praeputii

Labium minus

Raphe

Vestibule Labium majus Vagina Perineum Raphe

Scrotum

Anus

DISORDERS OF THE GENITAL MUCOUS MEMBRANES

Anus

Figure 9.2  Anatomy of the female genitalia. Figure 9.3  Anatomy of the male genitalia.

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without scarring. Complications of ocular varicella noted in the literature include dendritic keratitis, retinopathy, optic neuritis, ophthalmoplegia, oculomotor palsy, cataracts, lacrimal canaliculi obstruction, and optic disk pigmentation.19,21 Although HZ occurs less frequently in children than in adults, a comparable percentage of children have involvement of the trigeminal nerve,22 if one excludes the elderly. Ocular HZ most frequently affects the supraorbital or supratrochlear divisions of the frontal nerve; however, involvement of the nasociliary branch of the ophthalmic nerve has the most significant consequences. Hutchinson’s sign, vesicles on the tip of the nose, are an indication of this localization. All the ocular tissues may be involved in HZ ophthalmicus. Vesicles on the lid may cause ulceration, scarring, hyperpigmentation, trichiasis, permanent anesthesia, lid retraction, and chronic corneal exposure. The conjunctivae may become hyperemic and chemotic, with the occasional appearance of distinct vesicles. Scleritis, punctate uveitis with vesicles and pseudodendrites, serpiginous ulcerations, and severe stromal inflammation may also occur. Uveitis is reflected by photophobia, intense pain, a ciliary flush, pupillary constriction, corneal haziness, and anterior and posterior synechiae. A number of ischemic complications may also occur; however, these problems are relatively rare in children. Children with ocular HZ should have an immediate, thorough assessment by an ophthalmologist, who should also dictate management. Medications frequently used in the management of ocular herpes zoster include cycloplegics, topical corticosteroids, and, occasionally, systemic corticosteroids. Antiviral agents have to be given very early, if at all. Age, immunocompetence,

and general health of the patient must be taken into consideration when formulating individual treatment plans.

Because pruritus vulvae is a symptom and not a disease, the etiology reflects the incidence of disorders characterized by itching in the various age groups. In infants and young children, pruritus of the vulval area is most often due to atopic dermatitis, irritant contact dermatitis, allergic contact dermatitis, candi­ diasis, scabies, and pinworm infestation. In older children, in addition to these conditions, lichen sclerosus, psoriasis, ichthyosis, group A β-hemolytic streptococcal infection, and pubic lice may cause pruritus. Vulval itching at any age can result from poor hygiene as well as a bacterial, candidal, trichomonal, or nonspecific vaginitis associated with discharge. Bubble bath dermatitis with Pseudomonas aeruginosa superinfection is also a common cause of vulval itching in young girls. However, a specific cause for pruritus vulvae is often not found.24

21. Liesegang TJ. The varicella-zoster virus: systemic and ocular features. J Am Acad Dermatol. 1984;11:165. 22. Rogers RS III, Tindall JP. Herpes zoster in children. Arch Dermatol. 1972;106:204.

23. McCann J, Wells R, Simon J, et al. Genital findings in prepubertal girls selected for nonabuse: a descriptive study. Pediatrics. 1990;86:428. 24. Paek SC, Merritt DF, Mallory SB. Pruritus vulvae in prepubertal children. J Am Acad Dermatol. 2001;44:795–802.

DISORDERS OF THE GENITAL MUCOUS MEMBRANES Sexually transmitted diseases and infectious vaginitis are discussed in Chapter 28.

ANATOMY Additional information on this topic.23 (See also Figs 9.2, 9.3.)

PRURITUS VULVAE

Mucous membrane disorders

PINWORM INFESTATION (ENTEROBIUS VERMICULARIS) Pinworm infestation is the most common of all the helminth infections and occurs primarily in children. An estimated 20– 30% of children are infested with this parasite.25 Affected children usually experience intense perirectal and vulval itching due to migration of the adult worms over the perineal skin. Because the peak activity of the parasite occurs at night, pruritus often awakens the child and causes nocturnal irritability and restlessness. Occasionally, the infestation is reflected by a perianal or vulval eczematous dermatitis, excoriations, or vaginal discharge and inflammation resulting from migration of the worms into the vagina. Pinworm infestation is acquired by ingestion of eggs transmitted by fomites or via the fingers from the perianal skin or occasionally by inhalation of eggs from the environment. Ingested eggs hatch in the host’s duodenum, and the larvae mature during their passage through the small intestines. Sexually mature worms copulate in the cecum, following which they migrate to the perianal skin, where the gravid female deposits large numbers of eggs. The eggs become infectious 4–6 h after deposition on the perianal skin; if the eggs are then swallowed by a human host, the cycle begins again.25 The entire life cycle of Enterobius vermicularis from ingestion of eggs to maturation of the worms and deposition of fresh eggs takes 4–6 weeks. The child remains well except for the accompanying pruritus and occasional dermatitis. Although mild peripheral eosinophilia has been rarely reported, this hematologic finding should not be attributed to pinworm infection. Likewise, the suggestion that pinworms can cause enuresis, weight loss, and abdominal pain is based on anecdotal information and is regarded as doubtful by most authorities.25

25. Hoeprich PD. Infectious diseases. 3rd ed. Philadelphia: Harper & Row; 1983. 26. Sirivichayakul C, Pojjaroen-anant C, Wisetsing P, et al. Prevalence of enterobiasis and its incidence after blanket chemotherapy in a male orphanage. Southeast Asian J Trop Med Public Health. 2000;31:144–146. 27. Clark JA, Muller SA. Lichen sclerosus et atrophicus in children. A report of 24 cases. Arch Dermatol. 1967;95:476. 28. Powell J, Wojnarowska F, Winsey S, et al. Lichen sclerosus premenarche: autoimmunity and immunogenetics. Br J Dermatol. 2000;142:481–484.

The diagnosis of pinworm infection should be suspected in any child with either perirectal or vulval pruritus, or both, and dermatitis. At times the adult worms can be observed on the perineum at night when the distressed child awakens. The diagnosis is most easily made by brief application of a strip of transparent adhesive tape to the perirectal skin and microscopic examination of the tape with low-power objective. Enterobius vermicularis eggs are easily identified as thick-walled ovoid structures adherent to the tape. This test is most productive if performed in the early morning before the freshly deposited eggs are dispersed. Accepted therapy includes pyrantel pamoate in a single dose of 11 mg/kg (not to exceed 1 g) or mebendazole, 100 mg in a single dose. Simultaneous treatment of all household members is recommended. Retreatment in 2–3 weeks is indicated to kill any adult worms that have developed from eggs swallowed at the time of initial therapy because neither drug is effective against ova. Massive laundering of clothing, bed clothes, and other heroic measures are not required and are generally ineffective. Parents should be made aware of the ubiquity of this parasite and of the likelihood of reinfection, particularly by preschool children.26 A non-fluorinated topical corticosteroid can be applied for a few days to clear the dermatitis, if that is necessary.

DISORDERS OF THE GENITAL MUCOUS MEMBRANES

The clinical findings range from little change to florid dermatitis. The most important aspect of the visit will often be to obtain a thorough history, which should include all skin-care products and laundry products used, types of underclothing worn, presence of discharge, or nocturnal itching. Lack of cleanliness and poor technique in younger girls who begin independent hygiene as well as overuse of soaps, feminine hygiene products, lubricants, self-prescribed antibiotics or antifungal agents, and contraceptive agents can contribute to or cause pruritus vulvae. Potassium hydroxide (KOH) preparations; cultures for bacteria and fungi; mineral oil scrapings for scabies mites, eggs, and feces; a hand lens examination for pubic lice; and a tape test for pinworm ova may be indicated, depending on the physical findings, the age of the patient, and the historic information provided. Therapy will depend on the cause of the problem as determined by the history, examination, and appropriate laboratory procedures.

9

LICHEN SCLEROSUS This is known as lichen sclerosus (LS) in girls and balanitis xerotica obliterans and posthitis xerotica obliterans in boys. Although generally regarded as a disease of adulthood, 10–15% of persons with LS have onset before the age of 13 years. There is a strong female predominance in all age groups. Some 75% of children with LS have involvement of the anogenital area and, in most, the disease is confined to those sites.27 There is a strong association of infantile LS with HLADQ7, pointing at a higher risk of developing other autoimmune diseases.28 Anogenital lesions in girls can be asymptomatic or may be associated with irritation, itching, burning, vaginal discharge, pain on urination, and minor bleeding. GI symptoms associated with LS include constipation, fissures, bleeding with bowel movements, soiling and fecal impaction.29 Cutaneous changes consist of ivory-colored, flattened papules that coalesce into plaques of various sizes, most commonly producing a figure-ofeight or hourglass configuration around the vagina and anus (Fig. 9.4). The skin may feel indurated or become shiny, wrinkled, and parchment-like; occasionally serous or hemorrhagic bullae, erosions, and fissures develop. The differential diagnosis includes mainly vitiligo and leukoderma but also non-specific vulvitis, vulvitis circumscripta plasmacellularis and perianal dermatitis.30 The hemorrhagic friable surface of the affected skin is sometimes mistaken for child abuse. Genital LS is considered relatively rare in males, and particularly so in boys.31 Skin lesions are confined to the glans penis

29. Maronn ML, Esterly NB. Constipation as a feature of anogenital lichen sclerosus in children. Pediatrics. 2005;115:e230–e232. 30. Albers SE, Taylor G, Huyer D, et al. Vulvitis circumscripta plasmacellularis mimicking child abuse. J Am Acad Dermatol. 2000;42:1078–1080. 31. Mikat DM, Ackerman HR Jr, Mikat KW. Balanitis xerotica obliterans report of a case on an 11-year-old and review of the literature. Pediatrics. 1973;52:25.

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DISORDERS OF THE GENITAL MUCOUS MEMBRANES

At times, a fluorinated preparation may be required, but the least potent effective preparation should always be prescribed. Although there is some concern about carcinogenicity of calcineurin inhibitors, topical tacrolimus and pimecrolimus have been used quite successfully with no danger of atrophy or striae.37,38,38a There is literature supporting the use of topical estrogen, progesterone and testosterone for LS but these are usually not appropriate for the pediatric population. Studies demonstrating decreased serum levels of dihydrotestosterone and androstenedione in women with LS lend credence to the postulate that decreased 5α-reductase activity in the tissues may contribute to the development of LS. Increased levels of androgens coincident with puberty may induce 5α-reductase activity in the vulval skin, thereby accounting for resolution of the dermatosis around the time of menarche.39 Although topical corticosteroids and testosterone propionate have been used successfully in affected males, treatment is usually by circumcision. If meatal stenosis is present, meatotomy or meatoplasty may be required.40 Figure 9.4  Lichen sclerosus involving the vulvar and perianal skin. Note the hemorrhagic areas.

(balanitis xerotica obliterans) and prepuce (posthitis xerotica obliterans), sparing the scrotal and perianal skin. The prepuce becomes non-retractable due to a sclerotic ring at the tip of the foreskin, and petechiae may be evident.32 Less commonly, involvement of the urethral meatus leads to stenosis, dysuria, reduction of the urinary stream, and, potentially, obstructive uropathy. It has been suggested, on the basis of histologic evaluation of foreskins removed because of scarring phimosis, that LS occurs much more frequently in prepubertal males than has been generally appreciated.33,33a Circumcision has been found to have a preventive effect.34 Therapy for genital LS in prepubertal girls is required only if the patient is symptomatic.35 The disease is usually self-limited involuting spontaneously around the time of menarche in approximately two-thirds of patients. There is little residual skin change. Vulvar LS in prepubertal children does not predispose to neoplasia and is not an indication for surgical intervention. Reconstructive surgery for severe sequelae is rarely needed.36 Topical steroids remain the most commonly used agents to treat childhood LS and will often suffice to alleviate discomfort.

32. Barton PG, Foyd MJ, Beers BB. Penile purpura as a manifestation of lichen sclerosus et atrophicus. Pediatr Dermatol. 1993;10:129. 33. Chalmers RJG, Beuton PA, Bennett RF, et al. Lichen sclerosus et atrophicus. A common and distinctive cause of phimosis in boys. Arch Dermatol. 1984;120:1025. 33a. Kiss A, Király L, Kutasy B, et al. High incidence of balanitis xerotica obliterans in boys with phimosis: prospective 10-year study. Pediatr Dermatol. 2005;22:305–308. 34. Mallon E, Hawkins D, Dinneen M, et al. Circumcision and genital dermatoses. Arch Dermatol. 2000;136:350–354. 35. Serrano G, Millan F, Fortea J, et al. Topical progesterone as treatment of choice in lichen sclerosus et atrophicus in children. Pediatr Dermatol. 1993;10:201. 36. Breech LL, Laufer MR. Surgicel in the management of labial and clitoral hood adhesions in adolescents with lichen sclerosus. J Pediatr Adolesc Gynecol. 2000;13:21–22.

650

GENITAL HERPES SIMPLEX This is usually due to sexual abuse, both in girls and in boys. It presents as a primary herpetic infection with fever, malaise, regional tender lymphadenopathy as well as marked genital edema and disseminated clear vesicles rapidly turning yellow and breaking down to small ulcerations. Healing takes 2–3 weeks. Recurrences occur earlier and more frequently in HSV-2 than in HSV-1 infections. Treatment with systemic acyclovir, famciclovir or valacyclovir should be instituted as soon as possible.41

NON-SEXUALLY RELATED ACUTE GENITAL ULCERS IN PUBERTAL GIRLS This recently reported entity termed acute genital ulcers (AGU) is characterized by painful vulvar ulcers which are either unilateral or bilateral. Affected individuals may have prodromic tonsillitis and concurrent Epstein–Barr virus infections. The majority of the patients described with this condition ranged from ages 11–19 years and denied sexual activity. Studies for sexually transmitted diseases, including herpes simplex, were negative. This form of acute genital ulceration may be the result of a reactional non-specific inflammatory process. Some authors have suggested that AGU is a form of primary genital aphthosis.42

37. Ebert AK, Rösch WH, Vogt T. Safety and tolerability of adjuvant topical tacrolimus treatment in boys with lichen sclerosus: a prospective phase 2 study. Eur Urol. 2008;54(4):932–937. 38. Boms S, Gambichler T, Freitag M, Altmeyer P, Kreuter A Pimecrolimus 1% cream for anogenital lichen sclerosus in childhood. BMC Dermatol. 2004;4(1):14. 38a. Hengge UK, Krause W, Hoffman H, et al. Multicentre phase II trial on the safety and efficacy of topical tacrolimus ointment for the treatment of lichen sclerosus. Br J Dermatol. 2006;155:1021–1028. 39. Friedrich EG Jr, Kalra PS. Serum levels of sex hormones in vulvar lichen sclerosus and the effect of topical testosterone. N Engl J Med. 1984;310:488. 40. Khezri AA, Dovnis A, Dunn M. Balanitis xerotica obliterans. Br J Urol. 1979;51:229. 41. Leung DT, Sacks SL. Current recommendations for the treatment of genital herpes. Drugs. 2000;60:1329–1352. 42. Farhi D, Wendling J, Molinari E, et al. Non-sexually related acute genital ulcers in 13 pubertal girls: a clinical and microbiological study. Arch Dermatol. 2009;145(1):38–45.

Mucous membrane disorders

MUCOUS MEMBRANE ANATOMY Fundamental to the understanding of mucous membrane disorders is the prior understanding of the anatomic and functional relationships of these tissues (Fig. 9.5). A knowledge of which oral mucosal tissues are keratinized and which are nonkeratinized assists in understanding the function of these tissues (Box 9.1), and in the assessment and distinction of herpetic and aphthous lesions. The anatomic illustration shown in Figure 9.5 will enhance the subsequent understanding of pathologic processes involving these same oral mucosal tissues.

DENTAL ANATOMY Figure 9.6 illustrates the mature maxillary dental arch and bones of the hard palate. Table 9.1 provides the normal chronology of human dentition and Table 9.2 lists syndromes in which natal teeth occur.

ORAL HYGIENE INSTRUCTIONS FOR CHILDREN Oral hygiene instructions given to parents of infants and young children must be specifically tailored to the individual child. Although there are some general recommendations for cleaning their teeth, the age of the child, their manual dexterity, which is also somewhat dependent on the age, and the emotional and physical stature are significant factors in determining the best mechanism to provide oral hygiene effectively. The goal of oral hygiene is to remove plaque from the surfaces of the teeth and subgingival areas. Plaque adheres to the enamel

BOX 9.1 THE FUNCTION AND KERATINIZATION OF THE ORAL MUCOUS MEMBRANES Lining mucosa (non-keratinized/not attached)

>> Soft palate >> Buccal and labial mucosa >> Sulcular epithelium >> Ventrum of tongue >> Alveolar mucosae Masticatory mucosa (orthokeratinized/attached to underlying structures)

>> Hard palate >> Gingivae – Free marginal gingiva – Attached gingivae >> Dorsum of tongue >> Lip (transitional portion/parakeratinized, skin portion and vermilion/orthokeratinized)

Specialized mucosa

>> Filiform papillae >> Fungiform papillae >> Circumvallate papillae with taste buds

surfaces via mechanisms inherent to the plaque bacteria itself. Without an adequate daily regimen, including removal of the plaque, it will accumulate continually until the point of completely covering enamel surfaces. When this occurs, it is easy for the plaque bacteria to cause significant decalcification of mineral surfaces, beneath the area where the plaque resides. Often, children who do not brush their teeth regularly exhibit large white spot areas manifesting decalcified enamel via continual exposure to active acid from plaque bacteria excretions.

Infant positioning The most effective way of positioning an infant for oral hygiene is the same manner in which the dentist examines the infant. This is referred to as the ‘knee to knee position,’ where the child’s head is placed on the lap of the individual who is to clean their teeth, and the other individual (typically the other parent) places the legs of the child around their waist. The parent holding the legs around the waist also holds the arms, so that the other parent can have easy access to the mouth. Although this technique may be offensive, and could result in a rebellious response from the child, the enforcement of this technique on a daily basis will soon yield a responsive child who will desire the attention received from cleaning the teeth.

DISORDERS OF THE ORAL MUCOUS MEMBRANES

DISORDERS OF THE ORAL MUCOUS MEMBRANES

9

Intention Cleaning the teeth is not a random event, but a very specific identifiable process. The parent must clearly identify that the bristles of the toothbrush, which must be soft, are cleaning each tooth surface adequately. For this reason, it is essential to clean each tooth surface individually before progressing to the next. Although fluoridated toothpaste can be used as a final topical therapeutic agent for infants in small amounts, it is preferable to brush the infant’s teeth without the toothpaste, so that the parent can visualize the tips of the brush cleaning the tooth surfaces. The foaming action of toothpaste often does not allow the parent to visualize the tooth surfaces effectively. Upon complete cleaning of the teeth, a small amount of fluo­ ridated toothpaste, no more than the size of a pea, can be placed on the tooth surfaces to provide a therapeutic effect of fluoride.

School-age children School-age children can begin to brush their teeth themselves with good confidence and control. Although they may not have complete dexterity to brush all tooth surfaces, and will most likely require the assistance of the parent, they should be encouraged to thoroughly clean their teeth on their own with the approval and support of the parent. It is also a good age to begin teaching dental flossing to the child, so that they can provide the daily removal of plaque from the interproximal surfaces of the teeth, particularly the posterior teeth. Children at this age who gain confidence in their ability to clean their teeth will most likely continue to do so on their own. In school-age children, fluoride supplements may be given not only as adjunctive therapy to replace a fluoride deficiency that might exist in the water supply, but also as a topical agent to aid in the prevention of dental caries, which might be a particular problem for an 651

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Diseases of Mucous Membranes and Appendageal Structures

Figure 9.5  Anatomy of the oral mucous membranes.

Labial frenum Philtrum Vestibule

Incisive papillae

Palatine raphe

Gingiva

Fovea palatini

Hard palate

Soft palate

Maxillary tuberoscity Uvula

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Fauces

Terminal sulcus Tongue

Circumvalate papillae Fungiform papillae Median sulcus

Quadrant

Figure 9.6  Diagram of the maxillary dental arch and the bones of the hard palate.

Cingulum Incisal edge Labial surface

Lateral incisor Central incisor Canine 1st premolar

Palatal surface

2nd premolar

Buccal surface

1st molar

Occlusal surface

Midline of dental arch

Median Raphe

Anterior teeth

3rd molar

Mesial side of 3rd molar Distal side of 3rd molar Posterior teeth

652

2nd molar

Maxillary alveolar process

Maxillary tuberoscity Hamulus Palatine bones

Mucous membrane disorders

9

TOOTH Deciduous dentition   Maxillary teeth    Central incisor    Lateral incisor    Canine    First molar    Second molar   Mandibular teeth    Central incisor    Lateral incisor    Canine    First molar    Second molar Permanent dentition   Maxillary teeth    Central incisor    Lateral incisor    Canine    First premolar    Second premolar    First molar    Second molar    Third molar   Mandibular teeth    Central incisor    Lateral incisor    Canine    First premolar    Second premolar    First molar    Second molar    Third molar

HARD TISSUE FORMATION BEGINS

CROWN COMPLETED

ERUPTION

ROOT COMPLETED

4 months in utero 4 12 months in utero 5 months in utero 5 months in utero 6 months in utero

4 months 5 months 9 months 6 months 11 months

7 12 months 9 months 18 months 14 months 24 months

112 years 2 years 3 14 years 2 12 years 3 years

4 12 months in utero 4 14 months in utero 5 months in utero 5 months in utero

3 12 months 4 months 9 months 5 12 months

6 months 7 months 16 months 12 months

112 years 112 years 3 years 2 14 years

3–4 months 10–12 months 4–5 months 112 years–13 4 years 2–2 14 years Birth 2 12 –3 years 7–9 years

4–5 years 4–5 years 6–7 years 5–6 years 6–7 years 2 12 –3 years 7–8 years 12–16 years

7–8 years 8–9 years 11–12 years 10–11 years 10–12 years 6–7 years 12–15 years 17–21 years

10 years 11 years 13–15 years 12–13 years 12–14 years 9–10 years 14–16 years 18–25 years

3–4 months 3–4 months 4–5 months 13 4 –2 years 2 14 –2 12 years Birth 2 12 –3 years 8–10 years

4–5 years 4–5 years 6–7 years 5–6 years 6–7 years 2 12 –3 years 7–8 years 12–16 years

6–7 years 7–8 years 9–20 years 10–12 years 11–12 years 6–7 years 11–13 years 17–21 years

9 years 10 years 12–14 years 12–13 years 13–14 years 9–10 years 14–15 years 18–25 years

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Table 9.1  Normal chronology of human dentition

From Woelfel JB (1990) Dental Anatomy: Its Relevance to Dentistry, 4th ed. Philadelphia: Lee & Febiger,43 with permission.

individual child because of a high caries rate. This situation often requires the recommendation of daily use of over-the-counter fluoride rinses (0.05% fluoride) or tooth gels (0.4%), stannous fluoride or a weekly dose of a prescription fluoride of 0.2%. The over-the-counter topical fluoride rinse is used daily at bedtime. The stannous fluoride gel is used each morning and evening after brushing and flossing. The gel is applied to the teeth for 1 min and then spat out. Care must be taken to avoid recommending topical fluoride treatments to children who are not old enough to expectorate.

Congenital fistulas of the lower lip usually appear as bilateral transverse pits or as symmetric nipple-like projections on the vermilion portion of the lower lip. These pits are typically 1 cm

apart and equidistant from the midline. The lower lip occasionally appears swollen, thus accentuating the pits.44 The fistulas result from failure of closure of embryologic furrows located on the fetal mandibular process at the 7.5– 12.5 mm stage. This incomplete obliteration of the labial sulcus produces pits that range in depth from a few millimeters to 25 mm. The longer fistulas end in a tiny cul-de-sac embedded in the orbicularis oris musculature and, from the opposing open end, a viscous saliva may extrude either spontaneously or during mastication.45 The close association with facial clefts makes this minimal deformity quite significant. Nearly 70–80% of persons with paramedian sinuses of the lower lip have either an associated cleft lip or cleft palate, or both (van der Woude syndrome). The trait is transmitted in an autosomal-dominant fashion with a penetrance of almost 100%, but variable expression.46,47

43. Woelfel JB. Dental anatomy: its relevance to dentistry. 4th ed. Philadelphia: Lea & Febiger; 1990:29. 44. Shafer WG, Hine MK, Levy BM. A textbook of oral pathology. 4th ed. Philadelphia: WB Saunders; 1983. 45. Goodman RM, Gorlin RJ. The malformed infant and child, an illustrated guide. New York: Oxford University Press; 1983:234.

46. Cervenka J, Gorlin RJ, Anderson VE. The syndrome of pits of the lower lip and cleft lip and/or palate. Genetic considerations. Am J Hum Genet. 1967;19:416. 47. Klausler M, Schinzel A, Gnoinski W, et al. Dominant vererbte Unterlippenfisteln und Gesichtsspalten (Van-der-Woude-Syndrom). Eine Studie an 52 Fällen. Schweiz Med Wochenschr. 1987;117:127–134.

CONGENITAL FISTULAS OF THE LOWER LIP

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Diseases of Mucous Membranes and Appendageal Structures

Table 9.2  Syndromes with natal teeth

DISORDERS OF THE ORAL MUCOUS MEMBRANES

654

SYNDROME

ASSOCIATED ANOMALIES

INHERITANCE/CHROMOSOMAL ABNORMALITY/PREVALENCE

Ellis–van Creveld (chondroectodermal dysplasia)

Bilateral postaxial polydactyly of hands, chondrodysplasia of long bones resulting in cromesolic dwarfism, ectodermal dysplasia affecting nails/teeth, congenital heart malformation

Autosomal-recessive Not known 7/1 × 106

Hallermann–Streiff

Dyscephaly, hypotrichosis, micro-ophthalmia, cataracts, beaked nose, micrognathia, proportionate short stature

Sporadic Not known 150 cases to date

Pachyonychia congenita (1: Jadassohn–Lewandowsky) (2: Jackson–Lawler)

Dystrophic nails, palmoplantar keratosis, hyperhidrosis, follicular keratosis, oral leukokeratosis, cutaneous cysts

Autosomal-dominant Keratin gene mutations: Type I: 6a/16, type 2: 6b/17 0.071/1 × 106 9 : 5 male to female

Pallister–Hall (hypothalamic hamartoblastoma)

Hypothalamic hamartoblastoma, craniofacial abnormalities, postaxial polydactyly, cardiac and renal defects

Sporadic Not known 13 cases to date 8 : 5 male to female

Weidemann–Rautenstrauch

Endocrine dysfunction, aged facies, frontal and biparietal bossing, small facial bones, sparse scalp hair, prominent scalp veins, small beaked nose, low-set ears

Autosomal-recessive Not known 1 case to date

Natal teeth, patent ductus arteriosus, intestinal pseudo-obstruction

Dilatation/hypermobility of small bowel, Short or micro-colon without obstruction, incomplete rotation of mid gut, patent ductus arteriosus

X-linked recessive Not known 2 cases to date, brothers

An affected parent transmits the gene to half of the offspring, whereas a phenotypically normal child may then transmit all or any part of the syndrome (e.g., lip pits with or without clefting) to the subsequent generation. The estimated frequency of lower-lip pits is 1 : 75 000 to 1 : 100 000 and that of cleft lip or palate is 1 : 650. No sex linkage, sex limitation, or sex influence for congenital lip fistulas is recognized, but a slight female predominance has been reported with this anomaly.48 Histologically, the labial tubular lumen is lined by a stratified squamous epithelium continuous with that of the vermilion border of the lip. The fistula tapers to a small base, where scattered acini of mucous glands with tubular ducts are present. Occasionally these glands are considerably larger than normal labial glands. Variations of these labial sulci include single pits of the lower lip, commissural or angular lip pits, and the more rarely described fistulas of the upper lip. Persons with single pits have associated cleft anomalies in roughly the same frequency as for bilateral lip pits.46 These unilateral or midline fistulas are viewed as an incomplete expression of this trait and not as a distinct entity. Commissural or angular lip pits are thought to be separate entities with a higher incidence and a different embryology. Fistulas of the upper lip are the most rare of these anomalies and have not been shown to be inherited.46

Other anomalies associated with lip-pit, cleft-lip syndrome are the van der Woude syndrome and the popliteal web syndrome.49 Van der Woude syndrome includes missing second premolars with or without lower lip pits, with or without a cleft lip. Popliteal web syndrome is composed of popliteal webs, cleft palate, and lower lip pits. Congenital lower lip fistulas seldom cause significant deformity or self-harm. Therapy is necessary only to correct the cosmetic deformity or eradicate the aberrant salivation.

48. Lopes MA, Goncalves M, Di Hipolito Junior O, et al. Congenital lower lip pits: case report and review of literature. J Clin Pediatr Dent. 1999;23:275–277. 49. Smith DW. Recognizable patterns of human malformation. 3rd ed. Philadelphia: WB Saunders; 1982. 50. Gorlin TJ. Developmental anomalies of the face and oral structures. In: Gorlin RJ, Goldman HM, eds. Thoma’s oral pathology. 6th ed. St Louis: Mosby; 1970:21–95.

51. Witkop Jr CJ, Barros L. Oral and genetic studies in Chileans, 1960. I. Oral anomalies. Am J Physiol Anthrop. 1963;21:15–24. 52. Greenfield MF, Icochea R, Hoffman C, et al. Double lip: an unusual presentation. Cutis. 2000;66:253–256. 53. Reddy KA, Roa AK. Congenital double lip: a review of seven cases. Plast Reconstr Surg. 1989;84:420–423.

DOUBLE LIP The vermilion in the newborn is divided by a shallow furrow into the anterior pars glabra and posterior pars villosa. This facilitates suckling. When this transverse furrow persists in childhood, a double lip forms. Two variants occur: a duplication at the level between the vermilion and mucosa causes the prolabial form, which is permanently visible, whereas a more orally positioned furrow causes a flaccid pouch-like mucosal duplication only visible during speech and smiling. The former is associated with a hyperplasia of the minor labial salivary glands.50 Most cases are not pronounced and the condition is therefore underdiagnosed.51 Treatment is mainly for cosmetic reasons and consists in a transverse wedge excision of the tissue excess.52,53

Mucous membrane disorders

ASCHER SYNDROME

ANGULAR CHEILITIS This condition, also referred to as perlèche, angular stomatitis, and angular cheilosis, is characterized by inflammation, ulceration, and fissuring at the corners of the mouth. Although it is most common in older persons, particularly denture wearers, angular cheilitis can be attributed to a multiplicity of factors and occurs at any age.56 Typically, angular cheilitis presents as erythema and erosions radiating from the labial commissures; edema, scaling, and deep fissures may be associated. The inflammation extends onto the contiguous skin but not onto the buccal mucosa. The involved tissue becomes macerated and crusted, which may produce localized soreness, burning sensations, and pain. A variety of problems, both local and systemic, may cause or contribute to angular cheilitis (Box 9.2). Many of these factors result in the trapping of excessive moisture at the angles of the mouth, resulting in a constantly wet environment that macerates the skin and facilitates proliferation of certain microorganisms. Persistent or nocturnal drooling associated with mouth breathing, neurologic damage, or orthodontic appliances in the mouth are major contributory factors in some infants and children. The chapping that results from chronic lip licking also predisposes to angular cheilitis in childhood. Unlike adults, poor-fitting dentures are an infrequent cause in the younger age groups.57 Likewise, loss of vertical dimension, most frequently due to absence of teeth and sagging of the facial musculature, is relatively less common in children. Contact dermatitis, both irritant dermatitis due to excessive saliva and repetitive lip-licking as well as allergic reactions to toothpaste, mouthwash, chewing gum, medications, and cos54. Navas J, Rodriquez P, Chardo A, et al. Ascher syndrome: a case study. Pediatr Dermatol. 1991;8:122. 55. Cunliffe WJ. Disorders of connective tissue. In: Rook A, Wilkinson DS, Ebling FJG, eds. Textbook of dermatology. 3rd ed. Oxford: Blackwell Scientific; 1979:1629.

BOX 9.2 FACTORS RELATED TO ANGULAR CHEILITIS Oral factors

>> Drooling, nocturnal or constant >> Orthodontic appliances – Neurologic deficits – Persistent mouth breathing – Macroglossia >> Denture stomatitis: ill-fitting unhygienic dentures >> Lateral lip fistulae >> Xerostomia Reduced vertical facial dimension

>> Sagging of cheeks due to poor tone of facial muscles >> Disturbance of occlusal plane between mandible and maxilla >> Skeletal malformations >> Anodontia, total or partial

DISORDERS OF THE ORAL MUCOUS MEMBRANES

The presence of an acquired double upper lip in association with blepharochalasis and nontoxic thyroid enlargement constitutes Ascher syndrome. An abrupt onset characterizes the changes of the lip and eyelids.44,54 Although thyroid enlargement may lag several years behind the blepharochalasis, thyroid enlargement develops in a significant number of affected persons during adolescence.55 The blepharochalasis may be progressive, with or without antecedent attacks of edema. In addition, hypertrophy of the accessory lacrimal glands may result in pseudoedema of the upper lids. As the upper lip gradually enlarges during infancy or early childhood, discrete areas of soft tissue swelling identifiable by an irregularly lobular mucosal surface become fixed and permanent. The labial enlargement is the result of both hypertrophy and fibrocystic changes within the labial or accessory salivary glands, or both. Inflammation within these glands contributes to the lip distortion.54,55 Increased salivation is associated with these gland changes. Therapy is necessary only when speech, mastication, or cosmesis becomes impaired. Surgical excision of excess tissue is then indicated.44

9

Skin disorders

>> Dermatologic conditions – Atopic dermatitis – Contact dermatitis, allergic or irritant – Seborrheic dermatitis – Psoriasis – Granulomatous cheilitis: Crohn’s disease, Melkersson– Rosenthal syndrome

– –

Halogenoderma, pemphigus (vegetans) Pachyonychia congenita

>> Infections – Candidiasis – Herpes simplex infection, viral warts – Bacterial infection: streptococci, staphylococci, secondary syphilis, syphilis connata

>> Chronic irritation or trauma General medical disorders

>> Deficiencies: Riboflavin (vitamin B2), pyridoxine (vitamin B6),

pellagra (niacinamide), maple syrup urine disease, kwashiorkor, anorexia nervosa, nephrotic syndrome, essential fatty acid deficiency, glucagonoma syndrome

>> Zinc deficiency syndromes >> Biotin deficiency syndromes >> Anemias >> Gastrointestinal disturbances >> Malnutrition, debilitation metics, is a common etiology in children. However, atopic dermatitis appears to be the most frequent cause. Other dermatologic conditions, particularly seborrheic dermatitis, psoriasis, and acrodermatitis enteropathica, can also be responsible for skin changes at the angles of the mouth. Although angular cheilitis 56. Schoenfeld RJ, Schoenfeld FI. Angular cheilitis. Cutis. 1977;19:213. 57. Konstantinidis AB, Hatziotis JH. Angular cheilosis: an analysis of 156 cases. J Oral Med. 1984;39:199.

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is commonly attributed to primary or secondary infection with Candida albicans,56 opinions vary as to the prevalence of Candida in patients with angular stomatitis.57,58 S. aureus and β-hemolytic streptococci are also commonly cultured from the involved skin.58 Systemic disorders account for a minor proportion of patients with angular cheilitis. This easily perceived skin change is a hallmark of riboflavin deficiency but has also been associated with pyridoxine, iron, zinc, biotin deficiencies, and amino acid metabolism disease. Debilitated patients with gastrointestinal (GI) diseases and malnutrition as well as chronically ill patients receiving systemic corticosteroids, antibiotics, and chemotherapeutic agents may also develop angular cheilitis.59 In those instances, it is sometimes difficult to isolate the provocative factors.56 Therapy consists of correcting underlying disorders or contributory factors, if possible. Institution of measures to ensure good dental hygiene and avoidance of allergens, irritation, and trauma are often helpful. Antifungal agents, preferably in an ointment vehicle, are indicated when C. albicans has been identified by KOH preparation or culture. Topical antibacterial ointments (such as mupirocin or bacitracin) should be employed in those patients with a bacterial etiology. Miconazole is favored by some authors because of its broad therapeutic spectrum.58,60 Protection of the angles of the mouth by application of a thick ointment or bland paste may be palliative in instances where constant drooling or lip licking plays a major role. In patients with an allergic contact dermatitis, patch tests are usually required to identify the causative agent.

CHEILITIS GLANDULARIS Cheilitis glandularis is an uncommon inflammatory disease affecting the minor salivary glands and ducts. This disease is more commonly seen in adults, but has also been reported in children.61,62 Cheilitis glandularis simplex mainly involves the lower lip and is characterized by lip eversion and protrusion, painless diffuse enlargement and firm nodularity of the affected tissue. It is due to hypertrophy of the labial mucous glands and their ducts, the dilated orifices of which are readily apparent on the labial surface (Fig. 9.7). Pressure exerted on the lip produces a viscid mucous secretion from the ductal openings on the everted hypertrophic lip.63 Cheilitis glandularis suppurativa exhibits crusting, induration, and incipient ulceration. Cheilitis

58. Gobetti JP, Colquitt WN. Angular cheilitis – a bacterial infection. J Mich Dent Assoc. 1982;64:157. 59. Assmann K, Bonsmann G, Werner C, et al. Acrodermatitis enteropathicaähnliche Hautveränderungen bei Ahornsirupkrankheit. Z Hautkr. 2001;76:220–222. 60. MacFarlane TW, Ferguson MM, MacKenzie D. Sensitivity of miconazole of micro-organisms associated with angular cheilitis. Br Dent J. 1978;144:199. 61. Yacobi R, Brown DA. Cheilitis glandularis: a pediatric case report. J Am Dent Assoc. 1989;118:317–318. 62. Musa NJ, Suresh L, Hatton M, et al. Multiple suppurative cystic lesions of the lips and buccal mucosa: A case of suppurative stomatitis glandularis. Pathol Oral Radiol Endod. 2005;99:175–179. 63. Rada DC, Koranda FC, Katz FS. Cheilitis glandularis – a disorder of ductal ectasia. J Dermatol Surg Oncol. 1985;11:372–375. 64. Lederman DA. Suppurative stomatitis glandularis. Oral Surg Oral Med Oral Pathol. 1994;78:319–322. 65. Doku HC, Shklar G, McCarthy PL. Cheilitis glandularis. Oral Surg. 1965;20:563.

656

Figure 9.7  Cheilitis glandularis.

glandularis apostematosa is a deep suppurative infection resulting in crusting, ulcerations, abscesses and fistulous tracts.44 Rarely, other minor salivary glands may be involved.63 Although the cause is unknown, some cases are familial; others have been attributed to chronic trauma. It has also been suggested that glandular hyperplasia with superimposed longstanding bacterial infection is responsible for the suppurative forms of the disease.64–66 Squamous cell carcinoma of the lip has been associated in 18–35% of cases.44 Treatment options include avoidance of aggravating factors, improved oral hygiene, antibiotics if infection is suspected, intralesional corticosteroids, topical calcineurin inhibitors, and surgical stripping of the involved tissue.63,67

MELKERSSON–ROSENTHAL SYNDROME AND CHEILITIS GRANULOMATOSA Cheilitis granulomatosa is an inflammatory disorder characterized by diffuse, painless swelling of one or both lips, although any facial or oral structure may show granulomatous inflammation.68 Melkersson–Rosenthal syndrome (MRS) consists of the classic triad of recurrent or persistent facial swelling, peripheral facial nerve paralysis, and lingua plicata. The monosymptomatic and oligosymptomatic forms of MRS represent incomplete expression of the disorder. When patients manifest isolated, recurrent, non-inflammatory swelling of the lip, characteristic of Miescher’s cheilitis granulomatosa, the monosymptomatic form is present. When any two features of the classic triad are present, the oligosymptomatic form exists.69,70 The earliest literature on MRS is credited to Hübschmann71 in 1894. Melkersson72 later reported his collected cases of

66. Rogers RS, Bekic M. Diseases of the lips. Semin Cutan Med Surg. 1997;16:328–336. 67. Erkek E, Sahin S, Kilic R, et al. A case of cheilitis glandularis superimposed on oral lichen planus: successful palliative treatment with topical tacrolimus and pimecrolimus. J Eur Acad Dermatol Venereol. 2007;21(7):999–1000. 68. Hornstein OP. Glossitis granulomatosa – ein ungewöhnlicher Subtyp des Melkersson-Rosenthal-Syndroms. Mund Kiefer Gesichtschir. 1998;2:14–19. 69. Hornstein OP. Melkersson-Rosenthal syndrome – a challenge for dermatologists to participate in the field of oral medicine. J Dermatol. 1997;24:281–296. 70. Zimmer WM, Rogers RS III, Reeve CM, et al. Orofacial manifestations of Melkersson–Rosenthal syndrome. Oral Surg Oral Med Oral Pathol. 1992;74:610. 71. Hübschmann H. Über Recidive und Diplegie bei der sogenannten rheumatischen Facilislähmung. Neurology (NY). 1894;13:815. 72. Melkersson E. Ett fall av recidiverande facialispares i samband med angioneurotisk edem. Hygiea (Stockh). 1928;90:737.

seventh nerve paralysis and associated facial edema as a syndrome in 1928. Rosenthal73 added the third feature, plicated tongue, in 1931. Miescher’s74 description in 1945 of several patients with cheilitis granulomatosa suggests to some that the disorder should be named Miescher–Melkersson–Rosenthal syndrome.70 The diagnosis of MRS is based on the clinical findings. The nature of the syndrome is such that dermatologic, oral, or neurologic manifestations may predominate at a given time. Facial swelling, the symptom most frequently reported, occurred in 93% of patients, with the lips being affected in 66%.68 The edema occurs without prodrome, and signs of acute inflammation are absent. The swelling is usually non-erythematous, painless, non-pruritic, initially soft, and generally asymmetric. The inner aspect of the affected upper lip may enlarge two to three times its normal size (Fig. 9.8). The lip is rolled outwards by the edema, exposing the normally moist mucosa to the air, causing secondary chapping and fissuring of the surface.75 The edema may persist for 1 or 2 days but seldom lasts longer than 1 week.68–70 Intervals between attacks range from 1 day to 2 1 2 years, with a median time of 5 1 2 weeks.68 Following several recurrences, the swelling tends to become persistent, brawny, and deforming. Physiognomic changes resulting from the labial edema include occasional problems with speech and mastication.76 Despite the fact that the lips may become dry and fissured, xerostomia is not a complicating feature. Excess salivation has occurred in some instances.76,77 Lip swelling may be unilateral or bilateral and may involve either the upper or lower lip or both lips. Other oral structures that may become edematous include the tongue, buccal and palatal mucosa, alveolar process, and gingiva.68 When the gingiva is involved, a distinct, well-demarcated bluish-red swelling is

present. The forehead, eyelids, cheek, nose, and chin may become swollen when MRS is present.68–70 Most often the facial edema antedates the onset of facial paralysis, but the two may begin simultaneously. Alternatively, the paralysis may even precede the swelling.69,70 This paralytic component of the clinical triad usually begins suddenly, remains peripheral in nature, and is thus indistinguishable from Bell’s palsy. The paralyzed side of the face frequently corresponds to the side that develops swelling but, like the edema, the paralysis is occasionally bilateral.69,70 During subsequent attacks, the facial palsy may occur on the opposite side of the face from that previously afflicted.69 Scrotal tongue is the least frequently reported clinical finding in MRS. When present, as it is in 30–50% of cases,69 it is either present from birth or is a manifestation of granulomatous glossitis. Of 58 cases reported by Alexander and James,78 90% had facial paralysis, 86% had edema of the face, and 77% had lingua plicata. One study found the complete triad in only nine of 23 cases surveyed.68–70 Constitutional symptoms occasionally associated with MRS include migraine headaches, hyperpyrexia, hyperhidrosis, chills, loss of taste, and slight visual impairment. Neurologic and ophthalmologic aberrations may be quite severe in certain cases.69,70 The skin, hair, and nails remain normal, as do laboratory parameters. MRS seemingly has no racial predilection, and during the first two decades of life the condition occurs more commonly in females.69,70 Of 58 cases,78 45% had onset of their disease by the age of 20. Although the precise incidence is unknown, MRS was seen in 1 of 2100 cases in the dermatology outpatient setting.77 Infectious, allergic, and hereditary etiologies have been proposed, but to date no evidence exists to support an infectious or allergic basis for the disorder. It has been suggested that MRS may represent an incomplete autosomal-dominant trait of variable penetrance with the neural deficits and facial edema resulting from abiotrophic changes in the autonomic nervous system. An alternative theory68,69 attributes the edema of the seventh cranial nerve and oral mucosa to a non-specific stimulus that triggers vasomotor disturbances in the small arteries, capillaries, and nerves of the subcutaneous tissue. Histologically, early lesions show only edema below an acanthotic epidermis. Chronically enlarged tissues are due to fibrosis and an increase in connective tissue stroma. Both acute and chronic lesions contain perivascular aggregates of lymphocytes, plasma cells, and histiocytes when specimens are taken from the tongue, cheek, or buccal mucosa. Non-caseating epithelioid cell granulomas with multinucleated giant cells may be seen in the edematous stroma. These granulomas may bulge into the vascular lumina, causing obstruction.76 Oral Crohn’s disease may exhibit the same clinical and histopathological features,79 and it

73. Rosenthal C. Klinisch-erbbiologischer Beitrag zur Konstitutionspathologie. Gemeinsames Aufreten von (rezidivierender familiärer) Facialislähmung, angio-neurotischem Gesichtsödem und Lingua plicata in ArthritismusFamilien. Z Ges Neurol Psychol. 1931;131:475. 74. Miescher G. Uber essentielle granulomatöse Makrocheile (Cheilitis granulomatosa). Dermatologica. 1945;91:57. 75. Ziem PE, Pfrommer C, Goerdt S, et al. Melkersson–Rosenthal syndrome in childhood: a challenge in differential diagnosis and treatment. Br J Dermatol. 2000;143:860–863.

76. Worsaae N, Pindborg JJ. Granulomatous gingival manifestations of Melkersson–Rosenthal syndrome. Oral Surg. 1980;49:131. 77. Roseman B, Mulvihill JJ. Melkersson–Rosenthal syndrome in a 7-year-old girl. Pediatrics. 1978;61:490. 78. Alexander RW, James RB. Melkersson–Rosenthal syndrome: review of literature and report of case. J Oral Surg. 1972;30:599. 79. Haneke E. Cheilitis granulomatosa bei Morbus Crohn und MelkerssonRosenthal-Syndrom. Dtsch Z Mund-Kiefer- und Gesichtschir. 1985;9:232–234.

Figure 9.8  A teenager with Melkersson–Rosenthal syndrome (courtesy of Dr A. Torrelo).

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has been suggested that there is an association between granulomatous cheilitis and Crohn’s disease.80 A recent series of 14 patients with cheilitis granulomatosa/MRS examined the incidence of gastrointestinal disease and found that four of the 14 patients also had Crohn’s disease.81 Included in the differential diagnosis of facial palsy of childhood are Bell’s palsy, idiopathic paralysis, otitis media, sarcoid, brain stem tumors, Guillain–Barré syndrome, leukemia or solid tumor malignancies, Ramsay Hunt syndrome, Well syndrome, mycobacterial infections, Hansen’s disease, and acoustic neuroma.77 The differential diagnosis considered in evaluation of facial swelling includes angioneurotic edema, erysipelas, and Ascher syndrome.68 Therapeutic measures for controlling the facial edema include systemic and intralesional steroids. Neither has proved curative, however.68 Intralesional steroids injected every 4 weeks have provided fair results in some cases of chronic swelling.70 Antibiotics and antihistamines have failed to alter the course of the disease. Wedge resections of the inner aspect of the lip have yielded good results in some cases, but care must be taken to remove all the underlying glandular tissue and to operate only when the disease is quiescent.69 Some patients will require more than one surgical procedure to bring their disease under control. Clofazimine has been shown to suppress attacks of lip swelling in seven patients, and sustained control of swelling was maintained in the majority subsequent to discontinuation of the drug.82 Additionally, minocycline, both alone and in combination with prednisolone, was found to be effective.83,84 There have been several recent reports of the use of infliximab and adalimumab in the treatment of cheilitis granulomatosa/ MRS.80,81,85 The facial paralysis of MRS often undergoes spontaneous resolution. Surgical intervention should be reserved for those patients who fail to recover after 2 months or in whom spontaneous recovery is incomplete. No recurrences have been noted following such decompression surgery.68 During the acute stages of facial paralysis, some patients may benefit from ocular lubricants (artificial tears), analgesics, facial massage, and warm compresses. Therapy for lingua plicata is necessary only if trapped food particles inflame the dorsal surface of the tongue. In such instances, enhanced oral hygiene is usually curative. Relapses of MRS and cheilitis granulomatosa may occur many years after seeming recovery; therefore, a conservative approach is best in the management of the orofacial swelling.69

mucosa seems more resistant to primary irritants than does skin and appears to be less easily sensitized, perhaps because the constant dilution by and flushing action of the saliva results in less prolonged contact with the sensitizer. It has also been suggested that the extensive vascularization of the oral mucous membranes aids in the absorption and dispersion of allergens.86 Irritant reactions are usually due to heat or chemical injury and most often involve the palate, tongue, and lips. Contact with very hot liquids or foods such as melted cheese may cause intense erythema, vesicles, and bullae, resulting in painful erosions. Chemicals may also cause superficial erosions; a wellknown cause is acetylsalicylic acid, particularly when a tablet is held in contact with the buccal mucosa for a lengthy period. Chewing gum containing aspirin can also produce ulcerations of the oral mucosa.87 Allergic contact dermatitis can result from a variety of allergens and often involves the lips, angles of the mouth, and perioral skin as well as the oral mucosa (Fig. 9.9). In contrast to the skin, allergic stomatitis is usually characterized by a burning sensation, loss of taste, and numbness rather than itching. The mucosa develops intense erythema, inflammation, and edema, resulting in a smooth, shiny, glazed appearance. Although vesiculation occurs, these lesions are rarely evident because they rupture quickly; rather, erosions and ulcerations may be more prominent. The tongue may become edematous with atrophy of the filiform papillae. Acute allergic cheilitis may present as allergic contact dermatitis, often involving the neighboring skin, and commonly due to so-called herpes remedies, such as tromantadine. At times, there is angular cheilitis, and the lips may be dry, scaly, and fissured; edema and vesiculation of the lips are relatively less common.44,86 Burning, itching and prickling of the palate and/or tongue may be experienced as so-called pollinosis equivalents, in type I allergy, and several cross-allergies of pollen

CONTACT STOMATITIS AND CHEILITIS Contact stomatitis and cheilitis are less common than cutaneous dermatitis in all age groups; however, there are no figures for relative incidence in children as compared with adults. Like the skin, the oral mucosa is capable of two types of reactions: irritant contact dermatitis and allergic contact dermatitis. In general,

80. Barry O, Barry J, Langan S, et al. Treatment of granulomatous cheilitis with infliximab. Arch Dermatol. 2005;141(9):1080–1082. 81. Ratzinger G, Sepp N, Vogetseder W, et al. Cheilitis granulomatosa and Melkersson–Rosenthal syndrome: evaluation of gastrointestinal involvement and therapeutic regimens in a series of 14 patients. JEADV. 2007;21:1065–1070. 82. Neuhofer J, Fritsch P. Cheilitis granulomatosa (Melkersson Rosenthal– Syndrome): Behandlung mit Clofazimin. Hautarzt. 1983;35:459. 83. Olivier V, Lacour JP, Castanet J, et al. Cheilitis granulomatosa in a child. Arch Pediatr. 2000;7:274–277.

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Figure 9.9  Allergic contact dermatitis involving the lips and angles of the mouth due to toothpaste.

84. Stein SL, Mancini AJ. Melkersson–Rosenthal syndrome in childhood: successful management with combination steroid and minocycline therapy. J Am Acad Dermatol. 1999;41:746–748. 85. Kakimoto C, Sparks C, White AA. Melkersson–Rosenthal syndrome: a form of pseudoangioedema. Ann Allergy Athma Immunol. 2007 Aug;99(2):185– 189. 86. Fisher AA. Contact dermatitis. Philadelphia: Lea & Febiger; 1973. 87. Claman HN. Mouth ulcers associated with prolonged chewing of gum containing aspirin. JAMA. 1967;202:651.

Mucous membrane disorders

Dental or cosmetic preparations

>> Toothpastes >> Mouthwashes >> Lipstick, lip balm >> Acrylic monomer (also from nail varnish) >> Metal alloy base >> Sunscreen preparations >> Orthodontic elastics >> Dental amalgam Foods

>> Mangoes, oranges, lemons, and other fruits >> Candies, pastries, ice cream, chewing gum >> Selected vegetables >> Beverages: colas, herbal teas >> Fish and seafood, cheese >> Nuts, spices

fluorescein stains and eosin indelible dyes, but many of today’s pro­ducts have flavorings as well. Biting of acrylate as well as henna-stained nails can lead to severe allergic mucosal lesions. Piercing the lips or tongue may cause nickel allergy. A thorough history must be obtained; at times, repeated questioning is needed to uncover the offending agent. Diagnosis can sometimes be made by elimination of the suspected agent. Patch testing is useful to ascertain the specific sensitizer but must be performed in the correct manner by someone knowledgeable in the technique. Direct testing of the oral mucosa is possible but not easily accomplished.86 Differential diagnosis includes vitamin deficiencies, recurrent aphthous ulcerations, and angular cheilitis due to other causes. Treatment for acute dermatitis of the lips may include cold wet compresses, applications of petrolatum, and a corticosteroid ointment. When the buccal mucosa is involved, a corticosteroid in Orabase may be helpful. Viscous lidocaine (Xylocaine) may provide relief of discomfort in the event of painful ulceration that interferes with eating, but this therapy should be used with caution in small children due to dose-related toxicity. Most important is identification and discontinuation of contact with the inciting agent.

DISORDERS OF THE ORAL MUCOUS MEMBRANES

BOX 9.3 SUBSTANCES CAUSING CONTACT DERMATITIS

9

Therapeutic agents

>> Antibiotics, tromantadine >> Procaine >> Alcohol >> Cough drops, lozenges, troches

and food (birch pollen associated with apple and other fruit allergies, artemisia pollen and carrot and celery allergies) are well-known clinical syndromes.88 The causative agents of contact stomatitis and cheilitis are numerous and varied. A general classification is provided in Box 9.3; specific ingredients must be sought from specialized publications and manufacturers. Popular brands and available products change rapidly, and ingredients in a particular product may be altered periodically. Reactions to toothpastes89 and mouthwashes are often due to flavorings, antiseptics, preservatives such as parabens, or alcohol. Essential oils, such as clove and cinnamon, found in toothpastes, candy, chewing gum, and lipsticks, are commonly incriminated in contact stomatitis. Flavorings may also be responsible for reactions to therapeutic agents, such as antibiotics, lozenges, and troches. A number of plasma-cell gingivitis cases were associated with cinnamoncontaining toothpaste and chewing gum.90 However, most of these cases remained etiologically unclear.91 A variety of foods are capable of causing reactions,92 as well as medicaments and cosmetics. The most common sensitizers in lipsticks are

88. Gutschmidt E, Körner E, Haneke E. Saisonales gaumenbrennen bei Allergie gegen Gräserpollen. Z Hautkr. 1979;54:817–820. 89. Sainio EL, Kanetra L. Contact allergens in toothpaste and a review of their hypersensitivity. Contact Derm. 1995;3(2):100–105. 90. Silverman S, Lozada F. An epilogue to plasma-cell gingivostomatitis (allergic gingivostomatitis). Oral Surg Oral Med Oral Pathol. 1977;43:211–217. 91. Haneke E, Djawari D. Immunoglobulin demonstration in circumorificial plasmocytosis. In: MacDonald DM, ed. Immunodermatology. London: Butterworths; 1984:173–175.

MACROGLOSSIA Macroglossia is defined as a resting tongue that protrudes beyond the teeth or alveolar ridge. Enlargement of the tongue may develop as a primary or secondary phenomenon, but it is not itself considered a disease entity.93 A list of the conditions felt to be responsible for macroglossia is provided in Box 9.4. The tongue may be enlarged at birth or may become so only in adulthood. Macroglossia is not a common finding in the pediatric age group but, when discovered, should alert the clinician that a thorough evaluation is warranted. In congenital macroglossia, overdevelopment of the muscu­ lature occurs with or without associated generalized muscle hypertrophy or hemihypertrophy. The presence of macroglossia due to muscle hypertrophy in an otherwise normal child is rare. Four clinical varieties of muscular macroglossia exist: (1) nodular enlargement not confined to exactly one-half of the tongue; (2) unilateral enlargement associated with localized hypertrophy of the same side of the face or jaw or hemihypertrophy of the body (the most common form); (3) uniform enlargement associated with generalized muscular hypertrophy of the rest of the body; and (4) uniform enlargement with no other ascertainable abnormalities.94 These as well as other primary forms of macroglossia are less evident clinically than are secondary forms.95 Among the many causes of congenital macroglossia, the most frequently encountered is an underlying lymphangioma or venous lymphatic malformation. Enlargement of the tongue

92. Hausen BM, Hjorth N. Skin reactions to topical food exposure. Dermatol Clin. 1984;2:567. 93. Velcek FT, Klotz DH, Hill CH, et al. Tongue lesions in children. J Pediatr Surg. 1979;14:238. 94. Bronstein IP, Abelson SM, von Bonin G. Macroglossia in children. Am J Dis Child. 1937;54:1328. 95. Shafer AD. Primary macroglossia. Clin Pediatr. 1968;7:357.

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BOX 9.4 PRIMARY AND SECONDARY CAUSES OF MACROGLOSSIA Primary

>> Muscular hypertrophy Secondary

>> Congenital – Lymphangioma, hemangioma, hemangiomatosis, vascular malformations

>> Acute and subacute inflammatory – Mucosal erysipelas, abscess, actinomycosis, bee and wasp stings, angioedema

DISORDERS OF THE ORAL MUCOUS MEMBRANES

>> Chronic inflammatory – Granulomatous glossitis, dissecting glossitis in chronic

mucocutaneous candidiasis, glossitis interstitialis lucia, lepromatous leprosy

>> Chromosome abnormalities – Trisomy 4p syndrome, triploidy syndrome, trisomy 21 syndrome (Down’s syndrome), Panse syndrome

>> Dysplastic forms – Beckwith–Wiedemann syndrome (exophthalmosmacroglossia-gigantism syndrome)

– –

Bruck–de Lange syndrome Fetal face syndrome (Robinow syndrome), maxillo-facial (Peters–Hövels) syndrome

>> Metabolic storage disease – Mucopolysaccharidoses I, II, III, VI – Generalized gangliosidosis S – Glycogen storage disease >> Endocrine disorders – Congenital hypothyroidism >> Tumors – Granular cell tumor – Neurofibroma

may also result from the presence of tumor-like growths of developmental origin (i.e., hamartomas, neurofibromas) or may be due to epithelial inclusion cysts. Although the genesis of these tumors is developmental, they may not become apparent until adolescence or later, when hormonal influences increase. Dermoid cysts are rare in the tongue. The differential diagnosis of newborns with an enlarged tongue must include Down’s syndrome, congenital hypothyroidism, and Beckwith–Wiedemann syndrome (exophthalmos-macroglossia-gigantism syndrome with splanchnomegaly and glycolability) (Fig. 9.10).96 Pseudomacroglossia in which a normal tongue extends beyond the alveolar ridge secondary to a small mouth can be seen in some patients with Down’s, Marfan or Robinow syndrome. Many clinical syndromes have an associated macroglossia, particularly those due to inborn errors of metabolism. The lingual hypertrophy in such a setting is caused by excessive deposits of

96. Sotelo-Avila C, Gonzales-Crussi F, Fowler JW. Complete and incomplete forms of Beckwith–Wiedemann syndrome: their oncogenic potential. J Pediatr. 1980;96:47.

660

Figure 9.10  Macroglossia in a child with Beckwith–Wiedemann syndrome.

lipid or carbohydrate intermediates. In each case, other abnormalities accompany the macroglossia. Macroglossia that develops from either primary or secondary factors may displace the teeth and cause malocclusion because of the strength of the muscles involved and the pressure exerted by the tongue on the teeth. The lateral borders of the tongue may become scalloped or crenated when pushed against the teeth (impressiones dentatae).44 An enlarged tongue may interfere with respiration, feeding, and speech. Therapy should be aimed at treating the underlying cause, when feasible. Surgery may be necessary to reduce the tissue bulk.97

LINGUA PLICATA Lingua plicata represents the most common developmental anomaly of the tongue. A variety of names have been given to this benign condition including fissured tongue, scrotal tongue, and furrowed tongue. Lingua plicata is an autosomal-dominant trait with variable penetrance. Patterns of fissuring vary from a haphazard arrangement to one of symmetric branching from a central lingual groove that runs anteroposteriorly along the dorsum of the tongue.98 The fissures may intersect, resulting in a grossly pebbled or cushioned appearance of the surface of the tongue. These surface changes do not usually affect speech or mastication. The epithelium in the depth of the furrows is thinned with almost no keratinization. If the furrows are deep, they may serve as reservoirs of trapped food debris, permitting bacterial and mycotic proliferation and, ultimately, chronic inflammation. Occasionally painful, this condition responds well to brushing of the tongue with a toothbrush two to four times a day. Alternate therapeutic suggestions include warm (alcohol-free) mouthwash rinses and coating of the tongue with unflavored milk of magnesia. The overall incidence of fissured tongue increases with age. The prevalence ranges from 3% to 5% in the general population98 with children between the ages of 5 and 18 years having

97. Massengil R, Pickrell K. Surgical correction of macroglossia. Pediatrics. 1978;61:485. 98. Hornstein OP. Erkrankungen des Mundes. Stuttgart: Kohlhammer; 1996:138–140.

Mucous membrane disorders

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Figure 9.11  Geographic tongue (courtesy of Dr A. Torrelo).

a prevalence of only 1.08%.99 No significant race or sexual predominance is recognized. About 20% develop superimposed geographic tongue (Fig. 9.11).98 Lingua plicata is frequently seen in individuals with Down’s syndrome and is also one of the features of MRS.98

BLACK HAIRY TONGUE (LINGUA PILOSA NIGRA) Black hairy tongue is very rare in children. It is a relatively innocuous condition that affects the dorsum of the tongue. The clinical forms of hairy tongue may be divided into two groups. In the first form, true hairy tongue, filiform papillae become elongated with or without discoloration. The second group, pseudohairy tongue, encompasses discoloration of the tongue without associated hypertrophy of the lingual papillae.98 The combined effect of elongated, hypertrophic filiform papillae and diminished desquamation results in the development of a thick, matted layer on the mid-dorsal surface of the tongue. Although discoloration may be absent, it may also range from yellowish-white to brown or black.44 The etiology of this condition remains obscure, but it has been reported in patients on systemic antibiotic therapy and those with colonization of the tongue by Candida albicans. The use of systemic antibiotics may cause a shift in the oral bacterial–mycologic flora, allowing chromogenic bacteria to colonize the tongue and produce a dark pigment.100 It has also been hypothesized that a lower pH on the surface of the tongue predisposes to the development of black hairy tongue.101 Occasionally, the hypertrophied papillae are sufficiently long to cause tickling or gagging as a result of contact with the soft palate or uvula. In pseudohairy tongue, discoloration may result from fruits, other foods, candy, colored or flavored beverages,

99. Redman RS. Prevalence of geographic tongue, fissured tongue, median rhomboid glossitis, and hairy tongue among 3,611 Minnesota schoolchildren. Oral Surg. 1970;30:390. 100. Shklar G, McCarthy PL. The oral manifestations of systemic disease. Boston: Butterworths; 1976. 101. Lynch MA, Brightman VJ, Greenberg MS, eds. Burket’s oral medicine. 8th ed. Philadelphia: JB Lippincott; 1984.

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Figure 9.12  Geographic tongue.

and medicaments. The tongue coatings are usually removed by salivary flow, speaking, or the ingestion of food.101 Therefore, debilitated patients receiving no oral feedings or on tube feedings may be rendered particularly susceptible to the development of black hairy tongue. In addition, oral hygiene is typically suboptimal in such a setting. Therapy should be directed at enhancing the cleanliness of the oral cavity. Brushing the tongue with toothpaste and a toothbrush two to three times daily often remedies the condition within a few days’ time.

GEOGRAPHIC TONGUE (ANNULUS MIGRANS, EXFOLIATIO MUCOSAE AREATA) Annulus migrans or geographic tongue, sometimes also called migratory ‘glossitis,’ refers to discrete red patches surrounded by raised white to yellowish polycyclic borders affecting the tongue, buccal mucosa, soft palate, tonsils, or the floor of the mouth. The lateral edges, tip, or undersurface of the tongue may be involved in addition to the dorsal surface. Typically, non-lingual lesions are not seen unless the tongue is also involved.102 The lesions may start in early childhood. In 40%, geographic tongue is associated with plicated tongue. The collar-like polycyclic configurations in the oral cavity change in location and prominence from day to day. The elevated borders range in color from pale gray to bright yellowishwhite, and their visibility may span from barely perceptible to florid (Fig. 9.12). The condition may be manifest by a single patch or by multiple areas that are discrete or confluent. The onset of geographic stomatitis is rapid, and persistence is common, with lesions often lasting several months.103 The circinate lesions may, however, appear and disappear rapidly only to reappear at a later date. They often exacerbate during stress.104 The stomatitis usually begins on the lingual surface with loss of the filiform papillae around a fissure and hypertrophy of neighboring papillae. The progression of arcuate borders seemingly occurs in an anterior-medial direction, and changes in

102. Hume WJ. Geographic stomatitis: a critical review. J Dent. 1975;3(25):80. 103. Barton DH, Spier SK, Crovello TJ. Benign migratory glossitis and allergy. Pediatr Dent. 1982;4:249. 104. Redman RS, Vancwe FL, Gorlin RJ, et al. Psychological component in the etiology of geographic tongue. J Dent Res. 1966;45:1403–1408.

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configuration can occur as rapidly as within two hours.105 If only the tongue is involved, the terms of geographic tongue, lingua geographica, annulus migrans, exfoliata areata linguae, lingual dystrophy, and transitory benign plaques of the tongue may be applied. The term geographic tongue reflects the resemblances of the oral pattern to land masses and oceans on a map. The lesions of annulus migrans are typically asymptomatic but affected persons may report mild burning, irritation, or discomfort of the oral mucosal membranes or tongue when exposed to hot, cold, or spicy foods. When the polycyclic borders resolve, healing is complete and no scarring results. The reported frequency of this entity ranges from 0.28% to 14.4% of the population.103 Geographic stomatitis occurs more often in children than in adults. One study of 5425 infants up to 2 years of age noted the presence of geographic tongue in 775 (14.29%).106 Typical oral lesions have been seen as early as 2–4 weeks of life.102 There is no racial predilection, and, although some authorities107 believe that females are affected more often than males, it is probable that no true sex predominance exists.102 The precise etiology of geographic stomatitis remains uncertain. Although an infectious pathogenesis has been suspected, no organism has been isolated, and scrapings of the tongues of affected patients have not provoked disease in disease-free patients following inoculation.108 Circinate lesions of the tongue have been reported in patients with psoriasis (particularly pustular psoriasis),109 Reiter syndrome,110 and atopic dermatitis.111,112 Other diseases associated with geographic tongue include seborrheic dermatitis, spasmodic bronchitis of childhood, allergic diathesis, juvenile diabetes, and Down syndrome.111,113 The changes possibly represent a reaction pattern of the tongue to a number of different underlying conditions. Histologically, the lesions show typical spongiform pustules with necrosis of the superficial epithelium and are thus indistinguishable from those of pustular psoriasis or Reiter syndrome.110 Therapy of this benign condition is generally unsuccessful and unwarranted.103

MEDIAN RHOMBOID GLOSSITIS Among anomalies of the tongue, median rhomboid glossitis, or central papillary atrophy of the tongue, is the most likely to give rise to diagnostic problems. This abnormality has previously been attributed to failure of the tuberculum impar to retract, allowing interposition of a structure devoid of papillae before the lateral halves of the tongue fuse. The consistently median localization of this condition and an occasional notch in the tip

105. Zagarelli EV, Kutscher AH, Mercadante JA, et al. Geographic tongue: relation of change in appearance to time. J South Calif Dent Assoc. 1963;31:11. 106. Rahaminoff P, Muhsam HV. Some observations on 1246 cases of geographic tongue. Am J Dis Child. 1957;93:519. 107. Rowe NH. Diseases of the oral mucosa. In: Demis DJ, McGuire J, eds. Clinical dermatology. Vol 4. Philadelphia: Harper & Row; 1986: unit 28–21, 1. 108. Redman RS, Shapiro BL, Gorlin RL. Hereditary component in the etiology of benign migratory glossitis. Am J Hum Genet. 1972;24:124. 109. Hubler WR Jr. Lingual lesions of generalized pustular psoriasis. J Am Acad Dermatol. 1984;11:1069. 110. O’Keefe E, Braverman IM, Cohen I. Annulus migrans: identical lesions in pustular psoriasis, Reiter’s syndrome and geographic tongue. Arch Dermatol. 1973;107:240. 111. Marks R, Simons MJ. Geographic tongue – a manifestation of atopy. Br J Dermatol. 1979;101:159.

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of the tongue favor this theory. It is also suggested that a localized chronic infection, most commonly with Candida albicans, causes this alteration rather than a developmental defect. The peculiar anatomy of the mid-dorsal surface of the tongue is felt by some114–116 to permit proliferation of Candida in certain predisposed patients. The overgrowth of this organism results in loss of the filiform papillae on the dorsal surface of the tongue. Wright116 established the following six diagnostic clinical features: (1) a characteristic location in the median raphe anterior to the circumvallate papillae; (2) a roughly rhomboid shape; (3) a rosy color of the affected area; (4) variable surface changes (smooth to fissured) and absence of papillae, slightly depressed to raised and nodular; (5) slight induration of the tongue; and (6) lack of symptoms. The glossitis becomes evident when the filiform papillae are lost, particularly when the surface of the tongue appears coated or when the papillae are matted.44 The deeper red or rose color of the anomalous tissue contrasts sharply with the pink color of the normal tongue.98 The incidence of median rhomboid glossitis in the general population is approximately 1%.44,117 Although Baughman118 detected no cases in a survey of 10 000 schoolchildren, Redman99 reported three cases in patients under 10 years of age. The condition is without sex or racial predilection. On histologic examination, there is loss of papillae with varying degrees of parakeratosis, downward proliferation of the spinous layer with elongation of the rete ridges that may branch or anastomose, and a lymphocytic infiltrate within the connective tissue. Numerous blood vessels and lymphatics are apparent. Degeneration and hyalin formation within the underlying muscle are also seen.116 In two studies, 85% and 71% had evidence of candidal hyphae in the parakeratin layer.116 The lingual changes are typically asymptomatic. Anticandidal therapy in the form of topical nystatin, clotrimazole troches or even systemically active antifungals may reduce the fungal colonization but will not improve the appearance of the mucosal surface devoid of papillae. No additional specific therapy is warranted, although fastidious oral hygiene may hasten recovery. The differential diagnosis must include a well-developed thyroglossal duct or an aberrant thyroid gland.101

GLOSSITIS Glossitis refers to inflammatory alterations in the normal lingual coating as a result of nutritional deficiency, infection, allergy, or toxic reactions. Glossitis may also be idiopathic. Changes in the inflamed tongue may include erythema, edema, pain, and

112. Ullmann W. Korrelation zwischen Exfoliatio areata linguae und Atopie. Hautarzt. 1981;32:629–631. 113. Assimakopoulos D, Patrikakos G, Fotika C, et al. Benign migratory glossitis or geographic tongue: an enigmatic oral lesion. Am J Med. 2002;113(9):751–755. 114. Cooke BEO. Median rhomboid glossitis, candidiasis and not a developmental anomaly. Br J Dermatol. 1975;93:399. 115. Farman AG, Nutt G. Oral candida, debilitating disease and atrophic lesions of the tongue. J Biol Bucc. 1975;4:203. 116. Wright BA. Median rhomboid glossitis: not a misnomer. Review of the literature and histologic study of twenty-eight cases. Oral Surg. 1978;46:806. 117. Ullmann W, Hoffmann M. Glossitis rhombica mediana. Hautarzt. 1981;32:571–574. 118. Baughman RA. Median rhomboid glossitis: a developmental anomaly? Oral Surg. 1971;31:56.

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GLOSSODYNIA AND GLOSSOPYROSIS Glossodynia and glossopyrosis refer to sensations of pain and burning within the mouth, typically without pathological changes of the mucosa. The typical glossodynia patient is an edentulous postmenopausal woman, and occurrence in children is exceedingly rare.119 These paresthesias most frequently involve the tongue, but the palate, lips, and other sites in the oral cavity may be symptomatic (orolingual paresthesias). The sensations reported include itching, stinging, and a sandy feeling, in addition to pain and burning. Most often, no clinical lesions exist, and thus no physical alterations correlate with the paresthesias.44,119 A careful history and physical examination are indicated for patients who complain of glossodynia. The mouth should be examined thoroughly and a culture for Candida albicans obtained as pain or burning within the oral cavity may herald acute atrophic oral candidiasis. A therapeutic trial of an antiyeast agent such as nystatin is rarely helpful.120 Systemic diseases that must be excluded during an evaluation are vitamin B complex deficiency, iron deficiency anemia, diabetes mellitus, and Sjögren syndrome. Local irritation from tongue habits, carious teeth, medicaments, and dentifrices should be considered. Flavoring in chewing gum can produce a painful, burning tongue without observable clinical alteration.101,119 Therapy should be directed at correcting whatever systemic or local problems contribute to the oral paresthesias. Even when no etiology is found, chewing gum should be avoided, as the irritating action of the flavoring agents, medicaments, or the slightly abrasive chicle base may worsen pre-existing discomfort. Some benefit may be derived from chewing unmedicated paraffin, which enhances salivary flow.101

XEROSTOMIA Xerostomia may be divided into subjective and objective. Subjective xerostomia is mainly seen in psychiatrically ill persons who suffer from the sensation of dry mouth but have enough saliva to speak, chew and swallow normally.119 Objective xerostomia is a clinical manifestation of salivary gland dysfunction and does not of itself comprise a disease entity. Many factors predispose to xerostomia and an outline of these is provided in Box 9.5.121 The degree of dryness may range from a slight burning sensation with normal-appearing mucous membranes to complete lack of salivary flow with dry atrophic membranes that are pale and translucent.44 The minor salivary glands of the oral mucosa are mainly responsible for lubrication and oral well-feeling.119

119. Haneke E. Zungen- und Mundschleimhautbrennen. München-Wien: Hanser-Verlag; 1980. 120. Zegarelli DJ. Burning mouth, an analysis of 57 patients. Oral Surg. 1984;58:34.

BOX 9.5 ETIOLOGY OF XEROSTOMIA Congenital

>> Hypoplasia or aplasia of salivary glands; ectodermal dysplasia Drug-induced

>> Anticholinergics >> Sympathomimetics >> Opium and derivatives >> Ergotamine >> Diuretics Infections

>> Mumps >> Tuberculosis >> Syphilis >> Actinomycosis

DISORDERS OF THE ORAL MUCOUS MEMBRANES

hypertrophy, or loss of papillae. These changes may occur early in the course of an illness or vitamin deficiency or only after long-standing insult. In most instances, recovery is fairly prompt following institution of appropriate therapy. The various forms of glossitis are detailed under their appropriate etiologies. The discovery of glossitis signals the necessity for a careful history and physical examination (see also Box 9.4).

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Neoplasms

>> Primary tumors, benign and malignant >> Infiltrative processes, such as lymphoma Collagen vascular

>> Systemic lupus erythematosus >> Scleroderma >> Dermatomyositis >> Mixed connective tissue disease >> Sjögren syndrome Neurologic

>> Post-traumatic nerve injury >> Degenerative processes such as multiple sclerosis Obstructive

>> Stone (sialolithiasis) >> Tumor >> Inflammation >> Scar or stricture Dietary or absorption detect

>> Vitamin deficiency (vitamin A, riboflavin, nicotinic acid) >> Pernicious anemia >> Iron deficiency anemia Endocrine

>> Diabetes mellitus >> Hypothyroidism >> Postirradiation >> Graft-versus-host disease

121. Konzelman JL, Terezhalmy GT. Xerostomia: diagnosis and treatment. US Navy Med. 1983;74:16.

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In the pediatric age group, xerostomia rarely occurs. Children with agenesis of the salivary glands may have varying degrees of oral dryness. The hypoplastic salivary glands including the intraoral accessory glands predispose those with anhidrotic ectodermal dysplasia to dry mucous membranes. Xerostomia is also a near-constant symptom in chronic graft-versus-host disease,122 and seen in about one-third of children with AIDS.123 This is particularly troublesome when dentures are worn, as tenderness and discomfort result from a poorly lubricated interface. Xerostomia and caries often develop rapidly following initiation of irradiation to the lower face, but also after whole-body irradiation.124 The caries involve the dentin and cementum exposed at the cervical areas of the teeth and the cusp tips and incisor edges. These alterations are nearly pathognomonic for postirradiation cavities. Salivary substitutes in the form of sprays or liquids help moisten and lubricate the oral cavity.125 These agents are formulated to have a viscosity and electrolyte concentration that approximate whole saliva. Flavorings are added to give a pleasant taste, and salivary substitutes may be used, such as the following preparations:

• Rx Sodium carboxymethylcellulose 0.5% aq.sol. (prepared by your pharmacist) Disp: 8-oz bottle Rinse as often as needed to moisten and lubricate the mouth. • Rx Salivart saliva substitute (Westport Pharmaceuticals, Inc.) Disp: 50-mL spray can Sig: Spray into the mouth and throat as needed to moisten and lubricate the mouth. • Rx Moi-stir (Kingswood Laboratories, Inc.) Disp: 120-mL bottle Sig: Spray into mouth once or twice to coat all surfaces. Use as often as desired. • Rx Xero-Lube saliva substitute (Scherer Laboratories, Inc.) Disp: 6-oz bottle Sig: Rinse as often as needed to moisten and lubricate the mouth. Xero-lube is the only solution containing fluoride, and it is preferable in any patient with dentition. Daily application of stannous fluoride gel, 0.4% 5–10 drops in a moist carrier for 5 min, is recommended to promote remineralization of the tooth enamel in patients with xerostomia. Comprehensive management objectives for patients with xerostomia126 include: (1) discovery and treatment of the etiologic factor(s), if possible; (2) implementation of palliative therapy, including local and/or systemic use of various substances that may increase salivary flow; and (3) initiation and implementation of a well-organized preventative dental program to decrease or eliminate the incidence of clinical complications associated with xerostomia. 122. Nicolatou-Galitis O, Kitra V, Van Vliet-Constantinidou C, et al. The oral manifestations of chronic graft-versus-host disease (cGVHD) in paediatric allogeneic bone marrow transplant recipients. J Oral Pathol Med. 2001;30:148–153. 123. Kozinetz CA, Carter AB, Simon C, et al. Oral manifestations of pediatric vertical HIV infection. AIDS Patient Care STDS. 2000;14:89–94. 124. Majorana A, Schubert MM, Porta F, et al. Oral complications of pediatric hematopoietic cell transplantation: diagnosis and management. Support Care Cancer. 2000;8:353–365. 125. Hebert AA, Berg JH. Oral mucous membrane diseases of childhood: I, Mucositis and xerostomia. II. Recurrent aphthous stomatitis. III. Herpetic stomatitis. Sem Dermatol. 1992;11:80.

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LYMPHATIC MALFORMATION (See also Ch. 20) Lymphatic malformations (lymphangiomas) of the oral cavity are rare in children. When present, the majority are detected at birth or within the first 2 years of life.44,127 No sexual predilection or hereditary predisposition has been reported. Lymphatic malformations consist of multiple lymphatic vascular channels lined by single or multiple layers of endothelial cells. They can be macrocystic, microcystic or combined. The surrounding fibrous tissue may be abundant or scanty. Lymphatic malformations usually occur as solitary lesions, but bleeding may mimic other vascular malformations such as hemangiomas. Combined lymphatic/venous malformations are not uncommon. The tongue is the most common location of lymphatic malformations within the oral cavity, but the palate, buccal mucosa, gingiva, and lips may also be affected.44 Lymphatic malformations have been noted on the alveolar ridges of neonates.128 When macroglossia occurs as a result of a lymphatic malformations, the anterior dorsal two-thirds of the tongue is most often affected (Fig. 9.13). The nasopharynx thus remains patent despite enlargement of the tongue, and respiratory compromise is rare.129 Furthermore, taste is infrequently altered by the presence of a lymphatic malformations in the tongue. These intraoral vascular malformations are characterized clinically as spongy compressible masses. The lesions can be unilateral, bilateral, or diffuse. Most often they are bilateral with

Figure 9.13  Microcystic lymphatic malformation on the central portion of the tongue (courtesy of Dr A. Torrelo).

126. Navazesh M, Ship II. Xerostomia: diagnosis and treatment. Am J Otolaryngol. 1983;4:283. 127. Watson WL, McCarthy WD. Blood and lymph vessel tumors: a report of 1,056 cases. Surg Gynecol Obstet. 1940;71:569. 128. Levin LS, Jorgenson RJ, Jarvey BA. Lymphangiomas of the alveolar ridges in neonates. Pediatrics. 1976;58:881. 129. Rice JP, Carson SH. A case report of lingual lymphangioma presenting as recurrent massive tongue enlargement. Clin Pediatr. 1985;24:47.

Mucous membrane disorders

130. Koop CE, Moschakis EA. Capillary lymphangioma of the tongue complicated by glossitis. Pediatrics. 1961;27:800. 131. Dover JS, Arndt KA, Geronemus RG, et al. Neodymium-yag lasers. In: Illustrated cutaneous laser surgery. Norwalk, CT: Appleton & Lange; 1990:121. 132. Alani HM, Warren RM. Percutaneous photocoagulation of deep vascular lesions using fiberoptic laser wand. Ann Plast Surg. 1992;29:143. 133. Bozkaya S, Ug˘ar D, Karaca I, et al. The treatment of lymphangioma in the buccal mucosa by radiofrequency ablation: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;102(5):e28–e31.

Figure 9.14  Macrocystic lymphatic malformation of the tongue. DISORDERS OF THE ORAL MUCOUS MEMBRANES

indistinct lateral margins. Irregular nodularity of the surface of the tongue with gray and pink projections and accompanying macroglossia is pathognomonic of a lingual lymphatic malformations.44 The surface of the tongue varies in appearance with the emergence and regression of lymphangiomatous vesicles. Tiny papillomatous residues remain at the sites of resorbed vesicles. These papillomas are painful but, unlike their antecedent counterparts, do not bleed easily following trauma.130 Included in the differential diagnosis are condylomata acuminata, other oral verrucous lesions, Goltz syndrome, epidermal nevus or neurofibromas of the tongue, and hereditary hemorrhagic telangiectasia. The tongue with a lymphatic malformations may grow at a rate equal to or exceeding the growth of the affected child. Following trauma or an upper respiratory infection, the tongue may enlarge within hours and require months to return to its original size. Pain frequently accompanies such swelling. As lymphatic drainage becomes increasingly impaired in the course of repeated trauma or infection, the tongue becomes permanently hypertrophied. Certain foods, particularly salty ones, may trigger some lingual edema and discomfort, but these symptoms are usually temporary. Lymphatic malformations that produce marked enlargement of the tongue tend to cause abnormal bone development, drooling, and difficulties with feeding and speech. During sleep the protuberant tongue dries out, predisposing to both fissuring and bleeding. These clinical complications usually have their onset before 3 years of age. Lymphatic malformations causing overgrowth of adjacent structures and destruction of tissues may predispose to mandibular development that is out of proportion to maxillary growth. The associated carious teeth presumably result from pressure alteration of the tooth buds.130 Oral lymphatic malformation (Fig. 9.14) may communicate with lymphatic malformations in the neck. Surgery has proved the most efficacious therapeutic modality when such intervention is deemed necessary. Following surgical removal, the lesions have a tendency to recur. This tendency increases with the increasing age of the patient. This is probably due to the fact that intraoral lymphatic malformations often extend far beyond their visible border and can often not be removed completely. Electrodesiccation of hemorrhagic lymphangiectasias is followed by edema, pain, and inflammation of the tongue and therefore has little application. These vascular lesions are more radioresistant and insensitive to sclerosing agents than are hemangiomas (see Ch. 20). Spontaneous regression is rare. Neodymiun:YAG laser therapy, said to be able to ‘seal off’ lymphatic vessels, may prove beneficial for some tongue131 and other mucous membrane132 lymphatic malformations, but each case must be evaluated carefully before this modality is employed. Results of therapy with this laser may or may not be acceptable and current literature citing long-term follow-up are lacking. Several recent case reports have demon-

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strated successful treatment of oral lymphangiomas by radiofrequency ablation.133 Systemic steroids may lessen the swelling due to glossitis or postoperative edema but play no role in ongoing management of oral lymphatic malformations.

BENIGN PAPULAR LESIONS OF THE TONGUE In addition to lymphatic malformations, several other types of benign papular lesions can be localized to the tongue. These lesions differ somewhat in their clinical characteristics and can often be identified by their location, surface configuration, color, and consistency (Table 9.3134 and Figs 9.15–9.17). If the diagnosis is not apparent by inspection, histologic examination will usually provide a definitive diagnosis.

MUCOSAL CYSTS Epstein’s pearls and Bohn’s nodules are tiny, 1–3 mm, circumscribed asymptomatic cysts found in the oral cavity of newborn infants. Epstein’s pearls, found at the junction of the hard and soft palate along the midpalatine raphe, represent tiny mucous gland cysts that arise from remnants of salivary gland structures.89,135 Bohn’s nodules develop following entrapment of epithelial remnants during embryologic development of the oral cavity. These inclusion cysts are distributed in a linear fashion along the alveolar ridge (Fig. 9.18).89,135 Both varieties of cysts are typically multiple in the newborn, particularly when careful examination is performed within the first 24 hours of life.135,136 The highest incidence of these cysts occurs in Japanese infants (88.7–91.4%), followed by white (76.8–85%) and black (63–79%) newborns.135,137 Microscopically, keratin cysts are evident. Within the epithelial lining, the lumen is filled with desquamated keratin. No therapy is 134. Newland JR. Benign lingual lesions of intrinsic origin. Postgrad Med J. 1984;75:152. 135. Ikemura K, Kakinoki Y, Nishio K, et al. Cysts of the oral mucosa in newborns. A clinical observation. Sangyo Ika Daigaku Zasshi. 1983;5:163. 136. Flinck A, Paludan A, Matsson L, et al. Oral findings in a group of newborn Swedish children. Int J Paediatr Dent. 1994;4:67–73. 137. Fromm A. Epstein’s pearls, Bohn’s nodules and inclusion cysts of the oral cavity. J Dent Child. 1967;34:275.

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Table 9.3  Benign papular lesions of the tongue/oral mucosa

DISORDERS OF THE ORAL MUCOUS MEMBRANES

LESION

CLINICAL CHARACTERISTICS

HISTOLOGIC FINDINGS

Fibroma

Smooth, pink or white, firm, sessile or pedunculated; nonpainful; most common on dorsum, tip and lateral margin (Fig. 9.15)

Dense bundles of collagen, scattered fibrocytes in submucosa; tip may be keratotic

Pseudofibroma (proptosis [diapneusis] linguae, buccalis)

Mucosa-colored, soft, flat nodules opposite a missing tooth

Propulsion of normal mucosa, tip may exhibit denser epithelium

Pyogenic granuloma

Deep red, ulcerated, sessile; recurrent bleeding common; rarely painful; usually on dorsum

Localized proliferation of vascular tissue; mixed inflammatory infiltrate; ulcerated mucosa

Traumatic granuloma

Firm, sessile, ulcerated; nonpainful; most common on dorsum

Proliferation of fibroblasts and histocytes into striated muscle of tongue; mixed inflammatory infiltrate including eosinophils

Squamous papilloma

White, pedunculated, painless, digitate surface

Keratinized epithelium; thick connective tissue core; mild inflammation

Verruca (condyloma acuminatum)

Multiple, sessile, or pedunculated, white to pink; painless (Fig. 9.16)

Hyperkeratosis; acanthosis; vacuolated cells in spinous layer, intranuclear viral inclusions

Hemangioma

Red to blue, sessile, blanchable, and compressible; if large, may cause macroglossia; may ulcerate with trauma

Numerous dilated vascular spaces

Lymphatic malformation

Solitary or multiple; white, pink, or deep red; vesicopapules and nodules; if large, may cause macroglossia

Dilated lymph-filled vessels lined by single layer of endothelial cells

Lipoma

Yellow, compressible, sessile nodules; usually lateral borders

Nodules of fat in fibrovascular stroma

Granular cell tumor

Pink, firm, sessile nodules (Fig. 9.17)

Infiltrate of large oval cells with abundant fine granular cytoplasm within muscle bundles, neural markers positive

Neurofibroma, neurilemmoma

Diffuse or circumscribed pink nodule; lateral border of tongue

Proliferation of neurofibroblasts and collagen within tongue, neural markers positive

Neuroma

Circumscribed sessile pink nodules; usually dorsal surface; traumatic neuromas painful; mucosal neuromas painless

Fibrous connective tissue with intertwining nerve fibers and neurofibroblasts, neural markers including neurofilaments positive

Epidermal nevus

Papillomatous white or pink plaque or linear lesion

Hyperkeratosis, papillomatosis, acanthosis

Adapted from Newland JR (1984) Benign lingual lesions of intrinsic origin Postgrad Med J 75:152, with permission.

indicated, as these cysts are painless, exfoliate spontaneously, and heal without scarring. The presence of circumscribed, fluctuant swelling over the site of an erupting tooth is called an eruption cyst or eruption hematoma. When the circumcoronal cystic cavity contains blood, the swelling appears purple or deep blue. These lesions are common, occurring in 11% of infants during the eruption of the canines and molars.44 The cause of eruption cysts is unknown. No therapy is usually warranted, although removing a small portion of tissue overlying the tooth may facilitate its eruption.

FORDYCE SPOTS Fordyce spots (Fordyce granules) represent normal sebaceous glands within the oral cavity. Ectodermal tissue is included in the early formation of the maxilla and mandible and explains the unusual location of these structures within the mouth.44 The

138. Halperin V, Kolas S, Jefferis KR, et al. The occurrence of Fordyce spots, benign migratory glossitis, median rhomboid glossitis, and fissured tongue in 2,478 dental patients. Oral Surg. 1953;54:1072.

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primordial ectodermal tissue maintains its ability to differentiate into sebaceous glands during postnatal life.87 Clinically, Fordyce spots appear as white to yellow macules and papules visible through the transparent oral epithelium (Fig. 9.19). The well-circumscribed papules measure 1–3 mm in size and may occur singly or in great numbers. When many sebaceous glands are present, the papules and macules may coalesce into yellow plaques, projecting slightly above the mucosal surface. The lesions typically appear on the buccal mucosa in a symmetric fashion along the occlusive planes of the teeth. When present on the lips, Fordyce spots are more numerous on the upper lip. Areas less often demonstrating these granular lesions include the retromolar region lateral to the anterior faucial pillar, the tongue, gingiva, frenulum, and palate.44 Affected regions are asymptomatic. Although Fordyce spots are uncommon in children, the incidence approaches 80% in the adult.136,138 These sebaceous glands

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DISORDERS OF THE ORAL MUCOUS MEMBRANES

Mucous membrane disorders

Figure 9.17  Granular cell tumor on the tip of the tongue (courtesy of Dr A. Torrelo).

Figure 9.15  Fibroma on lateral border of the tongue of an infant, congenital.

Figure 9.18  Bohn’s nodules along the upper alveolar ridge.

Figure 9.16  Verrucous papilloma on the lower lip.

are androgen-dependent and therefore often larger in males than in females, but differences in incidence between the sexes or various races do not exist. Histologically, normal-appearing sebaceous glands are present immediately subjacent to the oral epithelium. The glands may be single or grouped about a short common duct. The glandular structures are rudimentary in young children, enlarge during puberty, and remain large throughout life. No pathologic significance should be attached to Fordyce spots, and no therapy is warranted.

Figure 9.19  Fordyce spots on the mid-upper lip. 667

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Figure 9.20  Typical mucocele on the lower lip.

Figure 9.21  Ranula on the ventral surface of the tongue (courtesy of

MUCOCELE The term mucocele is applied to several types of lesions characterized by a mucus-filled swelling within the oral cavity. Both the major and minor salivary glands can contribute to the contents of these soft masses.139 Histologic evaluation of the internal linings surrounding the fluid permits differentiation into true cysts, mucus extravasation cysts, and mucus retention cysts.101 Of these three types, the least common is the true cyst, which is lined by an epithelium and consists of a small fluid-filled cavity lying within the body of a salivary gland. Mucus extravasation cysts are in fact particular mucus-induced granulomas. They result from trauma to the excretory duct of a minor salivary gland, permitting mucus to flow into the surrounding tissues. Whereas most of the saliva constituents are resorbed, mucins remain in the stroma of the tunica propria attracting macrophages and neutrophils. The latter disappear when the granuloma matures and shows its typical architecture of central mucin lake, inner wall of mucophages, and outer wall of macrophages with fibrous pseudocapsule.140 The absence of an epithelial lining indicates that the cavity is not a true cyst. The overwhelming majority of these cysts are found on the lower lip (Fig. 9.20), although the floor of the mouth and the upper lip are occasionally affected.141 The mucus retention cyst is caused by dilation of a partially obstructed salivary duct, which forms a fluid-filled cystic structure. The cells lining the inner surface are either columnar or pseudostratified squamous epithelium. If the obstruction occurs in the submandibular or sublingual gland, the unilateral lesion formed in the floor of the mouth is called a ranula (Fig. 9.21). These are typically soft, fluctuant, and dark blue in appearance. If the lesion is large, it may interfere with normal oral function.

139. Gorlin RJ, Goldman HM. Thomas’s oral pathology. 6th ed. St Louis: CV Mosby; 1970. 140. Haneke E. Histologie, elektronenmikroskopie, Enzym- und Immunhistologie des Schleimgranuloms. Verh Dtsch Ges Pathol. 1983:67:640. 141. Maia DM, Merly F, Castro WH, et al. A survey of oral biopsies in Brazilian pediatric patients. ASDC J Dent Child. 2000;67:128–131.

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Dr A. Torrelo).

Clinically, all mucoceles have a bluish translucent appearance if superficially located.98 When they are deep, the overlying mucosal surface may appear fairly normal. The lesions are smooth, painless, and typically asymptomatic. They may slowly enlarge and rupture spontaneously. Although accidental trauma is occasionally curative, most mucoceles do recur.98 Similarly, if the mucoid contents are evacuated as a therapeutic measure, the sac fills up after a brief interval. No sexual predilection has been noted, although mucoceles seem to occur more commonly during the first three decades of life when indicated.44 Therapy should consist of surgical excision, marsupialization or micromarsupialization.142 Recurrences are common when the associated salivary gland acini are incompletely removed.

EPULIS The congenital epulis is a rare, benign tumor that presents as a protuberant mass from gum of the newborn. These arise most often in the region of the incisors of the upper jaw. Attachment to the gum can be via a slender stalk or broad pedicle, with the shape of the mass ranging from ovoid to spheroid. Although single tumors are the most common, lobulated and multiple growths have been reported.143 The maxilla is more often involved than is the mandible, and females are affected far more frequently than males. The congenital epulis seemingly does not enlarge after birth; thus growth probably ceases at parturition.144 Spontaneous regression typifies the natural course of this lesion, but simple surgical excision is warranted when there is interference with

142. Delbem AC, Cunha RF, Vieira AE, et al. Treatment of mucus retention phenomena in children by the micro-marsupialization technique: case reports. Pediatr Dent. 2000;22:155–158. 143. Rainey JB, Smith IJ. Congenital epulis of the newborn. J Pediatr Surg. 1984;19:305. 144. O’Brien FV, Pielou WD. Congenital epulis: its natural history. Arch Dis Child. 1971;46:559.

Mucous membrane disorders

FOCAL EPITHELIAL HYPERPLASIA Focal epithelial hyperplasia (FEH), or Heck’s disease, is a benign disorder of the mucous membranes of children. Human papillomavirus (HPV) has been identified as the cause of FEH, and the most frequent, consistent, and disease-specific HPV types are 13 and 32. Less commonly found but previously documented are HPV types 1, 6-related, 11, 13-related, 16, and 18.146 A high frequency of FEH occurs in Native American populations from North, Central, and South America; Eskimos from Greenland and North Canada; and Blacks from South Africa. However, some cases have also been observed in Europe. Female children are affected more frequently than male children and typical ages of FEH patients range between 3 and 18 years. The clinical findings include soft, discrete asymptomatic papules that may merge into plaques. They are predominantly located on the lower lip, occasionally also on the buccal mucosa, upper labial mucosa, tongue, and gingivae. Histologically, one sees focal acanthosis of the epithelium with horizontal anastomosis of the elongated and/or clubbed rete ridges. The presence of koilocytes, mitosoid cells (cells demonstrating a mitosis-like nuclear degeneration) and/or cells with ballooning degeneration and more than one distorted nucleus are found. Electron microscopy can be used to demonstrate typical virus particles.147 No therapy may be required for FEH as the lesions often involute spontaneously without scarring.146 Therapeutic modalities with variable efficacy have included cryotherapy, surgical excision, and carbon dioxide laser therapy.

GINGIVOSTOMATITIS Gingivostomatitis in the child or adolescent is most often due to an infectious etiology but can also be a reflection of one of a number of non-infectious processes. Infectious problems are most often viral; HSV, coxsackievirus, and varicella-zoster virus

145. Sen Gupta SK, Sharma ND. Congenital epulis of the newborn. Papua New Guinea Med J. 1982;25:53. 146. Cohen PR, Hebert AA, Adler-Storthz K. Focal epithelial hyperplasia: Heck disease. Pediatr Dermatol. 1993;10(3):245–251. 147. Nasemann T, Schaeg G. Der morbus heck. Z Hautkr. 1985;60:1750–1757. 148. Cherry JD, Jahn CL. Herpangina: the etiologic spectrum. Pediatrics. 1965;36:632.

are the three most common agents involved. Acute necrotizing ulcerative gingivitis is associated with a proliferation of fusospirochetal organisms, although the disorder is not clearly caused by these agents. Additional conditions that may present as gingivostomatitis include contact stomatitis, erythema multiforme, stomatitis due to chemotherapy agents, recurrent aphthous ulcers, Behçet’s disease, pemphigus vulgaris, cicatricial pemphigoid, and lichen planus. For viral mucosal infections, see also Chapter 25.

HERPANGINA This common acute infectious illness is caused by several of the Coxsackie viruses, mainly type A16, but also types A5, A9, A10, B2, and B5, as well as Echovirus types 6, 3, 7, 9, and 30. Onset is abrupt with high fever, vomiting, sore throat, anorexia, and dysphagia.148 Abdominal pain occurs in approximately 25% of cases.149 Multiple 1–2 mm vesicles rapidly breaking down to aphthoid lesions with an erythematous areola are distributed over the fauces, tonsils, uvula, pharynx, and soft palate. These lesions enlarge before forming shallow painful ulcerations. Laboratory findings are generally within normal limits. A similar disease, however, with papules on the soft palate only, is caused by Coxsackievirus A10 and known as acute lymphonodular pharyngitis. The differential diagnosis includes mainly hand, foot, and mouth disease, herpetic gingivostomatitis, and aphthous ulcers, all of which differ in sites of involvement and accompanying signs and symptoms (Table 9.4). The diagnosis can be confirmed by identification of the viral agent either by inoculation of material obtained from the throat or rectum into a newborn mouse or by demonstration of a rise in antibody titer. PCR has also been used recently for the identification of Coxsackie viruses in patients with herpangina.150 The course of the illness is brief, lasting approximately 4–6 days, and complete recovery without complications is usual. There is no known effective treatment.

DISORDERS OF THE ORAL MUCOUS MEMBRANES

feeding or respiration. The tumor does not recur postoperatively, and dentition is rarely impaired.145 Grossly, the tumor is a firm, moderately pink mass 1–9 cm in diameter. Histologically, uniform sheets of closely packed cells with an eosinophilic granular cytoplasm are present. The nuclei are centrally or eccentrically placed. Strands of fine collagenous stroma that are highly vascularized penetrate between the cells. The tumor is nonencapsulated but is separated from the surface epithelium by a zone of normal connective tissue. The surface mucosal epithelium is usually intact. Although the precise histogenesis remains unclear, congenital epulis can be distinguished from granular cell tumor by the absence of pseudoepitheliomatous hyperplasia and neural elements. Congenital epulis also has both a uniform structure and a prominent vascular component. The typical location in the incisor region of the maxilla or mandible and the almost exclusive incidence in females further distinguish the two lesions.

9

HAND, FOOT, AND MOUTH DISEASE Hand, foot, and mouth disease can usually be attributed to Coxsackievirus A16 infection; however, A5, A7, A9, and A10 are also occasionally implicated as etiologic agents.151 This viral syndrome was first described in 1956 and has been observed to recur in outbreaks since that time. There is generally a mild prodrome consisting of lowgrade fever, malaise, anorexia, and sore mouth. Coryza, cough, diarrhea, vomiting, and lymphadenopathy are less frequent findings. Oral lesions develop 1–2 days later and are typically sparse discrete vesicles, 4–8 mm in diameter, on an erythematous base; occasionally these lesions may be as large as 20 mm. Most commonly, the buccal mucosa, tongue, uvula, and anterior tonsillar pillars are involved. Gingival vesicles are rare. The oral lesions may be the only evidence of infection and, in those instances,

149. Krugman S, Ward R. Infectious diseases of children and adults. 5th ed. St Louis: CV Mosby; 1973. 150. Yamashita T, Ito M, Taniguchi A, et al. Prevalence of coxsackievirus A5, A6, and A10 in patients with herpangina in Aichi Prefecture, 2005. Jpn J Infect Dis. 2005;58(6):390–391. 151. Cherry JD. Viral exanthems. Curr Probl Pediat. 1983;13:1.

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Table 9.4  Common mucosal vesiculoulcerative syndromes

DISORDERS OF THE ORAL MUCOUS MEMBRANES

MUSOCAL LESIONS

SKIN LESIONS

ASSOCIATED FINDINGS

Herpangina

Pharyngotonsillar

None

High fever, sore throat

Hand, foot, and mouth disease

Sparse lesions; entire oropharynx

Oval vesicles, hand and feet; maculopapular rash, buttocks

Fever, sore mouth

Herpetic gingivostomatitis

Entire mouth involved; lesions rapidly coalesce, gingivae friable and bleeding

Perioral vesicles

Fever, irritability, fetid breath, lymphadenopathy

Varicella

Palate, lips, tongue

Centripetal vesicular eruption

Fever, malaise, headache, anorexia

Aphthous stomatitis

Ulcers, discrete and recurrent, aphthae do not coalesce

None

Prodrome of oral hyperemia, paresthesias

Erythema multiforme

Entire mouth; lips severely involved; gingivae relatively spared

Vesicular, urticarial, target lesions

Fever, malaise, anorexia

may be confused with aphthous stomatitis. The vesicles and ulcers of hand, foot, and mouth disease are larger than those of herpangina; in contrast to herpetic gingivostomatitis, they spare the lips and usually the gingivae. The cutaneous lesions are much more common in children than in adults and erupt 1 or 2 days after the oral lesions. They consist of 3–7 mm vesicopustules with an erythematous rim and may be sparse or numerous. They are typically oval with their long axis along the dermatoglyphics and are found on the palms, soles, backs of the hands, and around the nails of the fingers and toes. The lesions are non-pruritic and usually resolve without much crusting. A maculopapular eruption is frequently found on the buttocks and occasionally on the arms, legs, or face.151,152 The disease resolves spontaneously after 5–10 days. Diagnosis is usually made clinically, although isolation of the virus from vesicle fluid, throat swabs, and feces or documentation of a rise in serum antibody titer to one of the known etiologic agents is confirmatory. Electron microscopy shows typical virus particles.153 Tzanck smears are always negative for giant cells, balloon cells, and intranuclear inclusions and can be used to distinguish hand, foot, and mouth disease from herpesvirus infections.154 Treatment is symptomatic only (see also Ch. 25).

The most common form of primary herpes simplex infection is acute gingivostomatitis.155–158 Infants under 6 months of age usually have a protective maternal antibody; therefore, the infection is usually seen between the ages of 6 months and 5 years.155 However, only about 1% of the infected children develop this severe infection, 10% get uncharacteristic flu-like symptoms, and 90% will have no symptoms. Following an incubation period of

2–12 days, many patients experience a prodrome consisting of irritability, fever, headache, nausea, and vomiting. The oral eruption consists of small vesicles on an erythematous base scattered over the tongue, buccal mucosa, uvula, soft palate, pharynx, inner aspect of the lips, and floor of the mouth. The vesicles, which are intraepithelial in location, rupture quickly leaving shallow painful ulcers and erosions.159 The widespread presentation of herpetic lesions on both keratinized and non-keratinized mucosa in primary herpetic gingivostomatitis likely results from a combined bacterial and viral infection. This explains the deviation from the ‘rule’160 that herpes lesions occur only on keratinized mucosal surfaces. Typically, the gingivae are deeply erythematous and swollen and bleed easily when traumatized. In contrast to aphthous ulcerations, the lesions soon coalesce to form irregular shallow ulcers. Multiple vesicles may develop on the skin in the perioral area, even at quite a distance from the mouth; thumb suckers may acquire an acute herpetic whitlow on the thumb as well. Because of severe mouth pain, the child may drool excessively and refuse to eat or drink. The breath often has a fetid odor. Although fever is usually low grade, at times it may rise to 105°F. Tender cervical and submental lymphadenopathy is expected. Children immediately after measles or with immunosuppression may develop a particularly severe form of ulceration known as aphthoid of Pospischill–Feyrter with necrotic lesions around the mouth, perigenitally, and perianally that takes several weeks to heal and is an indication for systemic antiviral therapy. The diagnosis is usually made clinically but can be confirmed by a positive Tzanck smear, viral culture, or enzyme-linked immunosorbent assay (ELISA). Nearly all primary oral infections are caused by HSV-1. Convalescence coincides with a rise in neutralizing antibody titers that peak at three to four weeks.

152. Richardson HB, Leibovitz A. Hand, foot and mouth disease in children. J Pediatr. 1965;67:6. 153. Haneke E. Electron microscopic demonstration of virus particles in hand, foot and mouth disease. Dermatologica. 1985;171:321–326. 154. Cherry JD, Jahn CL. Hand, foot and mouth syndrome. Pediatrics. 1966;37:637. 155. Wright JM, Taylor PP, Allen EP, et al. A review of the oral manifestations of infections in pediatric patients. Pediatr Infect Dis. 1984;3:80. 156. Snavely SR, Liu C. Clinical spectrum of herpes simplex virus infections. Clin Dermatol. 1984;2:8.

157. McDonald MI, Durach DT. Viral blisters. Dermatol Clin. 1983;1:281. 158. Blackman JA, Andersen RD, Healy A, et al. Management of young children with recurrent herpes simplex lesions in special education programs. Pediatr Infect Dis. 1985;4:221. 159. Amir J, Harel L, Smetana Z, et al. The natural history of primary herpes simplex type I gingivostomatitis in children. Pediatr Dermatol. 1999;16(4):259–263. 160. Weathers DR, Griffin JW. Intraoral ulcerations of recurrent herpes simplex and recurrent aphthae: two distinct clinical entities. J Am Dent Assoc. 1970;81:81.

HERPETIC GINGIVOSTOMATITIS

670

Mucous membrane disorders

tions on the tongue, lips, palate, and gingiva (Fig. 9.22). They are generally asymptomatic and require no therapy. In herpes zoster infections, oral lesions are typically unilateral in distribution and more painful. Both types of varicella-zoster virus infections can be confirmed by obtaining a Tzanck smear from an oral vesicle or ulcer and by demonstrating ballooning degeneration of the epithelial cells and multinucleated syncytial giant cells.163 Although antiviral treatment is not mandatory in otherwise healthy children with

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Differential diagnosis includes herpangina and hand, foot, and mouth disease, aphthous stomatitis, infectious mononucleosis, streptococcal pharyngitis, and Stevens–Johnson syndrome. Evidence for recent contact with someone with an active herpetic infection is helpful in establishing the diagnosis. In an uncomplicated course, the fever subsides by the fourth day and subsequent healing of lesions occurs over the next 7–10 days. The entire course rarely lasts more than 2 weeks. Supportive treatment consists of antipyretics and topical anesthetics such as dyclonine (Table 9.5). When the manifestations are severe, hospitalization and administration of intravenous fluids may be required to maintain adequate hydration. Measures to improve oral hygiene such as dilute hydrogen peroxide or saline mouthwashes or gargles may reduce bacterial overgrowth and provide some relief from discomfort. Treatment of herpetic gingivostomatitis with acyclovir was shown in one randomized doubleblind study to reduce the duration of intra- and extra-oral lesions as well as viral shedding. Those patients treated with acyclovir had earlier resolution of fever and fewer days with difficulty in eating or swallowing.161 Suppressive therapy may be employed for patients with greater than two outbreaks annually, or with a history of ocular HSV disease.162 Parents should be educated as to the infectivity of the lesions when acute, in order to prevent spread to others in the immediate environment.158

9

VARICELLA-ZOSTER INFECTIONS Oral mucosal lesions are a common manifestation of varicella and often precede onset of the skin eruption. The vesicles are relatively transient and rapidly progress to small shallow ulcera-

Figure 9.22  Enanthem of chickenpox (Courtesy Dr A. Torrelo).

Table 9.5  Topical anesthetic agents suitable for use on the oral mucous membranes AGENT

MANUFACTURER

ANESTHETIC

SIZE

Benzo-jel gel (banana flavor)

Schein

20% benzocaine

1-oz jar

Cetacaine

Cetylite

14% benzocaine 2% butyl aminobenzoate 2% tetracaine HCl

  Liquid (for swab application)   Ointment (flavored)   Spray

2-oz bottle 37-g jar 56 g

Gingicaine gingipak (cherry, chocolate milk, piña colada, strawberry)

Schein

20% benzocaine

1-oz jar

Hurricane liquid or gel (original flavor, piña colada)   Spray

Beutlich

20% benzocaine

1 oz 2 oz

Lidocaine ointment 5% (mint-flavored)

Schein

5% lidocaine

50 g

Topex   Gel or liquid (banana, cherry, mint, piña colada)   Spray (cherry)

Sultan

20% benzocaine

2 oz

Xylocaine solution topical 4%

Astra

4% lidocaine

50 mL

Xylocaine viscous 2%

Astra

2% lidocaine

100 mL, 450 mL

Dyclone

Astra

0.5% or 1% dyclonine

1 fl oz

2 oz

161. Amir J, Harel L, Smetana Z, et al. Treatment of herpes simplex gingivostomatitis with acyclovir (SIC) in children: a randomized double blind placebo controlled study. BMJ. 1997;314(4097):1800–1803.

162. Wolverton S. Comprehensive dermatologic drug therapy. 2nd ed. Philadelphia: Elsevier; 2007:103. 163. Farman AQ. Clinical and cytological features of the oral lesions caused by chicken-pox (varicella). J Oral Med. 1976;31:94.

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Diseases of Mucous Membranes and Appendageal Structures

primary varicella infection, oral acyclovir given within 24 hours of illness onset has been shown to reduce the duration of fever by 1 day, and to decrease the severity of symptoms.164 Topical anesthetics and analgesic agents are palliative (Table 9.5).155

ACUTE NECROTIZING ULCERATIVE GINGIVITIS

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Acute necrotizing ulcerative gingivitis (ANUG) affects adolescents and young adults and occurs rarely in children. This inflammatory process involves mainly the gingival margins, crest of the gingiva, interdental papillae, and periodontium and is also known as trenchmouth, fusospirochetal gingivitis, and phagedenic gingivitis. When the lesions spread to the cheeks, tongue, soft palate, and pharynx, the term Vincent’s stomatitis or angina has been used.44 The disorder is characterized by abrupt onset of extremely painful hyperemic gingivae and sharply demarcated ulcerations of the interdental papillae. The eroded papillae and free gingiva bleed easily when touched and become covered by a gray necrotic pseudomembrane. A fetid mouth odor commonly accompanies these findings. Because of the gingival pain and tendency to bleed easily, the patients find it difficult to eat. Profuse salivation as well as a distinct metallic taste to the saliva are common complaints. The teeth may be extremely sensitive to pressure, are thought to be slightly extruded, and may be slightly movable. Rapid destruction of the dental ligament is observed in acute necrotizing ulcerative periodontitis.165 Headache, malaise, low-grade fever, as well as regional lymphadenopathy are usual. Although acute necrotizing ulcerative gingivitis occurs in epidemic patterns as well as sporadically, it is not believed to be a communicable disorder but is rather attributed to a mixed infection superimposed on certain predisposing conditions. Poor oral hygiene is thought to be an important factor as well as inadequate nutrition, heavy smoking, fatigue, and stress. Chronic changes in the oral cavity such as pericoronitis, ill-fitting crowns, inlays and prosthetic appliances, dental caries, impacted food, faulty restorations, and pre-existing marginal gingivitis are all considered possible contributory factors.101,166 Patients with acquired immunodeficiency syndrome, leukemia or blood dyscrasias causing bone marrow depression are also predisposed to this type of gingivitis. The organisms involved in this condition are the Gramnegative spirochete Borrelia vincentii and the fusiform Grampositive bacillus Fusobacterium dentium, which proliferate in the oral cavity and are invariably found in profusion in necrotizing gingivitis. Smears obtained from the gingival surface should demonstrate overwhelming numbers of those two organisms; however, other organisms will be present as well as polymorphonuclear leukocytes. Both B. vincentii and F. dentium require anaerobic conditions for culture. Ultimately, the diagnosis is made on clinical grounds because the organisms present in necrotizing gingivitis can also be found in other types of gingivitis as well as in the normal mouth, although generally in considerably fewer numbers.44

164. Mueller NH, Gilden DH, Cohrs RJ. Varicella zoster virus infection: clinical features, molecular pathogenesis of disease, and latency. Neurol Clin. 2008;26(3):675–697, viii. 165. Navak MJ. Necrotizing ulcerative periodontitis. Ann Periodontol. 1999;4:74–78.

672

Herpetic gingivostomatitis, which is much more common in young children, is most often confused with necrotizing gingivitis. Other conditions to be considered in the differential diagnosis include desquamative gingivitis, chronic gingivitis due to various causes, and mouth ulcerations in patients with blood dyscrasias. Herpetic gingivostomatitis, hand, foot, and mouth disease, aphthous stomatitis, Behçet syndrome, and Stevens– Johnson syndrome may also be confused with necrotizing gingivitis. Treatment of acute necrotizing gingivitis should be instituted by a dentist after a thorough dental evaluation. Management varies from a conservative approach advocating only superficial cleansing in the acute phase, followed by more thorough scaling and polishing later in the course,44 to aggressive debridement with irrigation and periodontal curettage early in the disease.89 Although oxygenating agents and antibiotics are often prescribed, there is no substantive evidence that they hasten resolution of the inflammatory process, which seems to run its course. When extensive involvement of the oral cavity, lymphadenopathy, or systemic signs of disease are present, antibiotic therapy is recommended. Penicillin and/or metronidazole are considered the drugs of choice. All authorities agree that measures to improve oral hygiene, such as gentle brushing and vigorous rinsing several times daily with dilute hydrogen peroxide mixed 1 : 1 with water, are important aspects of care. The patient should also be educated about the significance of predisposing factors. Subsequent to recovery from the acute process, a careful periodontal evaluation is appropriate. Recontouring of the gingival papillae by gingivoplasty may be required. Patients with extensive involvement of the oral cavity should be studied for underlying diseases, particularly blood dyscrasias and AIDS. Rarely, serious sequelae, such as gangrenous stomatitis, noma, or septicemia, have resulted from this condition. ANUG is considered the antecedent lesion of noma (cancrum oris) which is an infectious, but not contagious, disease destroying the oro-facial tissues and other neighboring structures in its fulminating course. Noma affects predominantly children aged 2–16 years in sub-Saharan Africa. The most important risk factors are poverty, malnutrition, poor oral hygiene, deplorable environmental sanitation, close residential proximity to livestock, and infectious diseases, particularly measles. Malnutrition acts synergistically with endemic infections in promoting an immunodeficient state, and noma results from the interaction of general and local factors with a weakened immune system as the common denominator. Recent studies suggest that evolution of ANUG to noma requires infection by a consortium of microorganisms with Fusobacterium necrophorum and Prevotella intermedia as the suspected key players.167

ORAL CANDIDIASIS The oral mucous membranes constitute the most frequent site of colonization by Candida in the pediatric age group. Host factors are responsible for the many different forms of candidiasis. C. albicans is the organism usually responsible for the white-

166. Rowland RW. Necrotizing ulcerative gingivitis. Ann Periodontol. 1999;4:65– 73, 78. 167. Enwonwu CO, Falkler WA, Idigbe EO, et al. Noma (cancrum oris): questions and answers. Oral Dis. 1999;5:144–149.

Mucous membrane disorders

Acute candidiasis Acute pseudomembranous candidiasis (thrush) Newborns become colonized with Candida as they traverse the maternal vaginal tract. Additional sources of colonization include the hands of the nursery personnel or other infants. When candidal vulvovaginitis develops late in the course of the pregnancy, the infant is at greater risk of developing thrush. Antepartum therapy with intravaginal clotrimazole reduces the risk of neonatal colonization in the birth canal. The great majority of newborns in whom thrush develops are otherwise healthy. Factors such as sex, season, prematurity, mode of feeding, amount of resuscitation, and use of broadspectrum antibiotics have not always conclusively influenced occurrence of clinical lesions.168 Often, candidiasis of the diaper area develops early on in the course of oral thrush. Newborns with thrush warrant treatment with nystatin oral suspension 200 000 units (2 mL) on to the tongue four times daily for 7–10 days. Such therapy usually produces prompt recovery. The solution should be slowly instilled into the mouth to permit adequate contact with affected tissues. Alternatively, a cotton-tipped swab may be employed to apply the medication to infected sites after feeding. Resistant cases may require 400 000 units of nystatin oral solution qid for seven to 10 days or gentian violet 0.5% aqueous solution bid for 3 days. An alternate method of treatment involves insertion of a 10 mg clotrimazole or amphotericin-B troche tightly into a nipple and allowing the child to suck these qid.169 Young children are also susceptible to transient episodes of thrush while their oral flora is becoming established. Most often, such infections are unrelated to any known predisposing factors. Immunocompromised children, especially those with AIDS, usually also develop candida esophagitis.170

Acute atrophic oral candidiasis This form of candidiasis is unique in that it is the only form that is consistently painful. Arising from acute pseudomembranous candidiasis or de novo, clinical manifestations include red, atrophic, painful, persistent ulcerations. White pseudomembranes are rarely seen.89 Acute atrophic oral candidiasis should be suspected if broadspectrum antibiotics have been prescribed and oral burning,

168. Shrand H. Thrush in the newborn. BMJ. 1961;2:1530. 169. Mansour A, Gelfand EW. A new approach to the use of antifungal agents in infants with persistent oral candidiasis. J Pediatr. 1981;98:161. 170. Flaitz CM, Hicks MJ. Oral candidiasis in children with immunosuppression: clinical appearance and therapeutic considerations. ASDC J Dent Child. 1999;66:161–166.

dysgeusia, or a sore throat are reported. Angular cheilitis may be present. KOH preparations from the denuded mucosa reveal budding yeasts and pseudomycelia.

Chronic candidiasis Chronic hyperplastic candidiasis This form of candidiasis, mainly seen in middle-aged men, is characterized by firm white plaques on the lips, tongue, or buccal mucosa, which tend to persist. Candida frequently colonizes oral leukoplakia, although such lesions are exceedingly rare in children.171 Alternatively, Candida does not invade leukoedema, lichen planus, squamous papilloma, or carcinoma. DISORDERS OF THE ORAL MUCOUS MEMBRANES

gray pseudomembranes (thrush) found on the buccal mucosa, palate, gums, and tongue. These white patches appear curd-like and friable and are easily removed by gentle pressure. Composed of almost pure colonies of Candida plus desquamated epithelial cells, inflammatory cells, and fibrin, the yeast is readily identified within such patches by either a KOH preparation or culture on Sabouraud or Mycosel agar, or both. Removal of the white plaques reveals an underlying area of erythema or shallow ulcerations that easily bleeds.

9

Chronic atrophic candidiasis Denture sore mouth is synonymous with chronic atrophic candidiasis and is frequently associated with angular cheilitis. Although common in adult denture wearers, it is rare in children even when they wear dentures, such as in the Papillon–Lefèvre syndrome.

Chronic mucocutaneous candidiasis Typically, this rare condition, which occurs as a result of various genetic defects, is first detected during childhood. Candida is one of the opportunistic pathogens that characterize this disease, and evidence of chronic involvement is seen in the skin, scalp, nails, and mucous membranes. Because of such immunodeficiencies as impaired cell-mediated immunity, neutrophil function defects, isolated IgA deficiency, and reduced serum candicidal activity, candidal infections are resistant to common forms of therapy.44 Ketoconazole, itraconazole and fluconazole therapy has proved effective in most cases.

Chronic familial mucocutaneous candidiasis Occurring early in life, this subset is genetically transmitted, probably as an autosomal-recessive trait. Clinical manifestations, including oral lesions, are seen by 5 years of age.

Chronic localized mucocutaneous candidiasis In this severe form of candidiasis, which seemingly lacks genetic transmission, granulomatous and horny masses are evident on the face and scalp. Other fungal and bacterial infections commonly occur. The mouth shows typical white pseudomembranes which cannot be easily wiped off, and the nails are often dystrophic by candidal infection.

Candida endocrinopathy syndrome The skin, scalp, nails, and mucous membranes are infected with Candida as a result of this genetically transmitted entity. Family

171. Hornstein OP, Gräßel R, Schirner E, et al. Orale Candida-besiedlung bei Leukoplakie und Karzinomen der Mundhöhle. Dtsch Med Wschr. 1979;104:1033–1036.

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Diseases of Mucous Membranes and Appendageal Structures

studies suggest an autosomal-recessive pattern of inheritance. The oral cavity frequently shows candidal lesions in association with hypoadrenalism (Addison’s disease), hypoparathyroidism, hypothyroidism, ovarian insufficiency, or diabetes mellitus. The thrush may precede the endocrinopathy by several years.172

Chronic diffuse mucocutaneous candidiasis

DISORDERS OF THE ORAL MUCOUS MEMBRANES

This syndrome usually has its onset during childhood, and patients lack associated endocrinopathies. Affected relatives are uncommon, although eight pedigrees suggest an autosomalrecessive mode of inheritance.173 Widespread erythematous serpiginous lesions involving the skin and mucous membranes characterize this condition. Hyperkeratosis is not a prominent feature. The nails are also infected with Candida. A subset of patients with chronic diffuse mucocutaneous candidiasis do not develop their disorder until adolescence. This group often receives multiple antibiotic courses for acne, furunculosis, or urinary tract infections. The antibiotics may alter their cutaneous and oral flora, allowing overgrowth of C. albicans. Why progression to chronic diffuse candidiasis occurs remains unclear.174

The precise diagnosis cannot be made without histopathologic evaluation of the involved gingiva. Immunofluorescence preparations and special stains may also be helpful. The disorder is chronic and responsive only to therapy specific for the particular underlying disease process.

ORAL-FACIAL-DIGITAL SYNDROME I (PAPILLON– LÉAGE–PSAUME SYNDROME) This X-linked dominant syndrome is due to mutations in the (OFD1) gene, which encodes a centrosomal protein that localizes in the basal body of primary cilia.178–180 Oral-facial-digital syndrome 1 represents a lethal factor for males and results in the following facial abnormalities: frontal bossing, pseudocleft of the upper lip, cleft or defect of the hard palate, multiple hyperplastic frenula, cleft tongue with hamartomas between the lobes, ankyloglossia, fibrous bands in upper and lower mucobuccal folds, absent lower lateral incisors, malpositioned and supernumerary teeth, hypoplasia of malar bones, broad nasal root, dystopia canthorum, hypoplasia of the alar cartilages, and milia of the ears and upper face in infancy (Table 9.6).181 Table 9.6  Differences between OFD I and OFD II syndromes

DESQUAMATIVE GINGIVITIS The term desquamative gingivitis is used to describe a specific clinical picture characterized by intense erythema of the gingiva and desquamation of the surface epithelium. Although it occurs primarily in adulthood, children and adolescents may rarely develop this condition as a manifestation of any one of several diseases. Desquamative gingivitis is not a disease per se but is in most cases a sign of erosive lichen planus, bullous pemphigoid, or cicatricial pemphigoid whereas pemphigus vulgaris, tuberculosis, histoplasmosis, or blastomycosis are rare.44,98,175,176 This condition has also been observed as an allergic reaction to tosylamide/formaldehyde resin in a female biting her lacquered nails.177 The clinical picture is one of intense erythema and swelling of the gingiva in a patchy distribution. The involved areas may become hemorrhagic and denuded, and occasionally intact vesicles can be found. The epithelium strips off the gingival surface easily, leaving a raw, sensitive, bleeding base. Oral structures other than the gingiva may also be involved, most frequently the buccal mucosa. There is extreme discomfort from the pain and hemorrhage caused by pressure from toothbrushing, and ingestion of coarse, hard, or spicy foods, or those that are extremely hot or cold.

172. de Padova-Elder SM, Ditre CM, Kantor GR, et al. Candidiasis endocrinopathy syndrome. Treatment with itraconazole. Arch Dermatol. 1994;130:19–22. 173. Wells RS, Higgs JM, MacDonald A, et al. Familial chronic muco-cutaneous candidiasis. J Med Genet. 1972;9:302. 174. Kirkpatrick CH. Host factors in defense against fungal infections. Am J Med. 1984;77:1. 175. Vaillant L, Chauchaix-Barthes S, Huttenberger B, et al. Chronic desquamative gingivitis syndrome: retrospective analysis of 33 cases. Ann Dermatol Venereol. 2000;127:381–387. 176. Yih WY, Richardson L, Kratochvil FJ, et al. Expression of estrogen receptors in desquamative gingivitis. J Periodontol. 2000;71:482–487.

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OFD I

OFD II

Genetics

X-linked dominant; females only

Autosomal-recessive; both sexes affected

Skin

Pilosebaceous dysplasia; milia

Normal

Hair

Coarse and sparse

Normal

Alveolar ridge

Thick frenula

Normal or flared

Dentition

Absent lateral mandibular incisors

Normal or absent lateral mandibular incisors

Nose

Alar hypoplasia

Broad bifid tip

Mandible

Hypoplasia of ramus of mandible

Hypoplasia of body of mandible

Digits

Unilateral polysyndactyly of hallux

Bilateral polysyndactyly of halluces

Hearing

Normal

Conductive hearing defect

OFD, oral-facial-digital.

177. Staines KS, Felix DH, Forsyth A. Desquamative gingivitis, sole manifestation of tosylamide/formaldehyde resin allergy. Contact Derm. 1998;39:90. 178. Ferrante MI, Giorgio G, Feather SA, et al. Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet. 2001;68(3):569–576. 179. Prattichizzo C, Macca M, Novelli V, et al. Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients. Hum Mutat. 2008;29(10):1237–1246. 180. Gurrieri F, Franco B, Toriello H, et al. Oral-facial-digital syndromes: review and diagnostic guidelines. Am J Med Genet A. 2007;143A(24):3314–3323. 181. Del C, Boente M, Prime N, et al. A mosaic pattern of alopecia in the oral-facial-digital syndrome Type I (Papillon–Leage and Psaume syndrome). Pediatr Dermatol. 1999;16:367–370.

Mucous membrane disorders

ORAL-FACIAL-DIGITAL SYNDROME II (MOHR SYNDROME) This autosomal-recessive syndrome includes the following facial features: lobate tongue, nodular hamartomas of the tongue, midline cleft of the upper lip, usually intact but high, arched palate, hypertrophied frenulum, dystopia canthorum with broad nasal root, broad nose with bifid tip, hypoplastic mandible, and variably absent mandibular central incisors. Additional findings include malformed incus and conductive hearing defect, short stature, digital anomalies (syndactyly, brachydactyly, clinodactyly, polydactyly) and bilateral reduplicated hallux, first metatarsal, cuneiform, and cuboid bones.185

TRICHO-DENTO-OSSEOUS SYNDROME

BÖÖK SYNDROME A hereditary syndrome involving a kindred of 172 members in which 25 were affected was described by Böök in 1950.189 Patients with hypodontia of the premolar region (P), hyperhidrosis of the palms and soles (H), and premature whitening of the hair (premature canities) (C) spanned four generations. This constellation of findings is also referred to as PHC syndrome. The penetrance of this autosomal-dominant gene is nearly complete for the aplasia of the bicuspid region and the premature canities. Expressivity is variable, however, in the number of bicuspids that fail to develop and the age of onset of whitening of the hair (range 6–23 years). The loss of hair color occurs in a uniform rather than spotty pattern, with the scalp hair being affected most often. No alteration of skin pigment has been reported. Two-thirds of affected persons with dental and hair changes were found to have detectable hyperfunction of the palmar and plantar sweat glands. Although there is no specific therapy for this disorder, attention should be directed toward providing cosmetic improvement and control of the hyperhidrosis.

Tricho-dento-osseous syndrome (TDO) is the result of a frameshift mutation in the coding sequence of the DLX-3 gene on chromosome 17. This gene codes for the transcription factor Distal-less-3, a protein that is thought to be crucial in the patterning of hair, teeth, and bone.186 This autosomal-dominant syndrome consists of kinky hair that is present at birth but often straightens during childhood, as well as small, pitted, widely spaced teeth and sclerotic bones. The facies is characteristic, with frontal bossing, a square jaw, and dolichocephaly. An additional characteristic finding is brittle, peeling nails. The teeth become discolored and erode up to the gingival margin due to the defective enamel. Periodontal abscesses are common. Dental radiographs show taurodontia (increase in size of the pulp chamber) in both sets of dentition, lack of contrast between the enamel and dentin, and a moth-eaten appearance of the enamel. By the second or third decade, many affected persons are edentulous. The sclerotic bones are most readily demonstrable on skull radiographs. Premature closure of the calvarial sutures may be seen. The skeletal findings are not associated with clinical symptoms. An elevation of serum acid phosphatase has been documented in a few affected patients.187,188

Papillon–Lefèvre syndrome (PLS) is an autosomal-recessive disorder characterized by palmoplantar keratoderma and severe, early onset periodontitis which results from deficiency of cathepsin C activity secondary to mutations in the cathepsin C gene on chromosome 11q14. Different cathepsin C mutations have been reported in PLS patients, 13 of whom are homozygous for a given mutation reflecting consanguinity, and three are compound heterozygotes and inherited as an autosomal-recessive trait.190–193 This condition has been described in both sexes and all races.194 Although the skin changes have been noted in a few affected persons at birth, most experience onset during the first 4 years of life. The cutaneous manifestations consist of a diffuse symmetric transgredient keratoderma involving the palms and soles, Achilles area of the heels, and frequently the dorsum of the fingers and toes, volar surfaces of the wrists, dorsal interphalangeal joints of the digits, and the elbows, knees, and lateral malleoli.194–198 The keratotic areas are sharply demarcated, often displaying an erythematous margin. In some patients, the areas of

182. Solomon LM, Fretzin D, Pruzansky S. Pilosebaceous dysplasia in the oral-facial-digital syndrome. Arch Dermatol. 1970;102:598. 183. Rimoin DL, Edgerton MJ. Genetic and clinical heterogeneity in the oro-facial-digital syndromes. J Pediatr. 1967;71:94. 184. Goodman RM, Gorlin RJ. Atlas of the face in genetic disorders. St Louis: CV Mosby; 1977. 185. Martinot VL, Manouvrier S, Anastassos Y, et al. Orodigitofacial syndrome type I and II: clinical and surgical studies. Cleft Palate Craniofac J. 1994;31:401–408. 186. Duverger O, Lee D, Hassan MQ, et al. Molecular consequences of a frameshifted DLX3 mutant leading to tricho-dento-osseous syndrome. J Biol Chem. 2008;283(29):20198–20208. 187. Wright JT, Kula K, Hall K, et al. Analysis of the tricho-dento-osseous syndrome genotype and phenotype. Am J Med Genet. 1997;72:197–204. 188. Lichtenstein J, Warson R, Jorgenson R, et al. The tricho-dentoosseous syndrome (TDO). Am J Hum Genet. 1972;24:569. 189. Böök JA. Clinical and genetical studies of hypodontia: premolar aplasia, hyperhidrosis, and canities prematura; a new hereditary syndrome in man. Am J Hum Genet. 1950;2:240. 190. Hart TC, Hart PS, Michalec MD, et al. Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet. 2000;37:88–94.

191. Hart TC, Walker SJ, Bowden DW, et al. An integrated physical and genetic map of the PLS locus interval on chromosome 11q14. Mamm Genome. 2000;11:243–246. 192. Nakano A, Nomura K, Nakano H, et al. Papillon-Lefevre syndrome: mutations and polymorphisms in the cathepsin C gene. J Invest Dermatol. 2001;116:339–343. 193. Allende L, Garcia-Perez M, Moreno A, et al. Cathepsin C gene: First compound heterozygous patient with Papillon-Lefevre syndrome and a novel symptomless mutation. Hum Mutat. 2001;17:152–153. 194. Haneke E. The Papillon-Lefevre syndrome: keratosis palmoplantaris with peridontopathy. Hum Genet. 1979;51:1–35. 195. Schaffer AW, Pearlstein HH. Hyperkeratosis palmoplantaris with periodontosis (Papillon-Lefevre syndrome). Oral Surg Oral Med Oral Pathol. 1967;24:180. 196. Coccia CT, McDonald RE, Mitchell DF. Papillon-Lefevre syndrome: precocious periodontosis with palmar-plantar hyperkeratosis. J Periodontol. 1966;37:408. 197. Brownstein MH, Skolnik P. Papillon-Lefevre syndrome. Arch Dermatol. 1972;106:533. 198. Gelmetti C, Nazzaro V, Cerri D, Fracasso L. Long-term preservation of permanent teeth in a patient with Papillon-Lefèvre syndrome treated with etretinate. Pediatr Dermatol. 1989;6:222.

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Additional anomalies are asymmetric shortening of the digits with or without clinodactyly and syndactyly, patchy alopecia, mild mental retardation, unilateral polysyndactyly of the hallux, renal cysts, and pilosebaceous dysplasia.182–184

9

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DISORDERS OF THE ORAL MUCOUS MEMBRANES

hyperkeratoses fluctuate in severity, even remitting episodically; in others, they persist, causing painful fissures, particularly during the colder months.145 Several authorities comment that the severity of the keratoderma often parallels the degree of periodontal inflammation. Biopsy of the keratoderma demonstrates hyperkeratosis with parakeratosis and acanthosis.197 The deciduous teeth erupt at the expected age and in normal sequence; the teeth are structurally normal. Once the primary dentition is complete, periodontal bone destruction ensues, accompanied by severe purulent gingivitis and fetid mouth odor. The deciduous teeth are shed prematurely in the same sequence in which they erupted and are usually completely exfoliated by the age of 4–6 years. Following loss of the teeth, the inflammatory process subsides and the gingivae return to a normal appearance. With the eruption of the permanent dentition, the inflammatory process is renewed and the second set of teeth are also shed, leaving only the third molars intact.194,195 While the process is active, chewing is painful because of the looseness of the teeth, which tilt and migrate within the gingivae (Fig. 9.23). Radiographic examination will demonstrate the complete resorption of alveolar bone, giving the teeth a ‘floatingin-air’ appearance. Painful regional lymphadenopathy has been observed while the gingivitis is present.195 Biopsy of the gingivae reveals only the nonspecific changes of acute and chronic inflammation. Variable findings in this syndrome include calcification of the falx cerebri, increased susceptibility to infection, hyperhidrosis,

Figure 9.23  Papillon–Lefèvre syndrome.

199. Haneke E, Hornstein OP, Lex C. Increased susceptibility to infections in the Papillon-Lefevre syndrome. Dermatologica. 1975;150:283–286. 200. Liu R. Cao C, Meng H, Tang Z. Leukocyte functions in 2 cases of Papillon-Lefevre syndrome. J Clin Periodontol. 2000;27:69–73. 201. Ghaffer KA, Zahran FM, Fahmy HM, et al. Papillon-Lefevre syndrome: neutrophil function in 15 cases from 4 families in Egypt. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:320–325. 202. Kressin S, Herforth A, Preis S, et al. Papillon-Lefevre syndrome – successful treatment with a combination of retinoid and concurrent systematic periodontal therapy: case reports. Quintessence Int. 1995;26:795–803. 203. Lundgren T, Crossner CG, Twetman S, et al. Systemic retinoid medication and periodontal health in patients with Papillon-Lefevre syndrome. J Clin Periodontol. 1996;23:176–179.

676

bromhidrosis, dystrophic nails, as well as scattered additional abnormalities in individual cases.194,195,199–201 Keratoderma palmoplantare of Unna–Thost and mal de Meleda must be distinguished from Papillon–Lefèvre syndrome, although neither is associated with dental problems. Conditions associated with gingivitis and causing exfoliation of the teeth include acrodynia, hypophosphatasia, cyclic neutropenia, Ehlers–Danlos type VIII, variable immune defects, and Takahara syndrome.194,196 The keratoderma should be treated with emollients and keratolytic agents. Most therapeutic modalities for the gingivitis have been without benefit, but etretinate and acitretin therapy resulted in healing of cutaneous and periodontal lesions within a few months’ time in some patients treated thus far.198,202–204 These patients should be closely followed by a dentist, so that prostheses can be provided at the appropriate time and by a physician due to the potential for life-threatening bacterial infections. Osseointegrated implants appear to be promising.205

ACATALASEMIA Acatalasemia is characterized by the absence of catalase in the blood and tissues, rendering affected persons unable to degrade exogenous or endogenous hydrogen peroxide, which accumulates in the periodontal tissues.206 The gingivae are thus deprived of oxygen, resulting in ulceration and necrosis of the soft and hard tissues. In more severe cases, inflammation develops into a far advanced gangrene of the maxilla or the soft tissues of the mouth (Takahara’s disease).207 Numerous pedigrees support an incomplete recessive monogenetic mode of inheritance in this disorder. Acatalasemia cannot be regarded as a single entity but rather as a group of mutations of the catalase gene that result in altered activity levels of a structurally normal enzyme.208 The general physical examination of patients with acatalasemia is normal, except for the oral and occasionally the nasal mucosa. No laboratory abnormalities are reported, except for the darkening of blood on exposure to hydrogen peroxide. Oral ulcerations result from the production of hydrogen peroxide by bacteria proliferating in the crevices of the teeth or tonsillar lacunae. The absence of catalase to metabolize the hydrogen peroxide leads to oxidation of hemoglobin and thus to ulceration or decay of the oral tissues, or both. The early removal of diseased teeth and tonsils and the administration of antibiotics halt the progress of the disease. The healing time for acatalasemics is identical to that of normal persons. Biopsies of ulcerated tissue show chronic inflammation. Immunologically,

204. Siragusa M, Romano C, Batticane N, et al. A new family with PapillonLefevre syndrome: effectiveness of etretinate treatment. Cutis. 2000;65:151–155. 205. Ullbro C, Crossner CG, Lundgren T, et al. Osseointegrated implants in a patient with Papillon-Lefevre syndrome. A 41/2-year follow up. J Clin Periodontol. 2000;27:951–954. 206. Aebi H, Suter H. Acatalasemia. In: Harris H, Hirshckorn K, eds. Advances in human genetics. Vol 2. New York: Plenum Press; 1971:143. 207. Perner H, Krenkel C, Lackner B, et al. Acatalasemia – Takahara’s disease. Hautarzt. 1999;50:590–592. 208. Goth L, Rass P, Madarasi I. A novel catalase mutation detected by polymerase chain reaction-single strand conformation polymorphism, nucleotide sequencing, and western blot analyses is responsible for the type C of Hungarian acatalasemia. Electrophoresis. 2001;22:49–51.

Oral ulcerations may occur as a manifestation of various forms of neutropenia, such as cyclic neutropenia, chronic benign neutropenia of childhood, agranulocytosis, as well as cyclic fever syndromes like PFAPA and leukemias.211 The ulcers may be relatively small, localized, and minimally painful or may enlarge gradually to form extensive painful necrotic lesions. A gangrenous stomatitis can develop in patients with severe neutropenia. In addition, necrotizing gingivitis (Vincent’s angina) may complicate the clinical picture. In cyclic neutropenia, the oral ulcers tend to remain small without much peripheral erythema and are randomly distributed throughout the oral cavity.211–213 The lesions develop during episodes of neutropenia that recur at 3- to 4-week intervals and usually last for 5–7 days. A mild gingivitis may also accompany the ulcerations.

Treatment consists of lavage and gentle debridement. Granulocyte-colony stimulating factor has been shown to hasten recovery of neutrophils, reducing the risk of secondary infection.214 Drug-induced agranulocytosis may result in necrotizing ulcerations of the oral mucosa, tonsils, and pharynx. The gingiva and palate are the mucosal surfaces most frequently involved in this condition. Shallow ulcers covered by a gray or black membrane are encircled by little or no inflammation. Complications range from severe secondary infection to hemorrhage from the gingiva. Excess salivation is a common finding. Histologically, denuded areas of mucosa lack polymorphonuclear leukocytes despite the presence of bacteria. Therapy is non-specific, except for elimination of the drug responsible for the agranulocytosis and administration of appropriate antibiotics. Dental procedures, particularly extractions, are contraindicated in the setting of agranulocytosis. The prognosis in drug-induced agranulocytosis is good if the offending agent can be identified and eliminated and infection controlled.44 Oral mucositis is a common consequence of intensive chemotherapy caused directly by the cytotoxic effect of chemotherapeutic agents and indirectly by sustained neutropenia. This form of mucositis is characterized by edematous erythema, epithelial necrosis, and ulcerations with fibrin membranes. It represents an important predisposing factor for life-threatening septic complications during chemotherapy-induced aplasia. A similar clinical picture, however, often associated with severe xerostomia, is also elicited by intraoral radiotherapy. Topical filgrastim (T-metHuG-CSF) in a viscous mouthrinse alleviated the symptoms in one study.215 Another syndrome with cyclic fever is called the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy syndrome (PFAPA). The onset of symptoms is between the age of 3 months and 12 years, with a mean age of 5 years. After an initial phase of generalized clinical symptoms such as asthenia, cranial neuritis, dysphagia, and anorexia, high fever suddenly occurs with temperatures over 40°C, shivering, multiple aphthous ulcers, pharyngitis and cervical lymphadenitis. Other symptoms may be headache, arthralgia and abdominal pain in about 50% of the cases. Fever recurs every 6–9 weeks. During the fever, there is an inflammatory syndrome of hyperleukocytosis, elevated sedimentation rate and increase of C-reactive protein which are not diagnostic. Differential diagnosis includes familial Mediterranean fever, hyper-IgD syndrome, and cyclic neutropenia. The prognosis is excellent. No specific cause or genetic basis has yet been identified. The most effective treatment is early administration of corticosteroids at a dose of 2 mg/kg.216–218 Cimetidine has also been used with some response to 150 mg

209. Guevara-Sangines E, Vilalobos A, Vega-Memije E, et al. Congenital generalized terminal hypertrichosis with gingival hyperplasia. Pediatr Dermatol. 2002;19(2):114–118. 210. Figuere LE, Pandolfo M, Dunne PW, et al. Mapping of the gengenital generalized hypertrichosis locus to chromosome Xq24-q27.1. Nature Genetics. 1995;10:202–207. 211. Andrews RG, Benjamin S, Shore N, et al. Chronic benign neutropenia of childhood with associated oral manifestations. Oral Surg. 1965;20:719. 212. Dale DC, Bolyard AA, Hammond WP. Cyclic neutropenia: natural history and effects of long-term treatment with recombinant human granulocyte colony-stimulating factor. Cancer Invest. 1993;11:219. 213. Rodenas JM, Ortego N, Herranz MT, et al. Cyclic neutropenia: a cause of recurrent aphthous stomatitis not to be missed. Dermatology. 1992;184:205.

214. Fink-Puches R, Kainz JT, Kahr A, et al. Granulocyte colony-stimulating factor treatment of cyclic neutropenia with recurrent oral aphthae. Arch Dermatol. 1996;132:1399–1400. 215. Karthaus M, Rosenthal C, Huebner G, et al. Effect of topical oral G-CSF on oral mucositis: a randomised placebo-controlled trial. Bone Marrow Transplant. 1998;22:781–785. 216. Marshall GS, Edwards KM, Butler J, et al. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110:43–46. 217. Feder HM. Periodic fever, aphthous stomatitis, pharyngitis, adenitis: a clinical review of a new syndrome. Curr Opin Pediatr. 2000;12: 253–256. 218. Ovetchkine P, Bry ML, Reinert P. Syndrome de Marshall: résultats d’une enquête nationale rétrospective. Arch Pediatr. 2000;3:578s–582s.

affected patients are normal, except for their inability to decompose hydrogen peroxide. Therapy consists of extracting affected teeth and tonsils at an early stage. Systemic antibiotics such as penicillin are necessary to control bacterial proliferation. Meticulous oral hygiene is necessary to prevent recurrence of the ulcerations. The overall prognosis in properly managed cases is good, except for the potential loss of all teeth and some alveolar bone. Topical hydrogen peroxide should be avoided by acatalasemic persons, as it is toxic to them.

CONGENITAL GENERALIZED HYPERTRICHOSIS WITH GINGIVAL HYPERPLASIA Congenital generalized hypertricosis is a rare disorder characterized by excessive hair growth over the entire body, with the exception of the palms and soles. The subgroup of generalized hypertrichosis characterized by hypertrichosis and gingival hyperplasia was first reported by Gross in 1856. At least 50 cases of hypertrichosis with gingival hyperplasia have been reported, both with and without seizures.209 Most cases of generalized hypertrichosis have an autosomal dominant pattern of inheritance, but an X-linked dominant pattern of inheritance has been suggested in a subset of patients. These observations are based on a Mexican family with 19 affected individuals in which men are more severely affected than women, and linkage has been identified with several markers from the long arm of the X chromosome, at the Xq24-q27.1 locus.210

ULCERATIVE STOMATITIS WITH NEUTROPENIA

9

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Mucous membrane disorders

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Diseases of Mucous Membranes and Appendageal Structures

once or twice daily or 20–40 mg/kg per day.219 Episodic flares in PFAPA were reduced in a small number of patients when colchicine was used prophylactically at a dose of 0.5–1.0 mg.220

RECURRENT APHTHOUS ULCERATION

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Recurrent oral ulcerations, also known as aphthae, aphthous stomatitis, and canker sores, are probably the most common cause of mouth ulcers and are classified as three distinct clinical types. Minor aphthous ulcers were first described by Mikulicz in 1888 and account for the greatest percentage of lesions (>80%). Major aphthous ulcers, described by Sutton in 1911, comprise approximately 8% of these lesions. herpetiform ulcers, so named by Cooke in 1960, have a similar frequency, but the latter types are considerably overreported.221,222 Despite the recommendation of the National Institute of Dental Research Workshop in 1977 that the term recurrent aphthous stomatitis be reserved for the major and minor types and that the term recurrent oral ulcerations be used to embrace all three clinical types,223 this suggested alteration in terminology has been applied only occasionally in subsequent publications. The confusion in nomenclature has been further compounded by failure in some publications to distinguish the lesions of recurrent intraoral herpes simplex infection, a totally different entity. Furthermore, even the term ‘stomatitis’ is a misnomer because the aphthae normally appear without a diffuse inflammation of the oral mucosa. Aphthous stomatitis occurs most frequently during the ages of 10–60 years, with the highest frequency of onset in the second decade of life.223 Estimates of prevalence vary from 5% to 60%, but the figure of 20% for the general population is the most widely accepted. A slightly higher prevalence has been observed in females. A positive family history is obtained in up to 40% of affected persons, but a definite mode of transmission has not been established.224 Children whose two parents are affected are much more likely to have aphthae (67%) than are offspring of affected mothers (53%), affected fathers (34%), or unaffected parents (9%).225 Twin studies have shown 90% concordance in identical twins as opposed to 57% concordance in fraternal twins.226 Non-Hispanic white patients have a fourfold increased prevalence of recurrent aphthous stomatitis compared with nonHispanic blacks. Patients from a higher socioeconomic background have almost twice the prevalence of aphthae than those from lower socioeconomic strata.227 The signs and symptoms of aphthous stomatitis vary with the particular form of the disorder.125,228–230

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Figure 9.24  Severe recurrent aphthous stomatitis in a child (courtesy of Dr A. Torrelo).

then into painful yellow necrotic ulcerations surrounded by an erythematous halo. A vesicular stage is absent. Lesions number less than 10, are smaller than 10 mm, and develop on the movable nonkeratinized mucosa of the labial, glossal, subglossal, and buccal surfaces and in the mucobuccal folds (Fig. 9.24). Ulcers localized to the hard palate and gingiva are extremely rare. The lesions heal within 7–10 days without the formation of scars. 2. Major aphthae are usually fewer in number (1–5 lesions) but do not differ in evolution. They may measure up to 3 cm in diameter, are deeper and more painful, and usually persist for longer periods, even up to 6 weeks. Resolution with scarring is expected. 3. Herpetiform ulcerations are profuse in number (up to 100 lesions) but relatively small, measuring only 1–2 mm. These ulcers, which have a brief vesicular stage, frequently coalesce to form plaques 5–20 mm in diameter and, therefore, have a herpetiform configuration. In contrast to minor and major aphthae, they may develop at any site in the oral cavity. They are intensely painful, persist for approximately 7–10 days, and heal without scarring.

1. Minor aphthae, the most common type of oral ulcerations, begin as erythematous macules that evolve into papules and

A premonitory stage is often experienced for all three types for 1–3 days prior to development of these lesions and is characterized by local sensations of tingling, paresthesias, burning pain, and a rough, raw spot on the mucosa. Once the erythema is visible, pain of variable intensity is a prominent feature. Generally, constitutional signs and symptoms such as fever, malaise, and lymphadenopathy are absent, but may occur with the first

219. Femiano F, Lanza A, Buonaiuto C, et al. Oral aphthous-like lesions, PFAPA syndrome: a review. J Oral Pathol Med. 2008;37:319–323. 220. Tasher D, Stein M, Dalal I, et al. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatrica. 2008;97:1090–1092. 221. Cooke BED. Recurrent oral ulceration. Br J Dermatol. 1969;81:159. 222. Merchant VA, Molinari J. Recurrent aphthous stomatitis and herpetiform ulcerations. J Mich Dent Assoc. 1984;66:357. 223. Graykowski EA, Hooks JJ. Summary of workshop on recurrent aphthous stomatitis and Behçet’s syndrome. J Am Dent Assoc. 1978; 97:599. 224. Lehner T. Progress report oral ulceration and Behçet’s syndrome. Gut. 1977;18:491.

225. Miller MF, Garfunkel AA, Ram CA, et al. The inheritance of recurrent aphthous stomatitis. Oral Surg. 1980;49:409. 226. Miller MF, Garfunkel AA, Ram CA, et al. Inheritance patterns in recurrent aphthous ulcers: twin and pedigree data. Oral Surg. 1977;43:886. 227. Shulman JD. An exploration of point, annual, and lifetime prevalence in characterizing recurrent aphthous stomatits in USA children and youths. J Oral Pathol Med. 2004;33: 558–566. 228. Rogers RS III. Recurrent aphthous stomatitis: clinical characteristics and evidence for an immunopathogenesis. J Invest Dermatol. 1977;69:499. 229. Rogers RS. Common lesions of the oral mucosa: a guide to disease of the lips, cheeks, tongue and gingivae. Postgrad Med J. 1992;91:141. 230. Field EA, Brooks V, Tyldesley WR. Recurrent aphthous ulceration in children: a review. Int J Paediatr Dent. 1992;2:1–10.

outbreak. Major aphthous ulcers may cause extreme discomfort and, because of their prolonged course, poor nutrition, and weight loss. Routine laboratory studies are usually normal. Exceptions occur when systemic disorders such as ulcerative colitis, Crohn’s disease, celiac disease, and Behçet syndrome are associated. In the group of patients with nutritional disorders, serum folate, vitamin B12, and iron levels may be altered. The histopathology of mature aphthae is that of a nonspecific ulcer. There is focal loss of the epithelium with edema and a mixed inflammatory infiltrate limited to the lamina propria. The infiltrate consists predominantly of mononuclear cells, mainly monocytes, macrophages, and blast-forming T lymphocytes.222,231 Immunofluorescence studies demonstrate immunoglobulins and C3 in submucosal vessel walls.228 A definite etiology has not been established for aphthous stomatitis. A number of trigger factors have been implicated in selected individuals including stress, dental trauma,232 and hormonal changes coincident with the menstrual cycle. Although food hypersensitivity has been considered as an etiologic factor, challenge studies have not substantiated this association.233 Nutritional deficiencies involving mainly iron, vitamin B12 and folate have been documented in approximately 15% of patients.234 The ulcers in these persons are not clinically distinctive but are often associated with glossitis and angular cheilitis and respond promptly to restoration of a normal nutritional state. Attempts to identify an infectious cause have been inconclusive. Adenovirus type 1 has been suspected but not proven as the cause of herpetiform aphthous stomatitis.223,224 Recovery of L forms of streptococci from patients with aphthae has prompted the suggestion that these organisms stimulate the formation of antibodies that cause cytolysis, a reaction to released antigens from epithelial tissue. Alternatively, an autoimmune reaction might precede direct infection. However, there is no firm evidence to validate the role of streptococci in the production of aphthous ulcerations. Most investigators favor a cell-mediated immunopathogenic mechanism, although the precise chain of events is still unclear. Circulating antibodies to oral mucous membrane antigens in individuals with aphthae have been identified by several techniques. In vitro assays using oral mucosa target cells have demonstrated cytotoxicity of lymphocytes from patients with all three types of aphthous stomatitis.235 In children, the differential diagnosis includes acute herpetic gingivostomatitis, herpangina, and hand, foot, and mouth disease, all of which not only differ clinically but are usually

associated with constitutional signs and symptoms. Viral cultures and acute and convalescent serum antibody titers will also help distinguish these infections. A positive Tzanck smear and ELISA will establish a diagnosis in herpetic gingivostomatitis and the rare instance of recurrent intraoral herpes simplex infection. Pemphigus vulgaris, Wegener’s granulomatosis, and lymphomatoid granulomatosis must be considered but are extremely rare in childhood; immunofluorescence studies and biopsy for histologic changes are diagnostic. Consideration must be given to associated systemic disorders such as inflammatory bowel disease, celiac disease, Behçet syndrome, cyclic neutropenia, and leukemia as well as to drug-related stomatitis. Aphthae occur significantly less frequently in smokers than in non-smokers.236 This underlines the observation that benign aphthae predominantly affect nonkeratinized mucosa. Treatment of aphthous stomatitis is aimed at reducing pain and promoting rapid healing of the ulcers. Treatments can be divided into categories including topical anesthetics, debridement/antiseptic agents, anti-inflammatory agents, and protective products.237,238 Topical corticosteroids or applied under a layer of carboxymethylcellulose (Orabase) are often recommended. Hydroxypropylcellulose (Zilactin) forms a more adherent film that outlasts Orabase and offers significant pain relief.237 Mild oral antiseptics and topical anesthetics such as viscous lidocaine may alleviate discomfort somewhat (see Table 9.5). Antibacterial oral rinse such as chlorhexidine gluconate (Peridex) or tetracycline mouthwash (250 mg/5 mL water) four times daily diminish secondary bacterial infection and provide symptomatic relief; however, the latter agent should not be used for children because, if swallowed, permanent staining of developing teeth may occur. An amount of 5% amlexanox oral paste (Aphthasol) applied four times daily accelerates healing and pain reduction.239 Compounded combinations of corticosteroid, diphenhydramine, kaopectate, viscous lidocaine, and tetracycline in various proportions are popular and probably afford some reduction in pain.125 Therapy with dyclonine (Dyclone) 0.5% swished or dabbed onto the ulcers may give relief for some patients. Recalcitrant ulcers or large ulcers may require triamcinolone acetonide (10 mg/mL) injected in the base for pain control and to promote healing. Cyanoacrylate adhesive provided symptomatic relief within minutes and shortened the healing time in one study.240 Thalidomide has been successfully used outside the USA to treat aphthous stomatitis in children.241 Although initially thought to be a promising drug, several studies of levamisole therapy in patients with aphthae have failed to prove efficacy, as has thymopentin.242 Likewise, cromolyn sodium, zinc sulfate, and topical azathioprine have been

231. Weathers DR, Griffin JW. Intraoral ulcerations of recurrent herpes simplex and recurrent aphthae: two distinct clinical entities. J Am Dent Assoc. 1970;81:81. 232. McCullough MJ, Abdel-Hafeth S, Scully, C. Recurrent apthous stomatitis revisited; clinical features, associations and new association with infant feeding practices? J Oral Pathol Med. 2007;36:615–620. 233. Eversole LR, Shoppers TP, Chambers DW. Effects of suspected foodstuff challenging agents in the etiology of recurrent aphthous stomatitis. Oral Surg. 1982;54:33. 234. Wray D, Ferguson MM, Hutcheon AW, et al. Nutritional deficiencies in recurrent aphthae. J Oral Pathol. 1978;7:418. 235. Rogers RS III, Sams M Jr, Shorter RG. Lymphocytotoxicity in recurrent aphthous stomatitis. Arch Dermatol. 1974;109:361. 236. Tuzun B, Wolf R, Tuzun Y, et al. Recurrent aphthous stomatitis and smoking. Int J Dermatol. 2000;39:358–360.

237. Barnes DP, Primosch RE. Therapeutic recommendations for aphthous ulcerations in children. Comp Contin Educ Dent. 1990;5:312–320. 238. Altenburg A, Zouboulis CC: Current concepts in the treatment of recurrent aphthous stomatitis. Skin therapy; Letter. 2008;13:7.1. 239. Khandwala A. Five percent amelexanox oral paste, a new teatment for recurrent minor aphthous ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;83:222–230. 240. Jasmin JR, Muller GM, Jonesco-Benaiche N. Local treatment of minor aphthous ulceration in children. ASDC J Dent Child. 1993;60:26. 241. Menni S, Imondi D, Brancaleone W, et al. Recurrent giant aphthous ulcers in a child: protracted treatment with thalidomide. Pediatr Dermatol. 1993;10:283. 242. Djawari D, Haneke E. Therapie der rezidivierenden oralen Aphthen mit Thymopoetin-Pentapeptid. Hautarzt. 1983;34:463–464.

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Table 9.7  Pigmentation of the oral mucosa in children CAUSE Diffuse macular hyperpigmentation   Racial pigmentation   Addison’s disease   Riboflavin deficiency   Heavy use of tobacco and snuff   Heavy metal pigmentation (silver, lead, mercury, bismuth)   Drug-related (antimalarial agents) DISORDERS OF THE ORAL MUCOUS MEMBRANES

Focal hyperpigmentation   Nevocellular nevi   Melanotic macules   Lentigines

  Amalgam tattoo

LOCATION

Gingivae, lips, tongue Generalized Generalized or irregular Generalized Generalized, gingival line; conjunctiva (bismuth, silver) Palatal line

Hard palate; less commonly buccal, labial mucosa, gingiva Lower lips, gingiva, buccal mucosa Lips; less commonly buccal mucosa, gingiva, hard palate, tongue Gingival and alveolar mucosa; buccal mucosa, floor of mouth, mucobuccal fold

given without significant response. In patients with severe disease, a short course of oral corticosteroid may be required to induce remission. Patients with minor aphthae may have recurrences as infrequently as once or twice yearly. Major aphthae and herpetiform ulcerations are likely to recur with greater frequency and may be present almost continuously. The ultimate prognosis is good for most patients, as spontaneous remission in 5–15 years is usual.

PIGMENTED LESIONS OF THE MUCOSAE Pigmented lesions of the mucous membranes are due to increased production of melanin in the melanocytes, to hyperplasia or neoplastic transformation of the melanocytes, or to deposition of exogenous substances such as heavy metals, iron, and drugs or metabolic products of drugs. In most cases, mainly the oral mucous membranes are affected. The pigmentation may be focal, patchy, or relatively diffuse and, in some entities, has a specific localization and coloration that facilitate diagnosis (Table 9.7).

DIFFUSE MACULAR PIGMENTATION Racial pigmentation

680

Figure 9.25  Racial melanosis involving the lower gingiva.

free and attached alveolar mucosa (Fig. 9.25). The band may parallel the line of closure of the teeth or pigment may be distributed in a patchy fashion. The tongue is rarely involved but, when it is, the pigment is characteristically localized to the tips of the filiform or fungiform papillae.243 Patches of pigment may occasionally be found on the buccal mucosa and the floor of the mouth or along the lips. This type of mucosal pigmentation is common in blacks but can also be found in darker-skinned persons of other races. This finding has been observed at all ages, including infancy, but occurs with greatest frequency after middle age.244 The hyperpigmentation has been attributed to increased activity of the melanocytes in affected areas of the mucosa.

Addison’s disease Macular hyperpigmentation of the oral mucosa is an early and prominent manifestation of Addison’s disease. The pigment is diffusely distributed in the gingiva, tongue, buccal mucosa, and hard palate; the color varies from blue-black to yellow. In the gingiva, the pigmentation may be spotty or streaked. Although cutaneous pigmentation usually disappears following therapy, mucosal pigmentation persists indefinitely.

Widespread oral mucosal hyperpigmentation Additional causes of widespread oral mucosal hyperpigmen­ tation are riboflavin (vitamin B2) deficiency, heavy use of tobacco and snuff, drug-induced pigmentation, and heavy metal deposition.

Familial progressive hyperpigmentation

The most common cause of oral melanosis is racial pigmentation, which occurs in several patterns. Most frequently, a diffuse band of increased pigmentation develops at the junction of the

Familial progressive hyperpigmentation245 is a very rare cause of hyperpigmentation, described in one family in which it was

243. Gray RLM. Pigmented lesions of the oral cavity. J Oral Surg. 1978;36:950. 244. Johnson SAM. The black skin. Norms and abnorms. Cutis. 1978;22:332.

245. Chernosky ME, Anderson DE, Chang JP, et al. Familial progressive hyperpigmentation. Arch Dermatol. 1971;103:581.

Mucous membrane disorders

transmitted in an autosomal-dominant fashion. A family study in China has also been described.246

α-methyl dopa can lead to increased mucosal melanin pigmentation.

Universal acquired melanosis

FOCAL HYPERPIGMENTATION

Also known as carbon baby, this exceedingly rare condition results in diffuse hyperpigmentation of the entire oral mucosa. The disorder is due to increased melanin and melanosomes in the epithelium of affected areas.

Heavy metal pigmentation Heavy metal pigmentation is relatively uncommon in infants and children but, when it occurs, can affect the oral and ocular mucous membranes.248 Mercury, lead, silver, and bismuth can all cause similar slate-gray hyperpigmentation of the gingivae. Mercury-induced pigmentation results from the presence of mercury granules in the dermis as well as increased amounts of melanin in the epithelium and dermal macrophages. Oral pigmentation due to this metal is usually associated with stomatitis and suppurative periodontitis.249 Bismuth causes conjunctival and oral mucosal hyperpigmentation as well as the blue-black gingival line first seen at the interdermal papillae. Metallic granules are found in the dermal layer on histologic examination. Some authorities believe that the predisposing factors of poor oral hygiene and bacterial interaction with the bismuth compound are required to produce the distinctive gingival line.192,193 Lead lines in the gingiva indicate chronic poisoning and are due to subepithelial deposits of lead granules that have been converted to lead sulfide. Lead pigmentation is gray and is usually noted a slight distance from the marginal gingiva. Silver is readily absorbed through the mucous membranes as metallic silver or in a relatively insoluble form such as oxide or sulfide.248 The silver granules are deposited in the subepithelial layer and show a predilection for association with the elastic fibers.

Drug-induced hyperpigmentation Drug-induced hyperpigmentation in the mucosae is most often seen with administration of antimalarial agents. Antimalarial drugs (quinocrine, chloroquine, hydroxychloroquine) may cause a line of pigmentation, sharply demarcating the soft and hard palates.248–251 In the skin, hyperpigmentation is presumed to result from deposition of the drug itself, as well as increased melanin and hemosiderin content. Additional drugs that cause dark patches on the oral mucosa are phenolphthalein, phe­ nothiazines, oral contraceptives, minocycline and mercurial diuretics in patients with impaired renal function.243 ACTH and

246. Ling DB, Lo T. Familial progressive hyperpigmentation: a family study in China (letter). Br J Dermatol. Dec; 1991;125:607. 247. Ruiz-Maldonado R, Tamayo L, Fernandez-Diaz J, et al. Universal acquired melanosis. Arch Dermatol. 1978;114:775. 248. Granstein RD, Sober AJ. Drugs and heavy metal-induced hyperpigmentation. Arch Dermatol. 1981;5:1. 249. Marlette RH. Generalized melanosis and nonmelanotic pigmentations of the head and neck. J Am Dent Assoc. 1975;90:141. 250. Kleinegger CL, Hammond HL, Finkelstein MW. Oral mucosal hyperpigmentation secondary to antimalarial drug therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Aug; 2000;90:189–194. 251. Ziering CL, Rabinowitz LG, Esterly NB. Antimalarials in children: indications, toxicities, and guidelines. J Am Acad Dermatol. 1993;28:764.

Nevocellular nevi are much less common in the oral mucosa than in the skin. The site of predilection is the hard palate, but they may also occur on the buccal and labial mucosa, the vermilion border, and the gingiva. They are variously gray, brown, black, or blue, range in size from one to several millimeters, and are most often elevated and sessile, although occasionally they can be flat or pedunculated. Because they are asymptomatic and not easily visualized, age of onset is usually unknown to the patient. Histologically, the most common type of lesion is intramucosal (intradermal), with blue nevi, and compound and junctional types being less frequent in occurrence.252,253 These lesions can be confused with amalgam tattoo, pigmented neuroectodermal tumor, melanotic macules, or patchy racial or drug-induced pigmentation. The propensity for malignant change is unknown. The decision to electively remove a pigmented nevus on the oral mucous membranes depends on the overall appearance of the lesion. If the nevus has grown larger, darker, thicker, or become painful or has bled, removal is recommended. Surgical excision should be performed if the edges are irregular or there is extrusion of pigment from the nevus into the surrounding mucosa. Intraoral nevi typically are totally excised rather than sampled due to the technical difficulty in removing these growths in children. Some authorities suggest prophylactic excision of all intraoral pigmented nevi.254

DISORDERS OF THE ORAL MUCOUS MEMBRANES

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Melanoma Melanoma of the oral cavity is very uncommon in adults and exceedingly rare in children. In several reported series, there have been no cases below the age of 20 years.255 A single case of a 16-year-old male with dysplastic nevus syndrome did develop a melanoma in situ on his hard palate.256 The preferred site of involvement is the maxilla; much less commonly, the mandibular alveolus, tongue, buccal mucosa, and lips may be involved. The signs and symptoms are similar to those of melanoma on the skin: development of a mass, changes in pigmentation, pain, ulceration, and bleeding.254 The presence of a suspicious lesion is an indication for immediate excisional biopsy.

Melanotic macules Melanotic macules253,257 are sometimes equated with lentigines or ephelides in the non-dermatologic literature, but do not seem

252. Buchner A, Hansen LS. Pigmented nevi of the oral mucosa: a clinicopathologic study of 32 new cases and review of 75 cases from the literature. Oral Surg. 1979;48:131. 253. Begleiter A, Moskona D, Gorsky M, et al. Benign solitary pigmented lesions of the oral mucosa. Dent Digest. 1983;1:9. 254. Batsakis JG, Regezi JA, Solomon AR, et al. The pathology of head and neck tumors: mucosal melanomas, part 13. Head Neck Surg. 1982; 4:404. 255. Liversedge RL. Oral malignant melanoma. Br J Oral Surg. 1975;13:40. 256. Themblay JF, O’Brien EA, Chauvin PJ. Melanoma in situ of the oral mucosa in an adolescent with dysplastic nevus syndrome. J Am Acad Dermatol. 2000;42:844–846. 257. Buchner A, Hansen LS. Melanotic macule of the oral mucosa. Oral Surg. 1977;48:244.

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to fit into either category clinically or histologically. They are most often solitary, occurring with greatest frequency (30%) on the vermilion borders, almost always on the lower lip. Additional sites of predilection are the gingiva (23%) and buccal mucosa (16%). These pigmented lesions are brown, gray, or blue and range in size from 0.1 cm to 2.0 cm but are most often 1–3 mm. They have been observed in children over 4 years of age, but there are no appreciable data on occurrence in infancy. A slight female predominance has been noted. Histologically melanotic macules have increased melanin in the basal epidermal layer without increased numbers of melanocytes. In one-half of the lesions, melanin in melanophages is also found in the lamina propria and, in approximately 10%, is found only at this site. Although melanotic macules are benign, clinically they may be confused with lentigines, nevocellular nevi, and malignant melanoma. One authority suggests excision of these lesions on a routine basis because of the confusion they cause diagnostically.254

Lentigines Lentigines are discrete, round-oval, brown, blue or black macules characterized histologically by elongation of the epidermal rete pegs, increased numbers of melanocytes, and increased basal melanin. These lesions develop in the oral mucous membranes in patients with the several syndromes: centrofacial lentiginosis,258 multiple lentigines with nystagmus and strabismus,259 lentiginosis with hemangiomas,260 Carney syndrome (NAME and LAMB syndromes),261,262 inherited patterned lentiginosis in blacks,263 Peutz–Jeghers syndrome,264 and Laugier–Hunziker– Baran syndrome.265 In patients with centrofacial lentiginosis, multiple lentigines with strabismus, Carney syndrome and inherited patterned lentiginosis in blacks,262 the hyperpigmentation is limited to the lips, whereas in patients with lentiginosis with hemangiomas, Laugier–Hunziker–Baran syndrome, and Peutz–Jeghers syndrome, the buccal mucosa is affected as well. In the latter syndrome, lesions have also been described on the gums, palate, and tongue.265,266 The macules in patients with Peutz–Jeghers syndrome are oval or irregular in configuration and most numerous on the lower lip; approximately 98% of affected persons possess these lesions. Onset of pigmentation is usually in early childhood or occasionally in infancy and, unlike the cutaneous lentigines, which may fade during adulthood, mucosal lentigines persist for life.266,267 Melanonychia is found in about half the cases with Laugier–Hunziker–Baran syndrome.

258. Dociu I, Galaction-Nitcelea O, Sirjita N, et al. Centrofacial lentiginosis. Br J Dermatol. 1976;94:39. 259. Pipkin AC, Pipkin SB. A pedigree of generalized lentigo. J Hered. 1950;41:79. 260. Bandler M. Hemangiomas of the small intestine associated with mucocutaneous pigmentation. Gastroenterology. 1960;38:641. 261. Rhodes AR, Silverman RA, Harrist TJ, et al. Mucocutaneous lentigines, cardiomucocutaneous myxomas, and multiple blue nevi: the ‘LAMB’ syndrome. J Am Acad Dermatol. 1984;10:72. 262. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine. 1985;64:270. 263. O’Neill JF, James WD. Inherited patterned lentiginosis in blacks. Arch Dermatol. 1989;125:1231. 264. Fulk CS. Primary disorders of hyperpigmentation. J Am Acad Dermatol. 1984;10:1.

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Amalgam tattoo Amalgam tattoo is a relatively common cause of pigmentation of the oral mucous membranes. Although most series include patients from the age of 12 years and up,268 these lesions occur in children as well. Amalgam tattoos may be produced in several different ways: (1) by abrasion or laceration of the mucosa by a rotary instrument and inoculation of amalgam particles; (2) by dropping pieces of amalgam into the socket following extraction; (3) by deposition of amalgam fragments into the wound during root canal therapy; and (4) by propelling fine particles through an intact mucosa by a high-speed drill. The embedded amalgam particles consist mainly of silver but also contain a significant amount of tin and smaller quantities of copper and zinc.269 Amalgam tattoos are clinically evident as blue or black macules or as slightly elevated lesions having sharp or indistinct margins. They occur most frequently in the gingiva and alveolar mucosa, particularly in the mandibular region; less frequently on the buccal mucosa, floor of the mouth, and mucobuccal fold, and occasionally on the tongue, labial mucosa, and palate.268,270 They range in size up to 2 cm, with most measuring less than 0.5 cm. Histologically, the amalgam is detectable in a biopsy specimen as fine dark granules and irregular solid fragments interposed between collagen fibers and around blood vessels and imbibition of elastic fibers is characteristic. There may be no inflammatory reaction or only macrophages or granulomas of the foreign body type with multinucleated cells and Langerhans cells. Diagnosis is made clinically and can often be confirmed by biopsy. Radiographs may demonstrate opaque particles at the site of the pigmented macule, but often the particles are too small or too diffuse to be visualized. Differential diagnosis includes melanotic macule, heavy metal pigmentation, nevocellular nevus, lentigo, and antimalarial pigmentation. Amalgam tattoos persist indefinitely and sometimes increase in size with time, presumably due to movement of phagocytic cells with ingested particles.268

NEVUS OF OTA This melanotic macular lesion, usually of a gray-blue color, involves the trigeminal area of the face, hence it has also been called nevus fuscoceruleus ophthalmomaxillaris. Nevus of Ota is most commonly found in Orientals and blacks and has a strong predilection for females. In approximately 60% of affected persons, the nevus is present at birth; in the remainder, the lesion usually develops gradually during the first decade, although in rare instances, it becomes apparent at or after puberty.271

265. Haneke E. Laugier–Hunziker–Baran Syndrome. Hautarzt. 1991;42:512–515. 266. Yoskowitz P, Hobson R, Reymann F. Sporadic Peutz–Jeghers syndrome in early childhood. Am J Dis Child. 1974;128:709. 267. Trovar JA, Eizaquirre J, Albert A, et al. Peutz–Jeghers syndrome in children: report of two cases and review of the literature. J Pediatr Surg. 1983;15:1. 268. Buchner A, Hansen LS. Amalgam pigmentation (amalgam tattoo) of the oral mucosa. Oral Surg. 1985;49:139. 269. Weathers DR, Fine RM. Amalgam tattoo of oral mucosa. Arch Dermatol. 1974;110:728. 270. Owens BM, Johnson WW, Schuman NJ. Oral amalgam pigmentation (tattoos): a retrospective study. Quintessence Int. 1992;23:805–810. 271. Kopf AW, Weidman AJ. Nevus of Ota. Arch Dermatol. 1962;85:195.

Mucous membrane disorders

MUCOSAL ALTERATIONS CAUSED BY DRUGS Phenytoin Gingival hyperplasia is one of the most frequently recognized sequelae of phenytoin therapy. Nearly one-half of those requiring this anticonvulsant develop painless enlargement of the gingivae. The interdental papillae may reflect changes as early as 2 weeks following the initiation of therapy, but more often 2–3 months are required. Maximum hyperplasia occurs following 9–12 months of phenytoin therapy.

272. Gold DH, Henkind P, Sturner WQ, et al. Oculodermal melanocytosis and retinitis pigmentosa. Am J Ophthalmol. 1967;63:271. 273. Haim T, Meyer E, Kerner H, et al. Oculodermal melanocytosis (nevus of Ota) and orbital malignant melanoma. Ann Ophthalmol. 1982;14:1132–1136. 274. Kopf AW, Bart RS. Malignant blue (Ota’s?) nevus. J Dermatol Surg Oncol. 1982;8:442. 275. Geronemus RG. Q-switched ruby laser therapy of nevus of Ota. Arch Dermatol. 1992;128:1618. 276. Ono I, Tateshita T. Efficacy of the ruby laser in treatment of Ota’s nevus previously treated using other therapeutic modalities. Plast Reconstr Surg. 1998;102:2352–2357.

Clinically, the earliest findings include stippling of the interdental papillae and gradual swelling of the gingiva, which acquires a warty, pebbled surface texture. With increasing enlargement, the gingivae begin to encroach on the upper portions of the teeth, obscuring them in some instances. The anterior teeth are more affected than the posterior teeth. The presence of bacterial plaque appears essential for the development of phenytoin-induced gingival hyperplasia. Therapy consists of meticulous oral hygiene. Surgical excision of excessive tissue is occasionally warranted when the hypertrophy is marked, but recurrences are the rule until the patient reaches middle age. Carbon dioxide laser gingivectomy has been recommended in selected patient populations.279 Cessation of phenytoin will produce a gradual spontaneous regression over 12 months’ time, provided the teeth are kept free of microbial deposits.

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Nevus of Ota has a unilateral distribution usually involving the forehead, temple, malar area, and ala nasi, but almost always sparing the nasolabial fold and the upper lip. Mucous membranes of the nose and mouth, the external auditory canal, and tympanic membrane are occasionally involved as well. The size of the patch, which has indistinct margins, usually exceeds 5 cm, and the color may vary from a tan-brown to slate blue-black. Although the nevus is usually macular, there may be elevated areas within the patch resembling discrete blue nevi.272–274 Twothirds of patients have blue-gray discoloration of the sclera on the affected side due to melanocytes in the sclera or episclera. The pigment is usually patchy in distribution, most often involving the superior and temporal aspects of the sclera. Rarely, pigmentation may extend to the conjunctiva and other ocular structures, such as the cornea, iris, choroid, and optic disk.272 Vision is not impaired. The pigmented patch is due to the presence of melaninproducing melanocytes in the upper and mid-dermis. Depending on the density and distribution of the dermal melanocytes, these nevi may resemble either the blue nevus or the Mongolian spot histologically. Clinically, these lesions are most often confused with Mongolian spots and may be referred to as aberrant Mongolian spots or oculodermal melanocytosis. Café-au-lait spot, ochronosis, contusion, chloasma, and heavy metal pigmentation are additional considerations in the differential diagnosis. When the mucous membranes are involved, Addison’s disease, racial melanosis, drug-induced hyperpigmentation, and heavy-metal deposition must also be included. Ocular pigmentation can be confused with scleral defects or pigmented nevi of the conjunctiva. Nevus of Ota, unlike Mongolian spot, persists indefinitely and has little propensity for malignant change, although melanoma arising in the skin or ocular tissues has been associated in rare instances.272–274 Q-switched ruby laser therapy has been reported to be an effective and safe method of removing or lightening nevus of Ota pigmentation of the skin.275–277 The Q-switched alexandrite laser has also been successfully used to treat this condition.278

9

Cyclosporine Cyclosporine has many of the same clinical effects on the gingivae as phenytoin. Gingival overgrowth may be seen as early as 3 months into therapy in predisposed individuals. Patients who develop gingival hyperplasia typically have higher salivary cyclosporine levels than those who are unaffected or have minimal changes. Gingival overgrowth is seen less frequently in bone marrow transplant recipients than other grafted patients. Both a young age at time of treatment and a high dose of cyclosporine predispose to this adverse effect of the drug. Decreasing the dose of cyclosporine may result in regression of the gingival hyperplasia, but gingivectomy may be required in rare cases. Other drugs potentially causing gingival hyperplasia are diltiazem, nifedipine, and some antihypertensive agents.

Acetylsalicylic acid (aspirin) Following the direct application of an aspirin tablet to a painful tooth or aphthous ulcer, a glistening denuded hyperemic erosion may develop on the oral mucosa, occasionally after an initial grayish-white discoloration. These ulcerations occur as a direct effect of the aspirin on the mucosal surface. The ulcers tend to be painful, although relatively short lived. Recovery occurs within several days and scarring is infrequent. Cotton-roll stomatitis is clinically almost identical.

Silver nitrate Silver nitrate is occasionally employed to cauterize lesions in the oral cavity, especially in recurrent oral aphthae. Some cases of

277. Pfeiffer N. Q-switched ruby laser used to remove pigmented lesions. J Clin Laser Med Surg. Jun; 1993;11:147–148. 278. Kang W, Lee E, Choi GS. Treatment of Ota’s nevus by Q-switched alexandrite laser: therapeutic outcome in relation to clinical and histopathologic findings. Eur J Dermatol. 1999;9:639–643. 279. Roed-Peterson B. The potential use of CO2-laser gingivectomy for phenytoin-induced hyperplasia in mentally retarded patients. J Clin Periodontol. Nov; 1993;20:729–731.

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giant oral ulcers after this treatment have been observed. Injudicious or excessive use results in the development of painful burns. Although long-term sequelae are rare when silver nitrate is used briefly, it is best avoided, when feasible, in the pediatric age group.

Oral ulcerations secondary to cancer chemotherapy

DISORDERS OF THE ORAL MUCOUS MEMBRANES

Mucositis and oral ulcerations frequently develop following administration of chemotherapeutic drugs. Commonly implicated chemotherapeutic agents are methotrexate, 5-fluorouracil, actinomycin D, Adriamycin, bleomycin, and daunorubicin. Less commonly 6-mercaptopurine, hydroxyurea, vinblastine, and procarbazine are implicated.89 Direct and indirect effects of such medicaments on the oral mucosa precipitate the ulceration.125 The direct effect of methotrexate on cell replication and growth of oral epithelial cells results in interference with nucleic acid and protein synthesis. Thinning is followed by focal ulceration within the oral cavity. Chemotherapeutic agents may have an indirect effect on the mucous membranes by depressing the bone marrow and immune response, ultimately predisposing the patient to invasive infections. Clinically, the oral ulcerations caused by cancer chemotherapy are deep, large, and necrotic with little inflammation at the base of the ulcer. Virtually all mucosal surfaces may be affected. A history of recent chemotherapy in the presence of these ulcers suggests the diagnosis, but cultures of the ulcers are warranted as Gram-negative sepsis may stem from untreated local infection. When fungal infection is suspected, culture and biopsy are mandatory. Ulcerative herpes simplex and erosive candidiasis must also be ruled out. When severe oral ulceration occurs, chemotherapy may, of necessity, have to be discontinued or the dosage decreased. These compromises are occasionally impossible. Symptomatic remedies in the form of topical anesthetic mouthwashes (see Table 9.5) and narcotic analgesics where appropriate should be offered to increase patient comfort. Granulocyte-colony stimulating factor may help the patient to recover earlier.

ORAL MANIFESTATIONS OF SYSTEMIC DISEASES Leukemia The oral manifestations of leukemia tend to reflect the general status of the patient, the type of leukemia, and the age of the patient.280–282 Although mucous membrane alterations occur in both acute and chronic forms of leukemia, they occur far more commonly in the acute states and most commonly in monocytic leukemia.283 In children, the oral manifestations of acute leuke-

280. Levy-Polack MP, Sebelli P, Polack N. Incidence of oral complications and application of a preventive protocol in children with acute leukemia. Spec Car Dentist. 1998;18:189–193. 281. Weckx LL, Hidal LB, Marcucci G. Oral manifestations of leukemia. Ear Nose Throat. 1990;69:341–342. 282. Childrs NK, Stinnett EA, Wheeler P, et al. Oral complications in children with cancer. Oral Surg Oral Med Oral Pathol. 1993;75:41–47. 283. Burket LW. A histopathologic explanation for the oral lesions in the acute leukemias. Am J Orthod Oral Surg. 1944;30:516. 284. Michaud M, Bachner RL, Bixler D, Kafrawy AH. Oral manifestations of acute leukemia in children. J Am Dent Assoc. 1977;95:1145.

684

Figure 9.26  Leukemia: monocytic infraorbital and gingival infiltrates.

mia have been found to be varied rather than pathognomonic.284,285 Of 292 pediatric patients with leukemia of various types, fewer than 30% had oral findings suggestive of leukemia. Acute lymphocytic leukemia, the most common form of leukemia in childhood, is the least likely to produce oral lesions.286 The primary clinical manifestations of leukemia include gingivitis, gingival hyperplasia (Fig. 9.26), hemorrhage, petechiae, and ulcerations of the oral mucosa.44 Pallor of the mucosa may reflect concomitant anemia. The teeth may become painful and loose, and a sore throat may be reported.287 Except for edentulous patients, gingival hyperplasia occurs as an almost constant feature of leukemia. The hyperplasia is typically generalized but varies in intensity. In severe cases, the hypertrophied gums may nearly mask the teeth. Changes in the gingivae include bogginess, edema, and erythema. The surface becomes friable and bleeds readily. The presence of leukemic cell infiltrates in areas of mild chronic irritation contributes to the gingival swelling. Ulcerations of the sulcus epithelium and necrosis of underlying tissue predispose to gingival hemorrhage. Purpura of the oral mucosa, like cutaneous ecchymoses, occurs as a result of thrombocytopenia. Focal oral ulceration may occur as a consequence of non-functioning leukocytes having the same effect as agranulocytosis, or as a direct effect of chemotherapy on mucosal epithelium. Such ulceration typically develops seven days after the onset of antileukemic drug therapy. Bacterial invasion due to severe neutropenia may also contribute to the formation of oral ulcers.288 These shallow, denuded foci may herald the onset of leukemia and are characteristically large, irregular, and foul

285. Gruszewska-Lewczuk L. Manifestations of acute leukemia in the oral cavity in children. Czasopismo Stomatologiczne. 1974;27:887–894. 286. Curtis AB. Childhood leukemias: initial oral manifestations. J Am Dent Assoc. 1971;83:159. 287. Stawiski MA. Skin manifestations of leukemias and lymphomas. Cutis. 1978;21:814. 288. Wananukul S, Nuchprayoon, I, Siripanich H. Mucocutaneous findings in febrile neutropenic children with acute leukemias. J Med Assoc Thai. 2005;88(6):817–823.

Mucous membrane disorders

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smelling. A pale mucosa surrounds these lesions, and an inflammatory response is lacking. Therapeutic goals for leukemic ulcers should include the prevention of localized infection, minimizing bacteremia, promotion of healing, and the reduction of pain.89 Local therapy is often effective in managing petechiae, ecchymosis, and minor hemorrhage. Irritants should be removed and direct pressure applied when bleeding occurs. Proper use of adsorbable gelatin sponges with topical thrombin or placement of microfibrillar collagen on packing or splints can reduce the need for platelet transfusions. Oral rinses with antifibrinolytic agents may help in certain cases.89

Oral and dental manifestations of Langerhans cell histiocytosis (LCH, histiocytosis X) can occur in all forms of the disorder. Oral lesions may predate more systemic manifestations and may mimic dental infection with or without osteolysis, therapyresistant peridontal disease or gingivitis.289 The incidence of oral involvement in several series has varied tremendously, ranging from 4.5% to 77%.290 This variation may be due, in part, to the thoroughness with which the oral cavity was examined in these patients. The presence of jaw swelling or a palpable mass is the most commonly reported finding.290 Intraosseous lesions predominantly affect the mandible, particularly in the posterior portion. Pain, gingivitis, inflammation, necrosis, and loosening of the teeth are also frequently noted (Fig. 9.27). In small infants, there may be premature eruption of fully or partially formed teeth. Radiologic studies of the jaw may show a sharply defined lytic lesion with variable loss of alveolar bone. When there is sufficient destruction of bone to permit displacement of teeth, the teeth may appear to be floating in air.291 Biopsy of gingival ulcerations and lytic bone lesions will demonstrate the characteristic pathology of LCH, thus confirming the diagnosis. The total clinical picture will dictate the type of therapy indicated. Eosinophilic bone granuloma in children is said to heal spontaneously in a high percentage of cases.291

WEGENER’S GRANULOMATOSIS Wegener’s granulomatosis is an uncommon disease in adults and is particularly rare in children, with less than 100 pediatric cases currently in the literature.292–300 Wegener’s granulomatosis

289. Mortellaro C, Pucci A, Plameri A, et al. Oral manifestations of Langerhans histiocytosis in a pediatric population: a clinical and histological study of 8 patients. J Carniofac Surg. 2006;17(3):552–556. 290. Cranin AN, Rockman R. Oral symptoms in histiocytosis X. J Am Dent Assoc. 1981;103:412. 291. Hartman KS. Histiocytosis X: a review of 114 cases with oral involvement. Oral Surg. 1980;49:38. 292. Orlowski JP, Clough JD, Dyment PG. Wegener’s granulomatosis in the pediatric age group. Pediatrics. 1978;61:83. 293. Chyu JYH, Hagstrom WJ, Soltani K, et al. Wegener’s granulomatosis in childhood: cutaneous manifestations as the presenting signs. J Am Acad Dermatol. 1984;10:341. 294. Patten SF, Tomecki KJ. Wegener’s granulomatosis: cutaneous and oral mucosal disease. J Am Acad Dermatol. 1993;28:710.

DISORDERS OF THE ORAL MUCOUS MEMBRANES

LANGERHANS CELL HISTIOCYTOSIS (HISTIOCYTOSIS X)

Figure 9.27  Langerhans cell histiocytosis: periodontal ulceration.

is a systemic illness characterized by concurrent findings of necrotizing perivascular granulomas and polyvasculitis. Multiple organs, including the skin, are affected by the venous and arteriolar vasculitis.299 Limited forms have also been described.294 In such cases, the disease remains localized for prolonged periods before multiorgan system involvement occurs. The necrotizing granulomatous vasculitis typically involves the upper and lower respiratory tract as well as the renal glomeruli. This condition often begins and remains for a long period in the head and neck region.295 This classic triad of nose, lung, and kidney involvement is less often encountered in children. If involvement of the lower respiratory tract or kidneys, or both, is evident when oral changes are detected, the prognosis is generally poor. A patient thus affected succumbs to the lung disease within a short period of time. If the kidneys and lungs become involved subsequent to the oral lesions, however, survival is prolonged due to the more localized nature of the disease.

295. Rasmussen N. Management of the ear, nose, and throat manifestations of Wegener granulomatosis: an otorhinolaryngologist’s perspective. Curr Opin Rheumatol. 2001;13:3–11. 296. Hall SL, Miller LC, Duggan E, et al. Wegener granulomatosis in pediatric patients. J Pediatr. 1985;106:739. 297. Moorthy AV, Chesney RW, Segar WE, et al. Wegener granulomatosis in childhood: prolonged survival following cytotoxic therapy. J Pediatr. 1977;91:616. 298. Rottem M, Fauci S, Hallahan CW, et al. Wegener’s granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr. 1993;122:26. 299. Verschuur HP, Struyvenberg PAA, van Benthem PPG, et al. Nasal discharge and obstruction as presenting symptoms of Wegener’s granulomatosis in childhood. Int J Pediatr Otorhinolaryngol. 1993;27:91. 300. Akikusa JD, Scneider R, Harvey EA, et al. Clinical feature and outcome of pediatric Wegener’s granulomatosis. Arthritis Rheum. 2007;57(5):837–844.

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Diseases of Mucous Membranes and Appendageal Structures

As the specific histologic findings of necrotizing, granulomatous inflammation with vasculitis are not always seen and the findings on renal biopsy are almost always nonspecific, other methods to confirm the diagnosis of Wegener’s granulomatosis have been developed. Nearly all cases of Wegener’s granulomatosis have elevations of the serum autoantibodies to a neutrophilic cytoplasmic antigen (ANCA).294 Elevation in ANCA titer also heralds disease relapses. However, in children ANCA titers may also be elevated in cystic fibrosis and juvenile rheumatoid arthritis.301 In adult patients, therapeutic response can be monitored with clinical improvement, a decrease in the erythrocyte sedimentation rate, and ANCA titer levels. Treatment may be discontinued after a disease-free interval of one year. Therapeutic agents used for pediatric patients with Wegener’s granulomatosis include cyclophosphamide, azathioprine, prednisone, and methotrexate.299,300 A persistent mucopurulent and sanguineous nasal discharge characterizes this granulomatous process.295,298 The nasal mucosa may appear swollen, granular, and friable, with rare development of nasal septal perforation.295 Although involvement of the oral cavity does occur with considerable frequency in Wegener’s granulomatosis, oral lesions are seldom the presenting sign.44 The distinctive hyperplasia of the gingiva that begins in the interdental papillae represents the most common manifestation and represents small vessel vasculitis. The gums become red to purple in color, with numerous petechiae that occasionally extend to the labial and buccal mucosa, eventually involving the entire gingiva and periodontium.294 Other alterations of the gingivae include ulcerations and friable granular growths. The presence of a diffuse ulcerative stomatitis may result in tooth mobility and subsequent spontaneous exfoliation of the teeth. Once these teeth are shed, their extraction sites fail to heal. The hard palate, cheeks and lips may also be involved. Large necrotic ulcers may penetrate the palate to the nose. Although up to 50% of adults with Wegener’s granulomatosis may have ocular involvement, reports of ocular mucosa involvement in children are infrequent.302 Ocular findings may include scleritis, iritis, dacryoadenitis, edema, erythema and proptosis. Histologically, the gingival lesions demonstrate pseudoepitheliomatous hyperplasia and a nonspecific chronic histiocytic inflammation. Vasculitis of the gingival tissues is uncommon.294,299 The presence of giant cells is variable and palisading granulomas, although common in classical lesions of Wegener’s granulomatosis found in the lung, are rare in gingival biopsy specimens.303,304 The inflammatory component of the submucosa includes a diffuse infiltrate of epithelioid histiocytes and occasional eosinophils.294 The true incidence of Wegener’s granulomatosis is unknown.303 Either sex may be affected, with young adult males showing the greatest propensity for the systemic form. Orlowski et al.292

doubt the authenticity of cases below 10 years of age, stating that the two infants described probably had chronic granulomatous disease of childhood. Recent studies have shown that more females than males may develop Wegener’s granulomatosis in adolescence, and children have a greater propensity to have subglottic stenosis than adults with the disorder.300 No genetic predisposition has been determined in Wegener’s granulomatosis. The precise etiology remains unclear, but a hypersensitivity reaction to an undefined antigen remains highly suspect. A number of Wegener-like cases have been described.305 Current therapy typically includes the use of cyclophosphamide and prednisone or regimens that include azathioprine, mycophenolate mofetil or methotrexate. The differential diagnosis of the oral lesions must include eosinophilic granuloma, nonspecific gingivitis, and periodontitis.

301. Sediva A, Kolarova I, Bartunkova J. Antineutrophil cytoplasmic antibodies in children. Eur J Pediatr. 1998;157:987–991. 302. Levi, M, Kodsi SR, Rubin SE, et al. Ocular involvement as the initial manifestation of Wegener’s granulomatosis in children. J AAPOS. 2008;12(1):94–96. 303. Roback SA, Herdman RC, Hoyer J, et al. Wegener’s granulomatosis in a child. Am J Dis Child. 1969;118:608. 304. Brooke RI. Wegener’s granulomatosis involving the gingivae. Br Dent J. 1969;127:34. 305. von Vigier RO, Trummler SA, Laux-End R, et al. Pulmonary renal syndrome in childhood: a report of twenty-one cases and a review of the literature. Pediatr Pulmonol. 2000;29:382–388.

306. Farmer ER, Hood AF. Graft versus host disease. In: Fitzpatrick TB, Eisen AZ, Wolf K, et al, eds. Update: dermatology in general medicine. 3rd ed. New York: McGraw-Hill; 1987:1344. 307. Barret AP, Belous AM. Oral patterns of acute and chronic graft-versus-host disease. Arch Dermatol. 1984;120:1461. 308. Woo SB, Lee SJ, Schubert MM. Graft-vs-host disease. Crit Rev Oral Biol Med. 1997;8:201–216. 309. Eisen D, Essell J, Broun ER. Oral cavity complications of bone marrow transplantation. Semin Cutan Med Surg. 1997;16:265–272.

GRAFT-VERSUS-HOST DISEASE Following bone marrow transplantation for leukemia, aplastic anemia, or immunodeficiency, the lymphocytic, hematopoietic, reticuloendothelial, and epithelial cells may undergo an inflammatory reaction mounted by the donor cells against these tissues.306 Graft-versus-host reaction is said to occur within the specified organ, with the skin, liver, and GI tract being most frequently involved. The host is said to undergo graft-versus-host disease. Mucous membrane alterations are common in the setting of graft-versus-host disease (GvHD).307 Furthermore, the manifestations reflected by the oral mucosa indicate successful treatment or progression of a graft-versus-host reaction.308,309 Three clinical patterns of acute graft-versus-host disease involve the oral mucosa.307–309 Each clinical alteration of the oral mucosa may occur as a single distinct finding or as part of a continuum including other mucosal changes. The first clinical variant is one in which numerous tiny papules develop abruptly in the oral cavity. The close proximity of the papules gives an appearance of generalized whiteness. This pattern typically lasts only 2–8 days and may precede the other two recognized forms. The second variant is characterized by the development of a reticular or ‘lichenoid’ pattern on the oral mucosa. Striae-like lesions of interlacing white strands emerge (Fig. 9.28). The third presentation is desquamative. The tiny papules of the first described clinical alteration coalesce. Within 12–24 days, these then evolve into irregular plaques of whitened mucosa. The desquamation that follows is asymptomatic with minimal to no surface erosion. The oral changes seen in acute graft-versus-host disease may gradually evolve into those seen in the chronic graft-versus-host disease. Chronic graft-versus-host disease is characterized by cutaneous and mucosal lesions that mimic lichen planus and scleroderma, both clinically and histologically. Lacy, reticular,

Mucous membrane disorders

9

DISORDERS OF THE ORAL MUCOUS MEMBRANES

diagnosis.307–309 Examination of the mucous membranes in those at risk for graft-versus-host disease is crucial, particularly in chronic graft-versus-host disease where changes may predate other manifestations by as much as several weeks.308 The treatment of oral GvHD lesions follows the general principles of GvHD therapy. Systemic treatment regimens have included cyclosporin and prednisone, sirolimus, mycophenolate mofetil, antimalarials, pentostatin and extracorporeal photophoresis. Topical treatments for oral mucosal disease manifestations have included dexamethasone elixir, cyclosporin rinses, azathioprine rinses and tacrolimus 0.1% ointment.311 The Sjögren-like symptoms may be improved using pilocarpine.312 Both intraoral PUVA and selective ultraviolet B irradiation are beneficial.313–315

LUPUS ERYTHEMATOSUS

Figure 9.28  Graft-versus-host disease.

keratotic lesions develop on the buccal mucous membranes, cheeks, lips, and gingivae.89 The salivary and lacrimal gland epithelium may also be involved. Histologically, the patchy and periductal infiltrates of lymphocytes and plasma cells resemble those of Sjögren syndrome.308,310 The inflammatory cells infiltrate the duct walls and glandular acini, producing fibrosis, ductal dilation with destruction, loss of acini, and replacement by fibrous tissue. Mucus production is markedly diminished in advanced cases.122 The combination of xerostomia and desquamation of the oral mucosa predisposes to caries and secondary infection as natural barriers to local tissue invasion are disrupted.307,308 Greater than three-quarters of patients undergoing bone marrow transplantation have subsequent infection within the oral cavity. Candida is a frequent problem, but other opportunistic organisms may also cause morbidity. Establishing the diagnosis of acute or chronic graft-versus-host disease requires that other factors contributing to mucosal membrane changes be ruled out. Both candidiasis and drug or irradiation-induced mucosal toxicity may simulate or mask the

310. Gratwhol AA. Sjögren-type syndrome after allogenic bone marrow transplantation. Ann Intern Med. 1977;87:703. 311. Imanguli MM, Pavletic SZ, Guadagnini J-P, et al. Chronic graft versus host disease of oral mucosa: review of available therapies. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(2):175–183. 312. Nagler RM, Nagler A. Pilocarpine hydrochloride relieves xerostomia in chronic graft-versus-host disease: a sialometrical study. Bone Marrow Transpl. 1999;23:1007–1011. 313. Redding SW, Callander NS, Haveman CW, et al. Treatment of oral chronic graft-versus-host disease with PUVA therapy: case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;86:183–187.

Approximately 25% of patients with lupus erythematosus have oral lesions, most commonly localized to the buccal mucosa, palate, and tongue.316 These lesions, which occur in both systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE), may develop as the initial manifestation or may accompany the onset of the cutaneous lesions. In DLE, the lip lesions consist of small atrophic areas surrounded by a narrow zone of white keratinization, with striae which are net-like or radiate from the margins.317 Occasionally, there is central ulceration and crusting. When the tongue is involved, deep fissures and atrophy of the papillae are salient features. The oral lesions of SLE are mainly parallel or radiating striae, hyperemia and petechiae. Edema of the involved tissue is more pronounced, and petechiae and ulcerations may be prominent findings. These lesions are most often symptomatic and painful. The differential diagnosis includes lichen planus, leukoplakia and aphthous stomatitis. Histologic findings on biopsy may be diagnostic, but sometimes even immunofluorescence studies fail to differentiate lupus erythematosus and lichen planus. Immunoglobulins and complement are deposited in a band at the dermo-epidermal junction, as in the skin lesions; this is a consistent finding in patients with SLE and is also noted in most patients with DLE.318 There is no specific treatment; the oral lesions may improve with therapy instituted for other manifestations of the disease.

KAWASAKI DISEASE Also known as mucocutaneous lymph node syndrome, this disorder is diagnosed on the basis of the following findings: (1) fever of ≥5 days; (2) bilateral injection of the bulbar

314. Elad S, Garfunkel AA, Enk CD, et al. Ultraviolet B irradiation: a new therapeutic concept for the management of oral manifestations of graft-versus-host disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:444–450. 315. Enk CD, Elad S, Vexler A, et al. Chronic graft-versus-host disease treated with UVB phototherapy. Bone Marrow Transpl. 1998;22:1179–1183. 316. Schiodt M, Halberg P, Hentzer B. A clinical study of 32 patients with oral discoid lupus erythematosus. Int J Oral Surg. 1978;7:85. 317. Andreasen JO, Poulsen HE. Oral discoid and systemic lupus erythematosus. Acta Odontal Scand. 1964;22:295. 318. Schiodt M, Holstrup P, Dabelsteen E, et al. Deposit of immunoglobulins, complement and fibrinogen in oral lupus erythematosus, lichen planus and leukoplakia. Oral Surg. 1981;51:603.

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outcome occurred between two groups of patients with or without the perineal rash.325 (The disorder and treatment are discussed in more detail in Chapter 23.)

DISORDERS OF MULTIPLE MUCOUS MEMBRANES

A B

Figure 9.29  (A,B) Swelling, fissuring, erythema, and crusting of the lips in two young children with Kawasaki syndrome.

DISORDERS OF MULTIPLE MUCOUS MEMBRANES

con­junctiva; (3) changes in the oropharyngeal mucous membranes, consisting of dryness, redness, and fissuring of the lips, strawberry tongue, and suffusion of the mucosa; (4) edema and erythema of the feet and hands and periungual desqua­ mation; (5) polymorphous rash; and (6) acute non-purulent cervical lymphadenopathy.319 Additional findings include arthralgia and arthritis, diarrhea, sterile pyuria, carditis, pneumonia, aseptic meningitis, hydrops of the gallbladder, aneurysms of the coronary arteries, coronary artery thrombosis, jaundice, and thrombocytosis, as well as other clinical and laboratory abnormalities.320 Changes in the ocular and oropharyngeal mucous membranes are considered major criteria for the diagnosis and occur within one to three days following onset of the fever. Ocular conjunctival injection, which is observed in almost all cases,11,319–324 is always bilateral, and the vascular engorgement is confined to the bulbar conjunctiva, with little change in the palpebral conjunctiva.321 Most striking is the prominence of individual vessels that may appear tortuous. Mild to moderate conjunctival discharge has been described but is uncommon.321–323 Also uncommon are the findings of subconjunctival hemorrhage and superficial punctate keratitis. Anterior uveitis has been detected in association with this disease and is usually mild.322–324 Marked suffusion of the oropharyngeal mucosa imparts a deep red color to the lips, which are also edematous, dry, and fissured (Fig. 9.29). The tongue is diffusely red with prominent papillae resembling the ‘strawberry tongue’ of streptococcal scarlet fever. Subsequently, the lips may crack and bleed, causing lip soreness, but frank oral ulcerations are rare. The mucous membrane manifestations persist into the second week of the illness and then subside, leaving no sequelae. An erythematous desquamating perineal eruption has been reported in patients with Kawasaki syndrome. The eruption typically develops in the first 6 days of the symptoms with a median day of onset on day 3. The desquamation of the skin of the perineum occurs earlier than on the fingertips. No differences in

319. Kawasaki T, Kasaki F, Okawa S, et al. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics. 1974;54:271. 320. Wortmann DW. Kawasaki syndrome. Semin Dermatol. 1992;11:37. 321. Ohno S, Miyajima T, Higuchi M, et al. Ocular manifestations of Kawasaki’s disease (mucocutaneous lymph node syndrome). Am J Ophthalmol. 1982;93:713. 322. Ammerman SD, Rao MS, Shope TC, et al. Diagnostic uncertainty in atypical Kawasaki disease and a new finding: exudative conjunctivitis. Pediatr Infect Dis. 1985;4:210.

688

LEUKOPLAKIA The term leukoplakia means ‘white patch,’ but it has been used in such a non-specific fashion as to render it practically meaningless. When applied to oral mucosal lesions, it denotes a white plaque that cannot be removed by rubbing and cannot be ascribed to a diagnosable skin disorder. One cannot make a specific diagnosis with any degree of accuracy from the clinical appearance of the lesion; rather, histopathologic examination is always necessary to establish diagnosis and prognosis. Oral leukoplakia is a problem of adults, usually of the middle years and beyond, but it is also encountered rarely in adolescents. A preponderance of males has been noted in all series.89 Etiologic factors include chronic trauma; chemical and thermal irritation, particularly the use of tobacco in any form; neglect of hygiene, and possible nutritional factors.98,107 Leukoplakia in the mouth may be limited to a focal area or may be diffuse, involving large areas of the oral mucosa; it is usually painless. Erosions, fissures, and the presence of pain signify malignant change or an erroneous diagnosis. Common sites of involvement are the cheeks near the oral commissure extending posteriorly along the line of closure of the teeth, the tongue, the palate, and the floor of the mouth. When the tongue is involved, the lesion is characterized by absence of papillae, a feature that distinguishes leukoplakia from geographic tongue. In children, disorders likely to be confused with leukoplakia include lichen planus, chronic candidiasis, cheek and lip biting, burns, Heck’s disease,146 and nevoid lesions such as white sponge nevus, epidermal nevus, hereditary benign intraepithelial dys­ keratosis, pachyonychia congenita, and dyskeratosis congenita (Box 9.6; Table 9.8).326 Biopsy must be obtained to distinguish most of these entities. Furthermore, histopathologic examination is required to identify dyskeratotic lesions, although these are rare in children. Treatment will depend on the cause of the lesion. Chronic irritation from jagged teeth or prosthetic devices should be eliminated. Oral hygiene should be improved and habits such as cheek biting curbed. Dyskeratotic lesions should always be excised because of the predisposition for malignant change. Careful long-term observation of these patients is mandatory. The term leukoplakia is equally vague when applied to clinical vulval changes. Some modern gynecology tests recommend elimination of the designation in the classification of

323. Germain BF, Moroney JD, Guggino GS, et al. Anterior uveitis in Kawasaki disease. J Pediatr. 1980;97:780. 324. Lapointe N, Chael Z, Lacrox J, et al. Kawasaki disease: association with uveitis in seven patients. Pediatrics. 1982;69:376. 325. Friter BS, Lucky AW. The perineal eruption of Kawasaki syndrome. Arch Dermatol. 1988;124:1805. 326. Haneke E. Klassifikation und beurteilung oraler leukoplakien. Hautarzt. 1983;34(suppl VI):53–54.

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9

gynecologic problems.327 Others state that vulvar leukoplakia has not been reported in children.328

BOX 9.6 WHITE LESIONS OF THE MOUTH IN CHILDHOOD Nevoid and hereditary

WHITE SPONGE NEVUS OF CANNON

>> Epidermal nevus >> White sponge nevus >> Hereditary benign intraepithelial dyskeratosis >> Hereditary mucoepithelial dysplasia >> Pachyonychia congenita >> Dyskeratosis congenita Acquired

>> Lichen planus >> Candidiasis >> Verrucae >> Heck’s disease >> Lichen sclerosus et atrophicans >> Darier’s disease >> Pityriasis rubra pilaris >> Lupus erythematosus >> Psoriasis >> Aphthous stomatitis >> Contact dermatitis >> Secondary syphilis >> Focal keratosis secondary to trauma and/or on top of many

DISORDERS OF MULTIPLE MUCOUS MEMBRANES

This rare autosomal-dominant nevoid condition most often affects the oral mucosa but can also occur on the labial, nasal, vaginal, and anal mucosa.329 The mucosal changes have been noted at birth in some affected infants; in others, onset has been noted variably in infancy, childhood, or adolescence.330 The nevoid change is believed to be fully developed in extent and severity by adolescence. Association with other skin symptoms is rare.331 Oral lesions may occur on the buccal mucosa, hard and soft palate, sides of the tongue, gingivae, and floor of the mouth. The involved tissues are spongy and thickened and have a deeply folded or corrugated appearance with an opalescent white tint. In general, the condition is asymptomatic. Histopathologic specimens show hyperkeratosis with occasional parakeratosis, marked acanthosis of the epithelium with large, swollen vacuolated cells in the granular and prickle cell layers, as well as numerous mitoses. The dermis is remarkable only for increased vascularity of the stroma and absence of inflammatory infiltrates.329–331 White sponge nevus is a benign disorder requiring no treatment.

common lesions

Table 9.8  Heritable and nevoid white lesions of the mouth CONDITION

INHERITANCE

ANOGENITAL LESIONS

OCULAR LESIONS

OTHER

COMPLICATIONS

Epidermal nevus

None







Epidermal nevus syndrome

White sponge nevus

Autosomal-dominant

+





None

Hereditary benign intraepithelial dyskeratosis

Autosomal-dominant



+



Blindness

Hereditary mucoepithelial dysplasia

Autosomal-dominant

+

+

Alopecia; hyperkeratotic papules

Fibrocystic-type lung disease; cor pulmonale; severe infections

Pachyonychia congenita

Autosomal-dominant



+ (Type III)

Nail dystrophy; keratoderma, bullae palms, and soles

Malignancy, oral mucosa

Dyskeratosis congenita

X-linked recessive; rarely autosomal-dominant

+

+

Nail dystrophy; poikilodermatous skin lesions; keratoderma and hyperhidrosis of the palms and soles; mental deficiency; immunologic abnormalities; alopecia, skeletal anomalies

Blood dyscrasias; pancytopenia; malignancy, oral mucosa

327. Danforth DN, Dignam WJ, Hendricks CH, et al. Obstetrics and gynecology. 4th ed. Philadelphia: Harper & Row; 1982. 328. Huffman JW, Dewhurst Sir CJ, Capraro VJ. The gynecology of childhood and adolescence. Philadelphia: WB Saunders; 1981. 329. Witkop Jr CJ, Gorlin RJ. Four hereditary mucosal syndromes. Arch Dermatol. 1961;84:762.

330. Zegarelli EV, Everett FG, Kutscher AH, et al. Familial white folded dysplasia of the mucous membranes. Arch Dermatol. 1959;80:97. 331. Haneke E. White sponge nevus and generalized follicular hyperkeratosis. In: Urabe H, Kimura M, Yamamoto K, et al, eds. Proceedings of the 4th International Congress of Pediatric Dermatology. University of Tokyo Press; 1988:425–427.

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HEREDITARY BENIGN INTRAEPITHELIAL DYSKERATOSIS

DISORDERS OF MULTIPLE MUCOUS MEMBRANES

This congenital disorder has been described in a tri-racial isolate of white, native American, and black persons in North Carolina and is inherited as an autosomal-dominant trait with a high degree of penetrance.332 A few more cases have been observed in other populations. A gene duplication at the chromosome locus 4p35 has been found in these patients.333 Oral lesions, which are asymptomatic, strongly resemble white sponge nevus, clinically. They consist of soft, spongy white folds and plaques of thickened mucosa on the buccal and labial surfaces, at the labial commissures, on the floor of the mouth, on the ventral and lateral surfaces of the tongue, as well as the gingivae, fauces, and palate.332 Ocular lesions distinguish this condition from others with similar oral lesions. The bulbar conjunctiva becomes hyperemic and foamy gelatinous plaques develop in perilimbal sites both temporally and nasally. Marked photophobia is usual, and temporary blindness can occur from overgrowth of the plaque. The plaques are sloughed spontaneously, usually in summer rather than winter, and vision may be temporarily restored. Permanent blindness may result eventually from vascularization of the cornea. Oral and conjunctival lesions demonstrate similar histologic features, including an acanthotic epidermis, vacuolization of the prickle-cell layer, and an intraepithelial dyskeratosis characterized by waxy eosinophilic cells and a cell-within-cell pattern. The latter features are also discernible on buccal and conjunctival smears stained with Papanicolaou (Pap) stain and are regarded as diagnostic. There is no known therapy for this condition.

HEREDITARY MUCOEPITHELIAL DYSPLASIA

690

papules may be present as well as diffuse nonscarring alopecia.337 Additional findings include chronic seborrhea, frequent upper respiratory infections that may progress to pneumonia, diarrhea, melena, pyuria, and hematuria. Spontaneous pneumothorax is common, resulting in fibrocystic-type lung disease and cor pulmonale. HMD should be considered in the differential diagnosis of childhood alopecia, follicular hyperkeratosis, keratoconjunctivitis, juvenile cataracts, gingival hyperemia, restrictive lung disease, and esophageal stenosis or webs. Biopsy specimens of mucosal epithelium demonstrate thinning, dyscohesion, and dyskeratosis. Mucosal Pap smears show cytoplasmic vacuoles and inclusions, individual cell dyskeratosis, and lack of epithelial maturation. Misinterpretation of these abnormal results could lead to unnecessary hysterectomy being performed on these patients. Ultrastructural studies show sparse desmosomes, cytoplasmic vacuolization, bands and aggregates of filamentous fibers and structures resembling desmosomes and gap junctions, and the absence of keratohyalin granules. It is speculated that the disorder is attributable to a panepithelial cell defect of desmosomal and gap junction structure predominantly affecting mucosal epithelium. Because of the predisposition to severe infections of the eye and respiratory tract, these patients should be carefully cultured and treated promptly with appropriate antibiotics, when infection is evident.334,335,337

PACHYONYCHIA CONGENITA This relatively rare syndrome is named for the peculiar identifying nail abnormality that may be associated with other multiple defects.338 Some authorities designate the following three types of the disorder based on the classification proposed by Kumer and Loos:339

• Type I Jadassohn–Lewandowsky (MIM-167200):

A rare autosomal-dominant multiepithelial disorder, hereditary mucoepithelial dysplasia, combines dyskeratoses of the oral, nasal, vaginal, urethral, bladder, and conjunctival mucosa with cataracts, follicular keratoses, nonscarring alopecia, lung disease, and premature death.334–336 Early signs, apparent in infancy, are severe photophobia, tearing and nystagmus, which precede the development of cataracts, corneal vascularization, and keratitis. Intense erythema of the tissues of the mouth and other mucous membranes occurs in infancy and persists throughout life. A generalized eruption of hyperkeratotic pinhead-sized follicular

Pachyonychia, palmoplantar keratoderma, follicular hyperkeratosis biochemically characterized by a mutation of the keratin 6a/16gene.340,341 • Type II Jackson–Lawler (MIM-167210): Pachyonychia, palmoplantar keratoderma, follicular hyperkeratosis, leukokeratosis of the tongue and buccal mucosa characterized by keratin 6b/17 mutations.342,343 A history of natal or neonatal teeth in half of these patients suggests this form of pachyonychia congenita.344 • Type III Corneal dyskeratosis or cataracts plus the features of type II.

332. Witkop Jr CJ, Shank LE, Graham JB, et al. Hereditary benign intraepithelial dyskeratosis. Arch Pathol Lab Med. 1960;90:696. 333. Allingham RR, Seo B, Rampersaud E, et al. A duplication in chromosome 4q35 is associated with hereditary benign intraepithelial dyskeratosis. Am J Hum Genet. 2001;68:491–494. 334. Witkop Jr CJ, White JG, King RA, et al. Hereditary mucoepithelial dysplasia; a disease apparently of desmosome and gap junction formation. Am J Hum Genet. 1979;31:414. 335. Scheman AJ, Ray DJ, Witkop CJ, et al. Hereditary mucoepithelial dysplasia. J Am Acad Dermatol. 1989;21:351. 336. Boralevi F, Haftek M, Vabres P, et al. Hereditary mucoepithelial dysplasia: clinical, ultrastructural and genetic study of eight patients and literature review. Br J Dermatol. 2005;153:310–318. 337. Urban MD, Schosser R, Spohn W, et al. New clinical aspects of hereditary mucoepithelial dysplasia. Am J Med Genet. 1991;1:338–341. 338. Su WP, Chun SI, Hammond DE, et al. Pachyonychia congenita: a clinical study of 12 cases and a review of the literature. Pediatr Dermatol. 1990;7:33–38.

339. Kumer L, Loos HO. Pachyonychia congenita (Typ Riehl). Wien Klin Wochenschr. 1938;48:174. 340. Smith FJ, Fisher MP, Healy E, et al. Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma. Exp Dermatol. 2000;9:170–177. 341. Lin MT, Levy ML, Bowden PE, et al. Identification of sporadic mutations in the helix initiation motif of keratin 6 in two pachyonychia congenita patients: further evidence for a mutational hot spot. Exp Dermatol. 1999;8:115–119. 342. Celebi JT, Tanzi EL, Yao YL, et al. Mutation report: identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2. J Invest Dermatol. 1999;113:848–850. 343. McGowan KM, Coulombe PA. Keratin 17 expression in the hard epithelial context of the hair and nail and its relevance for the pachyonychia congenita phenotype. J Invest Dermatol. 2000;114:1101–1107. 344. Karen JK, Schaffer JV. Pachyonychia congenita associated with median rhomboid glossitis. Dermatology. Available from .

Mucous membrane disorders

DYSKERATOSIS CONGENITA Dyskeratosis congenita (DC) is an inherited progressive bone marrow failure syndrome in which patients undergo premature aging352 and have a predisposition to malignancy. X-linked and autosomal (dominant and recessive)353 forms of the disease are recognized. The gene responsible for X-linked DC (DKC1) encodes a highly conserved nucleolar protein, dyskerin. This protein is believed to be essential in ribosome biogenesis and involved in telomerase RNP assembly. Peripheral blood cells have dramatically reduced telomere lengths but normal levels of telomerase activity. Also in autosomal DC, patients have significantly shorter telomeres than age-matched normal controls, suggesting that both forms of the disease are associated with rapid telomere shortening in hemopoietic stem cells.354–356 Clinically, DC consists of the classical tetrad of reticulated hyperpigmentation, nail dystrophy, pluriorificial leukoplakia, and immunologic abnormalities.357 A variety of less common

345. Hodes M, Norins A. Pachyonychia congenita and steatocystoma multiplex. Clin Genet. 1977;11:359. 346. Covello SP, Smith FJ, Sillevis Smitt JH, et al. Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2. Br J Dermatol. 1998;139:475–480. 347. Guistini S, Amorosi B, Canci C, et al. Pachyonychia congenita with steatocystoma multiplex. A report of two cases and a discussion of the classification. Eur J Dermatol. Apr–May; 1998;8:158–160. 348. Leachman SA, Kaspar RL, Fleckman P, et al. Clinical and pathological features of pachyonychia congenita. J Investig Dermatol Symp Proc. 2005;10(1):3–17. 349. Franzot I, Kansky A, Kavicic S. Pachyonychia congenita (Jadassohn– Lewandowsky syndrome). A review of 14 cases in Slovenia. Dermatologica. 1981;160:462. 350. Stieglitz JB, Centerwall WR. Pachyonychia congenita (Jadassohn– Lewandowsky syndrome): a seventeen-member, four-generation pedigree with unusual respiratory and dental involvement. Am J Med Genet. 1983;14:21. 351. Young LL, Lenox JA. Pachyonychia congenita. A long-term evaluation of associated oral and dermatologic lesions. Oral Surg. 1973;36:663. 352. Vulliamy T, Beswick R, Kirwan M, et al. Mutations in the telomerase component NHP2 cause the premature aging syndrome dyskeratosis congenita. PNAS. 2008;105(23):8073–8078. 353. Elliot AM, Graham GE, Bernstein M, et al. Dyskeratosis congenita: An autosomal recessive variant. Am J Med Genet. 1999;83:178–182.

B

A

Figure 9.30  (A,B) Ulcerations and leukoplakia on the tongues of two young boys with dyskeratosis congenita.

DISORDERS OF MULTIPLE MUCOUS MEMBRANES

Additional variable abnormal findings in these patients in order of decreasing prevalence include: focal palmoplantar keratoderma (plantar, 90%; palmar, 50%) hyperhidrosis (75%), oral leukokeratosis 50%, more prominent in PC-1), follicular keratosis in sites of friction steatocystoma multiplex,345–347 epidermal cysts (50% more common in PC-2), coarse or twisted hair 25% more common in PC-2), hoarseness due to laryngeal involvement (15%) and corneal abnormalities (90% of pediatric patients.420

Oral ulcers often antedate neurologic symptoms by several years.421,422 The oral lesions, clinically indistinguishable from aphthae, arise in small foci of erythema. The erythema is followed within hours by slight infiltration and, over the course of 24–48 h, shallow, round, to polyhedral ulcerations become evident.421 Covering these erosions is a white, gray, or yellowish pseudomembrane. The regular, discrete edges of the ulcers help distinguish these lesions from those of Stevens–Johnson syndrome and allergic aphthosis, in which edges remain irregular, and in Reiter syndrome, in which heaped-up borders characterize the mucosal lesions.423 The ulcers of Behçet syndrome preferentially form on the gingiva, the mucous membranes of the lips, the buccal mucosa, and the tongue (Fig. 9.32). In contrast to Stevens–Johnson syndrome and Reiter syndrome, the palate, tonsils, and pharynx are rarely involved. The ulcers develop in crops and range in size from several millimeters to 1 cm or more in diameter. They persist for several days to a few weeks424 but typically heal without scarring. The types of oral ulcerations may be minor, major, herpetiform, or combined, but herpetiform aphthae are relatively more frequent.98 The major factor contributing to morbidity of oral mucosal membrane ulcerations is diminished fluid and caloric intake.418 The genital lesions of Behçet syndrome resemble those seen in the oral cavity. In males they occur predominantly on the scrotum and base of the penis and in females on the vulva and vaginal mucosa.44,418,422 The perianal region and vaginal mucosa may be involved as well. As the genital ulcers are usually deeper than the oral ones, scarring is common. The genital area should be carefully examined for residual scarring when Behçet syndrome is suspected and no active ulcers are evident. Both oral

Figure 9.32  (A) Vulvar aphthae in Behçet’s disease. (B) Tongue ulcerations in Behçet’s disease (courtesy of Dr A. Torrelo).

B

A

417. Skopouli FN, Dafni U, Ioannidis JP, et al. Clinical evolution, and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum. 2000;29:296–304. 418. Ammann AJ, Johnson A, Fyfe GA, et al. Behçet’s syndrome. J Pediatr. 1985;107:41. 419. Chajek T, Fainaru M. Behçet’s disease: Report of 41 cases and a review of the literature. Medicine (Baltimore). 1975;54:179. 420. Yazici H, Yurdakul S, Hamuryudan V. Behçet disease. Curr Opin Rheumatol. 2001;13:18–22. 421. Haensch R. Behçcet’s disease (aphthosis). Cutis. 1974;14:353.

696

422. Cho MY, Lee S, Bang D, et al. Clinical analysis of 57 cases of Behçet’s syndrome in children. In: O’Duffy JD, Kokmen E, eds. Behçet’s disease. Basic and clinical aspects. New York: Marcel Dekker; 1991:41. 423. Michelson JB, Chisari FV. Behçet’s disease. Surv Ophthalmol. 1982; 26:190. 424. Mundy TM, Miller JJ. Behçet’s disease presenting as chronic aphthous stomatitis in a child. Pediatrics. 1978;62:205.

Mucous membrane disorders

425. Kone-Paut I, Geisler I, Wechsler B, et al. Familial aggregation in Behçet’s disease: high frequency in siblings and parents of pediatric probands. J Pediatr. 1999;135:89–93. 426. Jorizzo JL, Hudson RD, Schmalstieg FC. Behçet’s syndrome: immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy. J Am Acad Dermatol. 1984;10:205. 427. Haim S, Gilhar A. Clinical and laboratory criteria for the diagnosis of Behçet’s disease. Br J Dermatol. 1980;102:36. 428. O’Duffy JD, Kokmen E, eds. Behçet’s disease, basic and clinical aspects. New York: Marcel Dekker; 1991. 429. Marsahll SE. Behcet’s disease. Best practice and research. Clin Rheumatol. 2004;18(3):291–311. 430. Calin A. Reiter’s syndrome. Med Clin North Am. 1977;61:365. 431. Lockie GN, Hunder GG. Reiter’s syndrome in children. A case report and review. Arthritis Rheum. 1971;14:767.

REITER SYNDROME Reiter syndrome is a symptom complex that most frequently consists of the triad of conjunctivitis, urethritis, and arthritis.430 Asymptomatic mouth ulcers and lesions resembling glossitis/ stomatitis geographica are a less common feature, as is the associated cutaneous eruption, keratoderma blennorrhagicum. Although predominantly a disease of the young adult male, this syndrome also occurs in females and has occasionally been recognized in prepubertal children.431–433 Reiter syndrome is perceived as a reactive response to previous infection and most frequently follows Chlamydia urethritis, serotypes D–K, Salmonella or Shigella dysentery but has also been associated with Yersinia gastroenteritis. More than 80% of the patients are HLA-B27 positive, but the reasons for that are unclear.434 The mucosal manifestations of the disorder are frequently mild and may be overlooked or forgotten by the patient presenting with arthritis, unless the appropriate history is specifically elicited. In a series of 38 children, 66% had conjunctivitis as the initial finding, 34% had urethritis, and only 24% had arthritis.435 All three major features are generally detectable during the acute illness. The conjunctivitis of Reiter syndrome is bilateral and varies considerably in severity from a mild discharge to marked inflammation with edema and erythema of the bulbar and palpebral conjunctivae. Progression to corneal ulceration is uncommon but can occur.435 An accompanying keratitis436 or iritis,437 or both, has also been noted; the latter, if severe and chronic, can result in blindness,432 an outcome not yet reported in children. Urethral involvement is most often reflected by dysuria, although the manifestations may range from meatal inflammation only to frank urethral discharge.435 Pyuria is a common laboratory finding and should always be sought if the diagnosis of Reiter syndrome is under consideration. Balanitis and ulcerations of the labia437 have been noted in a few patients. The frequency of oral manifestations in children is unknown. Mouth lesions are nonspecific, consisting of erythema, erosions, and necrotic ulcerations, most commonly involving the buccal mucosa, gingivae, palate, and tongue. The histopathology of these lesions is nondiagnostic.88 Reiter syndrome and Kawasaki disease have some features in common.438 Generally, the mucosal lesions of Reiter syndrome are relatively benign and self-limited; occasionally, however, serious morbidity can result if the inflammatory process becomes chronic. Treatment is largely symptomatic, as no drugs are consistently effective in palliating this disorder. The overall course

DISORDERS OF MULTIPLE MUCOUS MEMBRANES

and genital ulcerations tend to remit within 1–2 weeks but often recur. Ocular manifestations, which range from simple photophobia and irritation to keratoconjunctivitis or uveitis, are less common in pediatric patients with Behçet syndrome.418,423 In adults, recurrent attacks of anterior and posterior uveitis may ultimately result in blindness. Anterior uveitis may precede hypopyon, a typical but transient clinical sign of Behçet syndrome. Posterior uveitis, hemorrhages, and exudates in the choroid and retina characterize chronic ocular involvement.419 Gastrointestinal and uncommon lesions are relatively more frequent in children.425 Histologically, the oral ulcerations show nonspecific changes similar to those of aphthae. However, the presence of endothelial swelling is characteristic of Behçet’s ulcers and helps to differentiate them from aphthae. Vasculitis is another characteristic of some mucocutaneous lesions, and the small vessels, particularly the venules, are filled with immune complex deposits. Neutrophil chemotaxis is enhanced.44,426 The diagnosis of Behçet syndrome cannot be verified by any reproducible hematologic, immunologic, or infectious studies. Various clinical criteria have therefore been outlined to assist in making the diagnosis.418–427 The cause of Behçet syndrome is unknown.420 Many cases have been shown to be HLA-B 51 positive, and a self-antigenic role for HLA B51 has been postulated. Familial cases are more frequent in childhood Behçet’s disease.425 Etiologies ranging from viral infection, exposure to environmental pollutants, and a variety of immunologic abnormalities have been proposed.419,426–428 This suspicion is supported by the fact that Turkish individuals who immigrate to Germany have a lower risk of developing this disease, although not as low as the native German population. Japanese immigrants to the US mainland or Hawaii lack the disease, despite a prevalence of 13–20 per 100 000 in Japan.429 Therapy is not entirely satisfactory. Systemic corticosteroids help control many of the clinical manifestations, but chlorambucil, colchicine, cyclosporine, tacrolimus, levamisole, and azathioprine may be required to maximize therapeutic efficacy. Recent studies have supported the use of infliximab or etanercept.429 Thalidomide is particularly effective therapy in the mucocutaneous form. No single form of drug therapy has proven uniformly effective for the treatment of Behçet syndrome. As this disorder has a high prevalence of spontaneous remissions and exacerbations during the course of the disease, the evaluation of the efficacy of any therapeutic regimen is difficult. Combined drug therapy may be more efficacious in some patients than single drug regimens.428

9

432. Cuttica RJ, Scheines EJ, Garay SM, et al. Juvenile onset of Reiter’s syndrome. A retrospective study of 26 patients. Clin Exp Rheumatol. 1992;10:285. 433. Aroroa S, Arora G. Reiter’s disease in a six-year-old girl. Indian J Dermatol Venereol Leprol. 2005;71:285–286. 434. Pavlica L, Mitrovic D, Mladenovic V, et al. Reiter’s syndrome – analysis of 187 patients. Vojnosanit Pregl. 1997;54:437–446. 435. Rosenberg AM, Petty RE. Reiter’s disease in children. Am J Dis Child. 1979;133:394. 436. Russell AS. Reiter’s syndrome in children following infection with Yersinia enterocolitica and Shigella. Arthritis Rheum. 1977;20:471. 437. Iveson JMI, Nanda BS, Hancock JAH, et al. Reiter’s disease in three boys. Ann Rheum Dis. 1975;34:364. 438. Bauman C, Cron RQ, Sherry DD, et al. Reiter syndrome initially misdiagnosed as Kawasaki disease. J Pediatr. 1996;128:366–369.

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Diseases of Mucous Membranes and Appendageal Structures

DISORDERS OF MULTIPLE MUCOUS MEMBRANES

This spectrum of hypersensitivity reactions includes erythema multiforme (EM) simplex, bullous EM, Stevens–Johnson syndrome, and toxic epidermal necrolysis (TEN) (Fig. 9.33). In EM simplex, bullous EM, and TEN, the mucous membranes are affected to a variable degree.44,440,441 By definition, Stevens–Johnson syndrome implies activity in at least two mucous membrane sites, most often the conjunctivae and oropharynx, but the nasal mucosa, and urethral, vaginal, and rectal mucosa can also be involved. This form of EM may remain confined to the mucous membranes or may involve the skin as well. The oral manifestations of this symptom complex are basically similar in all forms of EM but vary in extent and severity.440,441 The primary lesion is a macular area of erythema that evolves centrally into a thick-walled vesicle or bulla. The duration of the blister is brief and, following rupture, the characteristic irregularly shaped ulcer with indistinct margins and a yellow necrotic base becomes evident. These extremely painful lesions may then become covered with a pseudomembrane prior to healing. The

lesions occur in a crop so that, at a given time, lesions in all stages of development may be observed. Sites of predilection are the lips, where the labial mucosa alone may be affected, or the lesions may extend over the vermilion border to the keratinized skin, the anterior and lateral borders of the tongue, the buccal mucosa, and the palate. The dorsum of the tongue becomes coated but does not ulcerate. The gingivae remain relatively spared, an important clinical finding in differentiating this eruption from acute herpetic gingivostomatitis. As the disease progresses, the ulcers may become confluent on the labial surface so that the entire lip is overlaid with a thick hemorrhagic crust that typifies oral lesions of EM. Erosions of the pharynx occur in severe cases and may extend to cause a necrotizing esophagitis. During the acute stage, swallowing is so painful that ingestion of food and fluids may become impossible. Secondary infection may result in excessive salivation and a fetid mouth odor. Occasionally, ulcerations may also develop in the nasal mucosa and larynx causing bleeding, crusting, and airway obstruction. Healing in all these sites usually occurs without the formation of scars.442 Genital involvement in EM causes a urethritis associated with dysuria and purulent discharge. Vulvovaginitis and balanitis accompany the urethral lesions; at times, the rectal mucosa is also inflamed and ulcerated. Genitourinary lesions may be so painful that the child refuses to void, and an indwelling urinary catheter must be placed during the acute phase. Ocular lesions constitute the most dangerous of the mucous membrane lesions, as they may result in serious sequelae. The early acute phase consists of a mucopurulent conjunctivitis with inflamed swollen papillae in the conjunctiva. Focal ulcerations may lead to the formation of pseudomembranes and synechiae. Secondary complications include symblepharon, entropion, trichiasis, keratitis, corneal pannus, and stricture of the lacrimal puncta. Severe disease may result in profound loss of visual activity or even blindness.443 The diagnosis is often made by clinical assessment only but can be confirmed by biopsy of a typical lesion. (See Ch. 20 for a more extensive discussion of the EM spectrum.) Outcome depends on prompt diagnosis and meticulous nursing care for patients with an extensive or severe reaction. Immediate ophthalmologic evaluation is mandatory if the diagnosis of ocular EM is under consideration.444,445 Ocular sequelae may occur during the acute phase of the disease or more chronically with stem cell failure (ocular surface failure) or recurrent conjunctival inflammation.445 Damage to the cornea is the most severe form of ocular complication in erythema multiforme major. Patients with mild disease may need little other than symptomatic therapy. Those with fulminant painful mucosal lesions may require hospitalization and administration of intravenous fluids for correction of dehydration and electrolyte imbalance and maintenance of nutrition. The use of corticosteroids is controversial, since large double-blind multicentered controlled

439. Wu IB, Schwartz RA. Reiter’s syndrome: the classic triad and more. J Am Acad Dermatol. 2008;59:113–121. 440. Shklar G, McCarthy PL. Oral manifestations of erythema multiforme in children. Oral Surg Oral Med Oral Pathol. 1966;21:713. 441. Giallorenzi AF, Goldstein BH. Acute (toxic) epidermal necrolysis. Oral Surg. 1975;40:611. 442. Hebert AA, Lopez MD. Oral lesions in pediatric patients. Adv Dermatol. 1997;12:169–194.

443. Ginsburg CM. Stevens–Johnson’s syndrome in children. Pediatr Infect Dis. 1982;1:155. 444. Chang Y, Huang F-C, Tseng S-H, et al. Erythema multiforme, Stevens– Johnson syndrome and toxic epidermal necrolysis; acute ocular manifestations, causes, and management. Cornea. 2007;26(2):123–129. 445. DeRojas MV, Dart JK, Saw VPJ. The natural history of Stevens–Johnson syndrome: patterns of chronic ocular disease and the role of systemic immunosuppressive therapy. Br J Opthalmol. 2007;91:1048–1053.

Figure 9.33  Toxic epidermal necrolysis due to phenytoin.

of Reiter’s in children is reported to be milder, with fewer recurrences, although long-term arthritis-related morbidities have been reported.439

ERYTHEMA MULTIFORME SPECTRUM

698

Mucous membrane disorders

TOXIC SHOCK SYNDROME Toxic shock syndrome (TSS) is an acute febrile illness occurring in both sexes and all age groups, but most frequently in adult women.450–454 This condition is caused by a toxin elaborated by certain strains of Staphylococcus aureus that can be cultured from various body sites. The clinical criteria for diagnosis include: (1) fever of >38.9°C; (2) diffuse macular erythematous rash; (3) desquamation 1–2 weeks after onset of illness; (4) hypotension (1.5 cm if postpubertal); ≥2 neurofibromas or ≥1 plexiform neurofibroma; axillary or inguinal freckling; ≥2 pigmented iris hamartomas (Lisch nodules); a distinctive osseous lesion, such as sphenoidal dysplasia or tibial pseudoarthrosis; optic nerve glioma and a first degree relative with NF1, diagnosed by using the above listed criteria.21 Although these criteria are highly specific and sensitive in adults with NF1, they are not as sensitive in children under 8 years of age. Recommendations for evaluation and management are clearly delineated.22,23 Inguinal and/or axillary skin folds ‘freckling’ (Crowe’s sign), usually detected between 3 and 5 years of age, are small, 1–3 mm, and may also be present above the eyelids, around the neck and under the breasts. These are not strictly speaking freckles as they are not sun-induced and do not fade with age. A generalized background hyperpigmentation is also noted in NF1 patients as compared to their unaffected parents and siblings. NF1-like syndrome, an autosomal dominant disorder due to a mutation in SPRED1 on chromosome 15, includes multiple CALMs, axillary freckling and macrocephaly.24 Children with McCune–Albright syndrome (polyostotic fibrous dysplasia) are mosaic for mutations in the GNAS1 gene,25 that encodes a G-protein subunit (GS-α) that activates adenylate cyclase. The excess production of cAMP in mutant cells could affect melanogenesis and melanosome transport.26 The pigmentary changes are café-au-lait spots that are characteristically fewer, larger, darker, and have more jagged margins, supposedly resembling the coast of Maine (Fig. 10.3).27 Besides the characteristic bony lesions, this syndrome includes endocrinologic hyperfunction, especially precocious puberty in females, thyrotoxicosis, pituitary gigantism, and Cushing syndrome.28 Pathological fractures, ovarian cysts and breast hyperpigmentation are also associated.29 Watson syndrome is a much rarer disorder in which children have multiple large café-au-lait spots. It is an autosomal dominant disorder and is characterized by pulmonary stenosis, low intelligence, axillary freckling, pigmented patches and neurofibromas, reported at a much lower rate than in neurofibromatosis type 1.30 Other conditions in which café-au-lait spots have been described include Russell–Silver dwarfism, ataxia-telangiectasia, tuberous sclerosis, basal cell nevus syndrome, Hunter syndrome, Turner syndrome, Gaucher’s disease and others (Table 10.2). The prevalence of café-au-lait spots in idiopathic epileptic children

The term nevus spilus, originally coined by Ito and Hamada in 1952, also referred to as speckled lentiginous nevus,32 the preferred term by many, is characterized by a light-brown tan macule or patch stippled with punctuate, smaller, often 1–3 mm but occasionally larger dark-brown macules, papules or nodules usually present on the trunk or proximal extremities. The background macule or patch, usually 1–10 cm, is rarely seen at birth and usually develops in the first year of life. The speckles usually number 8–10, appear and increase during early childhood or later (Fig. 10.4). It is encountered in 1–2% of the population. The histologic findings include those of lentigines in the tan patchy areas, as well as changes of a variety of melanocytic nevi in the darker speckled sites, such as congenital, junctional, intradermic, compound, blue or Spitz nevi. Multiple clustered or agminated Spitz nevi have been described.33 Some of these lesions acquire over time an appearance suggestive of classic congenital nevi, or are ‘hybrids,’ with portions appearing as

20. Korf BR. Diagnostic outcome in children with multiple café au lait spots. Pediatrics, 1992;90:924. 21. Riccardi V. Pathophysiology of neurofibromatosis. J Am Acad Dermatol, 1980;3:157. 22. Williams VC, Lucas J, Babcok BS, et al. Neurofibromatosis type I revisited. Pediatrics. 2009;123:124–133. 23. Boyd KP, Korf BR, Theos A. Neurofibromatosis type 1. J Am Acad Dermatol. 2009;61:1–14. 24. Brems H, Chmara M, Sahbatou M, et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis1-like phenotype. Nat Gent. 2007;39:1120–1126. 25. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl J Med. 1991;325:1688–1695. 26. Passeron T, Bahadoran T, Bertolotto C, et al. Cyclic AMP promotes a peripheral distribution of melanosomes and stimulates melanophyllin/ Slac2α and actin association. FASEB J. 2004;18:989–991.

27. Benedict PH, Szabo G, Fitzpatrick TB, et al. Melanotic macules in Albright’s syndrome and in neurofibromatosis. JAMA. 1968;205:618. 28. Albright F. Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation, and a gonadal dysfunction. Endocrinology. 1938;22:411. 29. Roman R, Johnson MC, Codneer E, et al. Clinical and molecular study of Chilean patients with McCune-Albright. Rev Med Childh. 2001;129:1365–1372. 30. Allanson JE, Watson GH, Partington M, et al. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991;28:752–756. 31. Karabiber H, Sasmaz S, Turanli G, et al. Prevalence of hypopigmented maculae and café-au-lait spots in idiopathic epileptic and healthy children. J Child Neurol. 2002;17:57–59. 32. Stewart DM, Altman J, Mehregan AH. Speckled lentiginous nevus. Arch Dermatol. 1978;114:895–906. 33. Hueso L, Hernández A, Torrelo A, et al. Agminated Spitz nevi on a hypopigmented macule. Acta Dermatosifiliogr. 2008;99:69–72.

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PRIMARY CIRCUMSCRIBED EPIDERMAL HYPERMELANOSES

Figure 10.3  Broad Blaschko linear hyperpigmented macules in a child with McCune–Albright syndrome. (Courtesy of Dr Antonio Torrelo)

between the age of 2 and 17 years was shown to be 30% compared with 2.83% in healthy children.31 There are no medical indications for treating café-au-lait spots. These lesions have no malignant potential and are usually in locations of little cosmetic significance.

Nevus spilus

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Diseases of Mucous Membranes and Appendageal Structures

Table 10.2  Diseases associated with multiple café-au-lait spots

PRIMARY CIRCUMSCRIBED EPIDERMAL HYPERMELANOSES

DISEASE

MAJOR FEATURES

Ataxia telangiectasia

Progressive ataxia, lymphoreticular malignancy

Bannayan–Riley– Ruvalcaba syndrome

Macrosomia, megalencephaly, lipomas, intestinal polyps

Basal cell nevus syndrome

Multiple basal cell epitheliomas, jaw cysts, skeletal anomalies

Bloom syndrome

Short stature, photosensitivity, chromosome breaks, malignancy

Fanconi’s anemia

Limb anomalies, renal anomalies, pancytopenia

Gaucher’s disease

Jewish predilection, ataxia, mental retardation

Hunter syndrome

Thickened skin, coarse facies, skin papules, joint contractures

Jaffe–Campanacci syndrome

Fibromas of long bones, hypogonadism, mental retardation, ocular/cardiac anomalies

Maffucci syndrome

Venous malformations, enchondromas

McCune–Albright syndrome

Polyostotic fibrous dysplasia, precocious puberty

Multiple lentigines syndrome

Multiple lentigines, hypertelorism, pulmonic stenosis

Multiple mucosal neuroma syndrome

Mucosal neuromas, thyroid carcinoma, pheochromocytoma, parathyroid adenoma, dysautonomia

Neurofibromatosis

Neurofibromas, central nervous system tumors, iris hamartomas, axillary freckles, skeletal anomalies

Russell–Silver syndrome

Short stature, asymmetry, limb anomalies

Tuberous sclerosis

White macules, multiple hamartomas, central nervous system anomalies

Watson syndrome

Pulmonic stenosis, axillary freckles, low intelligence

Legius syndrome

Axillary freckling macrocephaly, a Noonan-like facial dysmorphism, lipomas

classic congenital nevi adjacent or admixed with portions appearing as speckled lentiginous nevi. These observations support the hypothesis that speckled lentiginous nevi are a subtype of congenital melanocytic nevi and not acquired pigmented lesions.34 Giant forms have been reported. Speckled lentiginous nevus syndrome is rare and refers to ipsilateral neurologic abnormalities such as dysesthesia,

34. Schaffer JV, Orlow SJ, Lazova R, et al. Speckled lentiginous nevus within the spectrum of congenital melanocytic nevi. Arch Dermatol. 2001;137: 172–178. 35. Happle R. Speckled lentiginous nevus syndrome: delineation of a new distinct neurocutaneous phenotype. Eur J Dermatol. 2002;12:133–135. 36. Ramolia P, Treadwell P, Haggstrom A. Speckled lentiginous nevus syndrome associated with musculoskeletal abnormalities. Pediatr Dermatol. 2009;26:298–301. 37. Vidaurri-de la Cruz H, Happle R. Two distinct types of speckled lentiginous nevi characterized by macular versus papular speckles. Dermatology. 2006;212:53–58.

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Figure 10.4  Characteristic nevus spilus with a large light-brown macule and numerous smaller brown macules. (Courtesy of Dr Antonio Torrelo)

muscular weakness or hyperhydrosis.35,36 Other associated abnormalities include pigmented sclera, kyphoscoliosis, verrucoid epidermal nevus, tuberous angioma, underlying muscular hypertrophy and complex phacomatosis. The macular speckled lentiginous nevus is distinct from the papular form in that the former demonstrate a rather even polka-dot pattern distribution of speckles associated particularly to type III and IV phakomatosis pigmentovascularis, whereas in the latter, the papules and nodules distribution is uneven with a star-map pattern associated to phakomatosis pigmentokeratotica and the speckled lentiginous nevus syndrome.37,38 Speckled lentiginous nevi are rare potential precursors of malignant melanoma.39,40 The majority of reported melanoma arising from nevus spilus were thin (10 cm. Over the next 1–4 years, it becomes less noticeable and eventually fades completely. Persistence of Mongolian spots beyond the first decade of life is uncommon. Only 3–4% of lesions remain beyond this time, particularly in Asians.84 Histologic examination of the lesion reveals a deep dermal melanocytic proliferation scattered among collagen bundles but without surrounding fibrosis. The pigment is entirely contained within melanosomes and as such is not phagocytosed by melanophages. This is fortunate because pigment within melanophages may remain indefinitely. There are several intriguing aspects in the pathogenesis of the Mongolian spot. It is reasonable to assume that incomplete migration of melanocytes accounts for the dermal location of these cells, but why does this occur preferentially in certain locations? One theory holds that local hindrance factors may prevent melanocytes from entering certain areas and the sacrogluteal area of susceptible individuals could lack these factors.85 Another interesting question is: why do these melanocytes disappear early in life and nevocellular nevus cells remain until the sixth or seventh decade? The answer is unknown, but the process of involution does involve the destruction of the melanocytes themselves. In adults, however, dermal melanocytes that are not synthetizing melanin can be detected and therefore are probably functionally altered. It is likely that Mongolian spots and other types of dermal melanocytoses are due to somatic mosaicism, a view that is supported by an association with other nevoid conditions in the form of twin-spotting (see below). The Mongolian spot is so distinctive that when present at birth in the characteristic sacral location, little can be confused with it. Congenital nevi share some similar features but usually have an irregular surface and have shades of brown interspersed with blue and gray colors. Blue nevi are very rare in young children and are smaller and more well defined than Mongolian spots and present distinctive histopathological features. The presence of a Mongolian spot should always be noted in the newborn medical record, since these lesions can be mistaken for ecchymoses in cases of suspected child abuse.85

83. Tanyasiri K, Kono T, Groff WF, et al. Mongolian spots with involvement of mandibular area. J Dermatol. 2007;34:381–384. 84. Leung AKC. Mongolian spots in Chinese children. Int J Dermatol. 1988;27:106. 85. Smalek JE. Significance of mongolian spots. J Pediatr. 1980;97:504. 86. Hasagawa Y, Yasuhara M. Phacomatosis pigmentovascularis type IVa. Arch Dermatol. 1985;121:651–655. 87. Happle R. Phacomatosis pigmentovascularis revisited and reclassified. Arch Dermatol. 2005;141:385–388. 88. Selsor LC, Lesher JL. Hyperpigmented macules and patches in a patient with GM1 type gangliosidosis. J Am Acad Dermatol. 1989;20:878. 89. Mishima Y, Mevorah B. Nevus of Ota and nevus of Ito in American Negroes. J Invest Dermatol. 1961;36:133.

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Mongolian spots are part of the non-allelic twin-spotting syndromes phakomatosis pigmentovascularis type II, IV, and V86 also referred to as phakomatosis cesioflammea and phakomatosis cesiomarmorata.87 Associated diseases have been described with Mongolian spots but because this is a common anomaly, most are probably coincidental. Unusual multiple large Mongolian spots may be associated with Hurler disease, Hunter syndrome and an abnormality of sphingolipid metabolism, GM1 type gangliosidosis, caused by a deficiency of the enzyme α-galactosidase. These children may have severe developmental delay, edema, unusual facies, hepatosplenomegaly, and cherryred spots of the retina.88 Mongolian spots are usually auto-resolutive and of no clinical consequence. Thus, there is no indication to treat these lesions.

Nevus of Ota/Ito Oculodermal melanocytosis was first characterized in 1939 in Japan, by Ota. The nevus of Ota, also referred to as naevus fuscocaeruleus ophtalmomaxillaris, occurs most commonly in Asians and blacks, but is noted in all races.89 Females account for at least 75% of all reported cases. It is usually sporadic but rare cases of familial nevus of Ota have been described.90 Over 50% of lesions are present at birth and 40% appear at puberty, all of which involve the skin over the ophthalmic and/or maxillary branches of the fifth or trigeminal cranial nerve. Only rare cases occur after age 21.91 It persists and extends locally and becomes more prominent with age. Four types were originally described: (1) an orbital type with tan-gray pigment limited to the eyelids or zygomatic region unilaterally; (2) a moderate type with deep slate-gray to brown densely spotted pigment on the eyes, zygomatic region, and base of the nose; (3) an intensive type with deep-blue or purple densely pigmented areas on the side of the scalp and face down to the zygomatic region; and (4) a rare bilateral type (5– 10%). They have been reclassified according to the histological dermal location of melanocytes, including superficial, deep, diffuse, superficial dominant and deep dominant types.92 The more superficial lesions tend to be located on the cheeks, whereas the deeper ones usually appear on the periorbital areas, forehead and temples. Mucous membrane pigmentation is common with all types, particularly of the ear canal, oral and nasal mucosa.89 Another clinical feature consists of intralesional or perilesional blue papules resembling blue nevi.93 Melanin pigment is deposited in the eye in 46–65% of reported cases. When the eye is affected, the sclera is always pigmented and the iris, the conjunctiva and the optic nerve are involved in 50%, 40% and 4%, respectively.94 Deposition of melanocytes at the ciliary body of the angle of the anterior chamber can cause secondary ipsilateral glaucoma in

90. Trese MT, Petit TH, Foos RY, et al. Familial nevus of Ota. Ann Ophthalmol. 1981;13:855. 91. Whitmore SE, Wilson BB, Cooper PH. Late-onset nevus of Ota. Cutis. 1991;48:213. 92. Hirayama T, Suzuki T. A new classification of Ota’s nevus based on histological features. Dermatologica. 1991;183:169–172. 93. Hartmann LC, Oliver GF, Winkelmann RK, et al. Blue nevus and nevus of Ota associated with dermal melanoma. Cancer. 1989;64:182. 94. Haim T, Meyer E, Kerner H, et al. Oculodermal melanocytosis (nevus of Ota) and orbital malignant melanoma. Ann Ophthalmol. 1982;14:1132.

Pigmentary abnormalities

supraclavicular brachial cutaneous nerves.

approximately 10% of patients. This usually occurs in blacks and Asians and is seen between the age of 20 and 40 years old, although it has been detected at birth.95 The retrobulbar fat, retina and cornea may also be affected. The so-called nevus of Hori refers to acquired bilateral nevus of Ota-like macules (ABNOM) usually during adulthood.96 Nevi of Hori are localized on the face. They are more frequent in Asian females and they usually appear later in life (range 16–69 years old; average 36 years old) and do not involve mucosal surfaces. They have been described in children as young as 6 years old.97 The nevus of Ito or naevus fuscoceruleus acromiodeltoideus probably represents the same pathologic process as the nevus of Ota, but it is located in a unilateral distribution over the supraclavicular, deltoid or scapular regions. These locations correspond roughly to the distribution of the posterior supraclavicular and the lateral brachial cutaneous nerves (Fig. 10.6). The patch of nevus of Ito varies in color from deep blue-purple to light brownish-blue. The cause of these dermal melanocytic disorders is unknown, although an intriguing hypothesis has been proposed. The embryonic environment determines the onset, pattern and extent of neural crest cell differentiation and these pluripotent cells mature along given phenotypic pathways in response to local factors.98 The nevus of Ota may occur secondary to glycosaminoglycan alterations favoring differentiation into melanocytes.99 Strong racial differences in incidence suggest that genetic factors are also operative. Sex hormones may also play a role in the pathogenesis of this hamartoma as suggested by the female predominance, the clinical onset at puberty and the reported variation in the color of the lesion with menstruation.89 95. Liu JC, Ball SF. Nevus of Ota with glaucoma: report of three cases. Ann Ophthalmol. 1991;23:286. 96. Hori Y, Kawashima M, Oohara K, et al. Acquired, bilateral nevus of Ota-like macules. J Am Acad Dermatol. 1984;10:961–964 . 97. Fe HL, Wong HC, Goh CL, et al. Characteristics of Hori nevus: a prospective analysis. Br J Dermatol. 2006;2:29–37. 98. LeDorain NM. The neural crest in the neck and other parts of the body. Birth Defects. 1975;11:19. 99. Benson MT, Rennie IG. Hemi-naevus of Ota: perturbation of neural crest differentiation as a likely mechanism. Graefes Arch Clin Exp Ophthalmol. 1992;230:226. 100. Inoue S. The mongolian spot. Hifubyoh-Shinryoh. 1979;1:104. 101. Patel BC, Egan CA, Lucius RW, et al. Cutaneous malignant melanoma and oculodermal melanocytosis (nevus of Ota): report of a cases and review of

Histopathology of nevus of Ota/Ito reveals melanocytes scattered, mainly in the upper corium of the dermis100 accounting for the browner color than that observed in the Mongolian spot. The main differential diagnosis is the Mongolian spot. In cases of extrasacral Mongolian spots, only time will distinguish these two entities: Mongolian spots usually resolve while the nevus of Ota/Ito is permanent. Several distinguishing features help in making the correct diagnosis: (1) nevus of Ota appears at puberty in 40% of cases, whereas the Mongolian spot always presents in infancy; (2) nevus of Ota has a brownish color with a ‘powder blast burn’ appearance, whereas the Mongolian spot is more uniformly bluish; (3) the characteristic sharp border of nevus of Ota is rarely seen with Mongolian spots; and (4) pigment is commonly present in the mucous membranes and eye in nevus of Ota but is rarely, if ever, seen in the Mongolian spot. Other differential diagnoses include melasma, melanoma, post-inflammatory hyperpigmentation, exogenous ochronosis, Riehl’s melanosis, and pigmentation associated with the ingestion of drugs, which will be addressed further on. Nevus of Ota is usually a benign dermatosis, but there have been more than 60 cases of associated melanoma, almost all of which occurred in white patients.101 These melanomas have developed in the skin, meninges, frontal brain, choroid, and iris and were ipsilateral in 97%.102 Intracranial melanocytosis as well as ipsilateral neurosensorial deafness have also been reported in children with nevus of Ota. Facial disfigurement often results in emotional distress. Laser surgery has now superseded other treatment modalities for the nevus of Ota. The pulsed Q-switched ruby laser emits a wavelength of light that is preferentially absorbed by melanin. Selective destruction of upper dermal melanocytes by this method can fade these lesions appreciably.103,104 Children, of mean age of 3 years old, required fewer Q-switched ruby laser treatments than adults, had less complication and a recurrence rate of 0.6–1.2%.105 Q-switched alexandrite and Q-switched Nd: YAG (532 nm) lasers are also used. After 4–8 treatments, skin pigmentation is dramatically reduced in 90–100% of cases with 250 mg/dL while the serum bilirubin is normal. The stools and urine are normal in color.177 Although the vast majority of children with carotenemia are in good health otherwise, there are several diseases that have been associated with increased serum carotene levels. In hypothyroidism and diabetes mellitus, there is thought to be a decreased conversion of carotene into vitamin A secondary to an increase in lipoproteins that transport carotene.177 Patients with anorexia nervosa have bizarre eating habits that may lead to carotenemia.178 There are also rare cases of inborn errors of carotene metabolism that may produce carotenemia.179 There is no good medical reason to reverse the changes of carotene deposition in the skin. The very slow conversion of the compound to the active vitamin A obviates any threat of hypervitaminosis A syndrome. Parents can be reassured that if the offending foods are eliminated, the skin color will return to normal within 2–6 weeks. Oral retinoids particularly associated with ultraviolet light can induce intense hyperpigmentation.180

Figure 10.12  Hyperpigmentation of the lips, tongue and palate in a patient with Addison’s disease.

In many instances of the acute type and in >90% of the chronic variety of adrenal hypofunction there is generalized hyperpig-

mentation,181 which may precede other manifestations of the disease. These children present with a generalized increased skin color marked over photoexposed areas, which is often a bronze hue in fair-skinned individuals, and is accentuated in skin folds such as the palms and frictional sites. The mucous membranes, tongue, nipples, and areolae are also hyperpigmented. In the oral mucosa, one may find spotty or speckled blue-brown macules of the gingivae, tongue, palate, and buccal mucosa (Fig. 10.12). In dark-skinned children, this increase in skin color may be mistaken for a suntan, but the mucous membrane and palmar crease color changes should lead to suspicion of adrenal insufficiency. Histologic examination reveals nonspecific increase in epidermal melanin and dermal pigment in macrophages. The pathogenesis of the hyperpigmentation is not completely clear and there is considerable debate about what role, if any, is played by the pituitary hormones. It is possible that adrenocorticotropic hormone (ACTH) and/or ß-lipotropic pituitary hormone (ß-LPH) have sufficient melanotropic potential that their excess in Addison’s disease can produce generalized hyperpigmentation. Additional evidence for this hypothesis comes from the fact that in Cushing syndrome there is an increase in ACTH and probably in ß-LPH secretion. Many of these patients also develop pigment changes similar to those of adrenocortical insufficiency. Adequate adrenocortical hormone replacement therapy usually results in a decrease in pigmentation in those with Addison’s disease. In some younger patients, the skin color may eventually return to normal. A recessive disorder, Allgrove syndrome, includes achalasia, alacrimia and adrenal insufficiency with progressive hyperpigmentation.182

173. O’Branskii EE, Ware RE, Prose NS, et al. Skin and nail changes in children with sickle cell anemia receiving hydroxyurea therapy. J Am Acad Dermatol. 2001;44:859–861. 174. Marcoux D, Anex R, Russo P. Persistent serpentine supravenous hyperpigmented eruption as an adverse reaction to chemotherapy combining actinomycin and vincristine. J Am Acad Dermatol. 2000;43: 540–546. 175. Lascari AD. Carotenemia. Clin Pediatr. 1981;20:25. 176. Gupta AK, Haberman JF, Pawlowski D, et al. Canthxanthin. Int J Dermatol. 1985;24:528. 177. Cohen L. Observations in carotenemia. Ann Intern Med. 1958;48:219.

178. Crisp AH, Stonehill E. Hypercarotenemia as a symptom of weight phobia. Postgrad Med J. 1967;43:721. 179. McLaren DS, Zekian B. Failure of enzymic cleavage of β-carotene. Am J Dis Child. 1971;121:278. 180. Carlin CS, Florell SR, Kruegger GG. Induction of dramatic hyperpigmentation in a patient with generalized lichen planus treated with re-PUVA. J Cutan Med Surg. 2002;6:125–127. 181. Norup J. Addison’s disease – clinical studies. A report of 108 cases. Acta Endocrinol. 1974;76:127. 182. Chiheb S, Slaoui Z, Nejjam F, et al. Allgrove’s syndrome. Ann Dermatol Venereol. 2001;128:1043–1045.

HYPERPIGMENTATION IN SYSTEMIC DISEASE Adrenocortical insufficiency (Addison disease)

10

ACQUIRED DERMAL CIRCUMSCRIBED MELANOSES

Pigmentary abnormalities

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Acromegaly Acromegaly is a rare disorder, but 17% of patients with this syndrome have the onset of symptoms during adolescence.183 Both sexes are affected equally. Approximately 45% of these children will develop generalized increased pigmentation along with trophic changes of the skin, sweat glands, sebaceous glands, and hair follicles. Inasmuch as there is no known function of growth hormone in melanin production, there is no satisfactory explanation as to the cause of the hyperpigmentation.

Hemochromatosis

ACQUIRED DERMAL CIRCUMSCRIBED MELANOSES

Idiopathic hemochromatosis is rare in children and occurs mainly in men over the age of 40 years. There are reports of symptomatic teenagers, however. The HFE gene maps to 6p21.3, within HLA genes. It is inherited as an autosomal-recessive defect. Heterozygotes may show iron storage abnormalities but usually do not develop clinical disease. The signs of this disease are observed when large amounts of iron are deposited in the liver parenchymal cells. This leads to periportal cell destruction and scarring, which results in cirrhosis. The most dramatic cutaneous finding is a generalized bronze hyperpigmentation that appears in patients with advanced disease. Mucous membranes are pigmented in about 20% of cases.184 Most of the increased color comes from melanin production rather than from cutaneous iron deposition and this was confirmed by the study of an individual with vitiligo and hemochromatosis who presented bronze hyperpigmentation in unaffected areas of the skin, while the vitiliginous sites remained white even though, histologically, it contained iron deposits.185

Childhood cirrhosis Hepatic fibrosis and cirrhosis in children usually occur secondary to extrahepatic biliary atresia but may also be a consequence of other inherited abnormalities, such as cystic fibrosis, toxins, infections, metabolic disturbances, or autoimmune phenomena. In patients with chronic liver disease, there is usually a diffuse dull-brown hyperpigmentation of the skin. A yellowish hue may also be interposed in those patients with jaundice. In children who are very pruritic, chronic scratching can lead to darker areas of linear hyperpigmentation as a manifestation of post-inflammatory change.

Scleroderma Morphea is the most common form of scleroderma in children and occasionally produces hyperpigmentation, especially in patches of the Pasini–Pierini variant, when sclerosis is absent (Fig. 10.13). In patients with long-standing extensive sclerosis of the skin, a diffuse increase in pigmentation may occur. This is often interspersed with depigmented macules, giving a confetti-

183. Gardner LI, ed. Endocrine and genetic diseases of childhood and adolescence. Philadelphia: WB Saunders; 1975. 184. Chevrant-Breton J, Simon M, Bourel M, et al. Cutaneous manifestations of idiopathic hemochromatosis. Arch Dermatol. 1977;113:161. 185. Perdrup A, Poulsen H. Hemochromatosis and vitiligo. Arch Dermatol. 1964;90:34. 186. Krieg T, Meuer M. Systemic scleroderma. J Am Acad Dermatol. 1988;18:457. 187. Deleixhe-Mauhin F, Krezinski JM, Rorive G, et al. Quantification of skin color in patients undergoing maintenance hemodialysis. J Am Acad Dermatol. 1992;27:950.

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Figure 10.13  Hyperpigmentation in patches previous to sclerosis in a child with morphea.

like appearance to the skin.186 On the contrary, hypopigmentation is a striking clinical feature of systemic sclerosis in black patients. Blue macules resembling nevus of Ito have been reported with systemic scleroderma.

Renal failure Children with chronic renal failure, particularly those on hemodialysis, have been noted to have diffuse hyperpigmentation, caused by changes in the amount of chromogens such as lipochromes, melanins, hemoglobin, and carotenoids.187 Because many of these patients are pruritic, this increased color is often accentuated in scratched and traumatized areas, such as the forearms and legs. Thus, a component of this pigment change is postinflammatory, as in hemochromatosis. Melanogenesis is increased in the epidermis of these patients. This may be due to the increased serum half-life of ß-LPH. The clearance of this hormone in chronic renal failure is markedly prolonged,188 and there is probably no feedback inhibition once serum levels are elevated.

The H syndrome It was initially described as ‘pigmented hypertrichotic plaques and induration of the skin’ of the upper inner thighs with variable involvement of the genitalia, trunk and limbs in children with disordered immune regulation with development of inflammatory infiltrates in the skin, soft tissues, lymph nodes and a predisposition to insulin-dependent diabetes and other immunemediated disease.189 The term H syndrome was later coined

188. Gilkes JJH, Eady RAJ, Rees LH, et al. Plasma immunoreactive melanotrophic hormones in patients on maintenance hemodialysis. Br Med J. 1975;1:656. 189. Prendeville J, Rogers M, Kan A, et al. Pigmented hypertrichotic dermatosis and insulin dependent diabetes: manifestations of a unique genetic disorder? Pediatr Dermatol. 2007;24:101–107.

Pigmentary abnormalities

Pregnancy in adolescence Although not a systemic disease, endocrinologic changes in pregnant adolescent girls cause hyperpigmentation in up to 90% of cases.192 This pigment change is usually generalized with accentuation in areas that are normally deeply pigmented such as the areolae of the breasts, axillae, and perineal skin. Nevocellular nevi, ephelides, and lentigines may also become darker. A characteristic linear darkening often occurs on the anterior abdomen from the umbilicus to the symphysis pubis (linea nigra). Most of the hyperpigmentation appears during the first trimester.193 In most instances, the color returns to prepregnancy levels but some localized hypermelanotic sites (e.g., nevi) may remain darker indefinitely. Melasma (chloasma) of pregnancy, which appears during the later half of pregnancy, was discussed earlier in this chapter. The physiologic mechanism of hyperpigmentation in pregnancy is thought to be due to elevated levels of a compound with MSH activity, but the source and nature of this activity are unknown. One interesting hypothesis is that the melanotropin may be of fetal origin, since the fetal pituitary gland is thought to synthesize α-MSH.

DISORDERS OF HYPOPIGMENTATION Eulalia Baselga Hypopigmentation refers to a lighter color of the skin in an individual, which can be generalized or localized. Hypopigmentation may result from decreased skin vascularization as in nevus anemicus, and also from abnormalities in the pigmentation system of the skin, both from reduced number or melanocytes and from a decreased melanin production. Hypopigmentation from melanin pigment or melanocyte dysfunction is called hypomelanosis. Hypomelanosis may occur as a primary phenomenon or as part of multiple manifestations of many skin disorders. Primary genetic disorders of hypopigmentation have

190. Molho-Pessach V, Agha Z, Aamar S, et al. The H syndrome: a genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin with systemic manifestations. J Am Acad Dermatol. 2008;59:79–85. 191. Molho-Pessach V, Lerer I, Abeliovich D, et al. The H syndrome is caused by mutations in the nucleoside transporter hENT3. Am J Hum Genet. 2008;83:529–534. 192. Wade TR, Wade SL, Jones HE. Skin changes and diseases associated with pregnancy. Obstet Gynecol. 1975;52:233. 193. Wong RC, Ellis CN. Physiologic skin changes in pregnancy. J Am Acad Dermatol. 1984;10:929. 194. Mollet I, Ongenae K, Naeyaert JM. Origin, clinical presentation, and diagnosis of hypomelanotic skin disorders. Dermatol Clin. 2007;25:363–371.

been thoroughly discussed in Chapter 7, and hypopigmented lesions appearing in the setting of other conditions are discussed elsewhere in this textbook. In the present section, we will deal with non-heritable disorders of hypopigmentation that have not been discussed in other chapters. For an appropriate approach to hypomelanosis, it is essential to distinguish between congenital or acquired disorders and between circumscribed or diffuse hypomelanosis. Circumscribed hypomelanosis may take the form of a single lesion or multiple lesions may be present. Recognizing lesion patterns, especially patterns of mosaicism, is also of great help for a correct diagnosis and management of hypopigmented lesions. Morphologic characteristics such as the shape of the hypopigmented patches, their outlines, the demarcation from the normally pigmented skin, and the confluence of lesions are so important that in many instances permit an accurate diagnosis without further testing. In any case, a good history and a detailed physical examination, including the use of a Wood’s light lamp, are always required. The use of Wood’s lamp enhances the differences between normal and hypopigmented skin, and may reveal inadvertent hypopigmented patches. Biopsying hypopigmented lesions sometimes yields poor aid for the diagnosis, but may be the diagnostic key test for mycosis fungoides or lichen sclerosus.194,195 In case a biopsy is performed, a comparison with normally pigmented skin is advisable, preferably taking a sample from the border of the hypopigmented patch including some normal skin.

CONGENITAL CIRCUMSCRIBED HYPOMELANOSIS

because of the many manifestations beginning with the letter ‘h’: hyperpigmented, hypertrichotic, and indurated cutaneous patches involving the middle and lower parts of their bodies, scrotal masses, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and potentially hyperglycemia,190 hypotrichosis and halo nevus have also been described (A. Torrelo, personal observation). It is inherited as a recessive trait and is due to mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3.191

10

CONGENITAL CIRCUMSCRIBED HYPOMELANOSIS HYPOPIGMENTED MOSAICISM Under this term, we include a variety of hypopigmentation disorders which share a common pathomechanism of mosaicism appearing as hypopigmented patches of skin. This includes conditions called nevus depigmentosus, nevus achromicus, hypomelanosis of Ito, nevoid hypomelanosis, and many others. Nevus depigmentosus (ND), or achromic nevus, is a congenital, non-familial, well-circumscribed leukoderma most commonly present at birth, although it may appear during early childhood.196,197 In many other instances, the macules may be more extensive and follow a pattern of mosaicism, mainly Blaschko lines or blocks.198 One or multiple mosaic segments may be affected, and in instances where multiple nevus depigmentosus follows a Blaschko linear pattern, the term hypomelanosis of Ito has been used, especially if extracutaneous manifestations occur (see later). The term ‘hypomelanosis of Ito,’ as well as other

195. Ruiz-Maldonado R. Hypomelanotic conditions of the newborn and infant. Dermatol Clin. 2007;25:373–382. 196. Xu AE, Huang B, Li YW, et al. Clinical, histopathological and ultrastructural characteristics of naevus depigmentosus. Clin Exp Dermatol. 2008;33:400–405. 197. Sugarman GI, Reed WB. Two unusual neurocutaneous disorders with facial cutaneous signs. Arch Neurol. 1969;21:242–247. 198. Happle R. Mosaicism in human skin. Understanding the patterns and mechanisms. Arch Dermatol. 1993;129:1460–1470.

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unfortunate names such as ‘incontinentia pigmenti achromians,’ must never be used because they refer to no specific disease but to different types of mosaicism. The distinction between nevus depigmentosus and ‘hypomelanosis of Ito’ is merely semantic, because both are due to mosaicism leading to a less pigmented area of the skin, and it is factors such as timing of mutation during embryo development or the type of mutation involved which most likely determine the pattern, number and extension of lesions and the possible association with extracutaneous features.199–201 Therefore the terms nevoid hypopigmentation or hypopigmented mosaic disorder may be a more general term to encompass both disorders preferred by some clinicians as more descriptive terms.

CONGENITAL CIRCUMSCRIBED HYPOMELANOSIS

Epidemiology Nevus depigmentosus is a common, non-heritable disorder occurring in around 0.4–0.7% of infants; both males and females are equally affected.195 More extensive Blaschko linear cases occur in 1/8000–10 000 cases.202–204 Familial cases with an autosomal dominant or autosomic recessive pattern of inheritance have been rarely reported,205–208 but it is likely that these patients do not represent true mosaic hypopigmentation.

Pathogenesis In hypopigmented mosaicism, different cytogenetic abnormalities have been reported in the affected patches, including polyploidy, aneuploidy, chromosomal deletions, insertions and translocations, but not in normal skin, thus proving mosaicism most likely due to chromosomal non-disjunction during embryo development; however, other types of somatic mutations have been also reported.199,206,209,210 Many different chromosomes disrupting either the expression or function of pigmentary genes can be affected, but the short arm of the X-chromosome, the short arm of chromosome 12, and chromosome 18 are more commonly involved.199,211 Often the state of mosaicism can be demonstrated only in fibroblasts, whereas cytogenetic investigations of peripheral lymphocytes are normal.212 Nevoid hypopigmentation therefore should be considered not a single disorder but a phenotype of different types of genetic mosaicism.

199. Kuster W, Konig A. Hypomelanosis of Ito: no entity, but a cutaneous sign of mosaicism. Am J Med Genet. 1999;85:346–350. 200. Loomis CA. Linear hypopigmentation and hyperpigmentation, including mosaicism. Semin Cutan Med Surg. 1997;16:44–53. 201. Ruggieri M, Pavone L. Hypomelanosis of Ito: clinical syndrome or just phenotype? J Child Neurol. 2000;15:635–644. 202. Pascual-Castroviejo I, Roche C, Martinez-Bermejo A, et al. Hypomelanosis of Ito. A study of 76 infantile cases. Brain Dev. 1998;20:36–43. 203. Pascual-Castroviejo I, Lopez-Rodriguez L, de la Cruz MM, et al. Hypomelanosis of Ito. Neurological complications in 34 cases. Can J Neurol Sci. 1988;15:124–129. 204. Ruiz-Maldonado R, Toussaint S, Tamayo L, et al. Hypomelanosis of Ito: diagnostic criteria and report of 41 cases. Pediatr Dermatol. 1992; 9:1–10. 205. Montagna P, Procaccianti G, Galli G, et al. Familial hypomelanosis of Ito. Eur Neurol. 1991;31:345–347. 206. Vormittag W, Ensinger C, Raff M. Cytogenetic and dermatoglyphic findings in a familial case of hypomelanosis of Ito (incontinentia pigmenti achromians). Clin Genet. 1992;41:309–314. 207. Amon M, Menapace R, Kirnbauer R. Ocular symptomatology in familial hypomelanosis Ito. Incontinentia pigmenti achromians. Ophthalmologica. 1990;200:1–6.

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Figure 10.14  Nevus depigmentosus: a localized patch. (Courtesy of Dr Antonio Torrelo)

Histology Biopsies from affected skin have shown no abnormality or just rare lymphocyte infiltration around blood vessels in the superficial layer of the dermis. Under silver stain, the ratio of melanin content may be decreased. Melanocytes may be normal or decreased in number.213,214 In some cases, ultrastructural studies have shown a large reduction in the number of melanosomes and aggregated melanosomes were more often observed in keratinocytes of the affected area.196

Clinical features Hypopigmented mosaicism is not completely achromic but hypopigmented, which helps differentiating from vitiligo. Nevus depigmentosus is usually a solitary, well-demarcated, round or oval lesion on trunk and proximal limbs which may show a regular or an irregular outline resembling ‘splashed paint’ (Fig. 10.14). Multiple lesions have been described, as well as lesions affecting the iris.215 As has been stated, Blaschko linear and block patterns are also a common presentation, and they may affect a single segment or become systematized (Fig. 10.15). Although lesions are often present at birth they may not be recognized

208. Ruggieri M, Tigano G, Mazzone D, et al. Involvement of the white matter in hypomelanosis of Ito (incontinentia pigmenti achromians). Neurology. 1996;46:485–492. 209. Taibjee SM, Bennett DC, Moss C. Abnormal pigmentation in hypomelanosis of Ito and pigmentary mosaicism: the role of pigmentary genes. Br J Dermatol. 2004;151:269–282. 210. Sybert VP, Pagon RA, Donlan M, et al. Pigmentary abnormalities and mosaicism for chromosomal aberration: association with clinical features similar to hypomelanosis of Ito. J Pediatr. 1990;116:581–586. 211. Komine M, Hino M, Shiina M, et al. Linear and whorled naevoid hypermelanosis: a case with systemic involvement and trisomy 18 mosaicism. Br J Dermatol. 2002;146:500–502. 212. Moss C, Larkins S, Stacey M, et al. Epidermal mosaicism and Blaschko’s lines. J Med Genet. 1993;30:752–755. 213. Kim SK, Kang HY, Lee ES, et al. Clinical and histopathologic characteristics of nevus depigmentosus. J Am Acad Dermatol. 2006;55:423–428. 214. Lee HS, Chun YS, Hann SK. Nevus depigmentosus: clinical features and histopathologic characteristics in 67 patients. J Am Acad Dermatol. 1999;40:21–26. 215. Sharma P, Pai HS, Kamath MM. Nevus depigmentosus affecting the iris and skin: a case report. J Eur Acad Dermatol Venereol. 2008;22:634– 635.

Pigmentary abnormalities

(Courtesy of Dr Antonio Torrelo)

until the child is exposed to the sun and the affected areas remain without changes throughout life. Hypopigmented mosaicism is more readily seen in children with darker skin. Very rarely, lentigines may appear within the hypopigmented macules.216 Hypertrichosis has been described both localized within the hypopigmented area and generalized in rare instances.217–219 Hypopigmented mosaicism has been reported to coexist with Becker’s nevus or partial unilateral lentiginosis as a possible manifestation of twin spotting.220 Extracutaneous abnormalities, mainly neurological, ocular and musculoskeletal manifestations, may appear associated with hypopigmented mosaicism, especially in patients with multiple Blaschko linear or block-like patterns. In some series, systemic manifestations have been reported to occur in 30–75% of cases leading to a characterization as a neurocutaneous disorder.201–203,221,222 However, this high rate of associated anomalies is most likely the result of a reporting bias. Extracutaneous manifestations associated with extensive Blaschko linear lesions were given the unfortunate name of hypomelanosis of Ito, even though the original case reported by Ito was a pure cutaneous form with only asymmetry of breast size. The most frequent central nervous system features are developmental delay and mental retardation.201–203,222 The second most common manifestation is epilepsy. The most frequent seizure types are generalized tonic-clonic seizures, partial seizures, myoclonic seizures, and infantile spasm. Many children with mental retardation, especially those with autistic-like behavior, have also seizures. Other anomalies may include: microcephaly, hypotonia, hyperkinesia, ataxia, and deafness. Magnetic resonance imaging may show white matter abnormalities but it may be normal even in those

216. Bolognia JL, Lazova R, Watsky K. The development of lentigines within segmental achromic nevi. J Am Acad Dermatol. 1998;39: 330–333. 217. Ballmer-Weber BK, Inaebnit D, Brand CU, et al. Sporadic hypomelanosis of Ito with focal hypertrichosis in a 16-month-old girl. Dermatology. 1996;193:63–64. 218. Khandpur S, Minz A, Sharma VK. An unusual association of pigmentary mosaicism (hypomelanosis of Ito) with generalized hypertrichosis. Clin Exp Dermatol. 2006;31:467–468. 219. Monteagudo SB, Leon ME, Cabanillas GM, et al. Hypertrichosis localizada y mosaicismo pigmentario tipo Ito (hipomelanosis de Ito). Ann Pediatr (Barc). 2008;68:307–309. 220. In SI, Kang HY. Partial unilateral lentiginosis colocalized with naevus depigmentosus. Clin Exp Dermatol. 2008;33:337–339. 221. Zvulunov A, Esterly NB. Neurocutaneous syndromes associated with pigmentary skin lesions. J Am Acad Dermatol. 1995;32:915–935.

with severe mental retardation or seizures.202,208 Other MRI abnormalities include atrophy, hemispheric asymmetry, cerebellar hypoplasia, agenesis or dysplasia of the corpus callosum, gray matter heterotropias, lissencephaly, porencephaly, periventricular cystic lesions, moyamoya disease, arteriovenous malformations and absence of normal demarcation between gray and white matter.202,208 In many of these manifestations, a neuronal migration anomaly is the hallmark. However, the varied array of different neurological manifestations associated with a single skin lesion favors genetic heterogeneity in hypopigmented mosaicism, as has been previously stated. Ophthalmological abnormalities have also been associated with hypopigmented mosaicism, and include microphthalmia, ptosis, non-closure of the upper lid, symblepharon, dacryostenosis, strabismus, nystagmus, myopia, amblyopia, corneal opacification, cataracts, iridal heterochromia, scleral melanosis, striated patchy hypopigmented fundi, and retinal degeneration.201,207,223 Skeletal defects include short stature, facial and limb asymmetry, thoracic deformity (pectus carinatum or excavatum), scoliosis, and various finger and toe anomalies (syndactyly, polydactyly, brachydactyly, clinodactyly).201–204,224 Enamel changes and other dental defects such as hamartomatous dental cusps have also been observed.225

CONGENITAL CIRCUMSCRIBED HYPOMELANOSIS

Figure 10.15  Hypopigmented mosaicism following the lines of Blaschko.

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Differential diagnosis Localized patches of mosaic hypopigmentation may be indistinguishable from hypopigmented lesions of tuberous sclerosis. Vitiligo macules are usually completely depigmented. Under Wood’s lamp examination, the lesion of ND showed an offwhite accentuation without fluorescence, in contrast to the chalky-white accentuation with obvious fluorescence observed in vitiligo. Vitiligo sometimes appears in a segmental pattern resembling blocks of hypopigmented mosaicism.

Treatment There is no medical treatment available for hypopigmented mosaicism, although 308-nm excimer laser has been used.226

OTHER CIRCUMSCRIBED CONGENITAL HYPOPIGMENTED LESIONS Hypopigmented macules can be the first sign of tuberous sclerosis (see Ch. 7). Phylloid hypopigmentation is a characteristic pattern of hypopigmentation resembling leafs or reminiscent of floral ornaments, which may be associated with extracutaneous

222. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54 cases of hypopigmentation and hyperpigmentation along the lines of Blaschko. Arch Dermatol. 1996;132:1167–1170. 223. Rott HD, Lang GE, Huk W, et al. Hypomelanosis of Ito (incontinentia pigmenti achromians). Ophthalmological evidence for somatic mosaicism. Ophthalmic Paediatr Genet. 1990;11:273–279. 224. Jelinek JE, Bart RS, Schiff SM. Hypomelanosis of Ito (‘incontinentia pigmenti achromians’). Report of three cases and review of the literature. Arch Dermatol. 1973;107:596–601. 225. Happle R, Vakilzadeh F. Hamartomatous dental cusps in hypomelanosis of Ito. Clin Genet. 1982;21:65–68. 226. Kim DY, Lee KY, Park YK. Use of the 308-nm excimer laser for nevus depigmentosus: a promising treatment for either nevus depigmentosus or vitiligo. J Dermatol. 2007;34:217–218.

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anomalies including cerebral, ocular, and skeletal defects. This phenotype is due to mosaic partial or total trisomy or tetrasomy of chromosome 13.227,228 In Cole disease, an autosomal dominant trait, multiple round hypopigmented macules predominantly on the trunk and limbs appear at birth or shortly thereafter, accompanied by punctuate keratoses of the palms and soles.229 The term cutis tricolor refers to congenital paired hyperchromic and hypochromic macules on a background of normal colored skin; it reflects a phenomenon of allelic twinspotting (see Ch. 7). In patients with multiple lesions of cutis tricolor neurological and ophthalmological associated manifestations may occur.230,231

ACQUIRED CIRCUMSCRIBED HYPOMELANOSIS

ACQUIRED CIRCUMSCRIBED HYPOMELANOSIS Post-inflammatory hypomelanosis In children, many varied inflammatory dermatoses such as atopic eczema, psoriasis, seborrheic dermatitis, pityriasis lichenoides chronica, insect bites, chickenpox, burns, and minor trauma may provoke hypopigmentation after healing, which is more evident in darker skin types. The cutaneous pigmentary changes correspond to the areas of preceding inflammation, and their shape is usually similar to that of the previous condition. These two facts are important to establish a correct diagnosis. In atopic patients, hypopigmented areas may be seen without preceding overt eczematous areas. The underlying mechanisms for developing hypopigmentation are not well understood; an inherited individual predisposition has been proposed as a pathogenic factor.232

Differential diagnosis

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Treatment There is no satisfactory treatment for post-inflammatory hypo­ pigmentation, but when residual inflammation remains, lowpotency topical corticosteroids or topical calcineurin inhibitors may help to solve the pigmentary alteration; however, most hypopigmented macules will eventually resolve completely. Nevertheless, there are some patients in whom hypopigmentation remains for prolonged periods of time or indefinitely, when more intense or severe damage has been inflicted to the skin. Repigmentation also depends on the age, anatomical location, presence of pigment cell reservoir, a specific response of each individual to inflammation, and other factors.

Lichen sclerosus et atrophicus and morphea Genital and extragenital lichen sclerosus may present as shiny, pin-pointed, hypopigmented macules, which have received the name of morphea ‘en gouttes’ (Fig. 10.16). Other findings that help in diagnosis are atrophy, follicular plugging and, in the anogenital region, purpura and hemorrhagic vesicles. Hypopigmented lesions on the skin or genitalia of recent onset may be difficult to distinguish from vitiligo and a biopsy is required for a definite diagnosis. On histologic examination, epidermal atrophy and vacuolar degeneration of the basal cell layer are seen; in the papillary and upper dermis, edema and homogenization of collagen with an underlying band-like mononuclear infiltrate are observed; a reduction in the number of melanocytes in active lesions has been reported. Patients with morphea may develop both hypo- and hyperpigmentation in areas of chronic sclerosis. In addition, focal depigmentation with perifollicular or punctate hyperpigmentation on the upper trunk and extremities is a peculiar and characteristic form of leukoderma in scleroderma, ovelap syndromes and scleromyxedema.234 The coexistence of vitiligo and scleroderma has also been described.235–237

Post-inflammatory hypopigmentation can be confused with tinea versicolor, but the past history of a previous lesion and a negative KOH preparation rule out this diagnosis. It differs from vitiligo by the poor margination and absence of a milk-white color, easily detected under Wood’s light examination. In young infants who have suffered an intense diaper dermatitis, a wellmarginated hypopigmentation on the groins and perineal region may develop, resembling vitiligo (see below). A typical macular hypopigmentation has been reported in children with severe ichthyosiform erythroderma, sometimes referred to as ichthyosis ‘en confetti’; it is likely that these macules are triggered by oral retinoid therapy for the original condition.233

Discoid lupus often results in scarring, atrophy and hypopigmentation. There is usually a rim of hyperpigmentation around the plaques. Neonatal lupus in dark-skinned infants may present with depigmented macules on the face.238 A case of chilblain lupus with depigmentation on the hand mimicking vitiligo has been reported.239 True vitiligo has also been described in

227. Gonzalez-Ensenat MA, Vicente A, Poo P, et al. Phylloid hypomelanosis and mosaic partial trisomy 13: two cases that provide further evidence of a distinct clinicogenetic entity. Arch Dermatol. 2009;145:576–578. 228. Dhar SU, Robbins-Furman P, Levy ML, et al. Tetrasomy 13q mosaicism associated with phylloid hypomelanosis and precocious puberty. Am J Med Genet A. 2009;149A:993–996. 229. Moore MM, Orlow SJ, Kamino H, et al. Cole disease: guttate hypopigmentation and punctate palmoplantar keratoderma. Arch Dermatol. 2009;145:495–497. 230. Ruggieri M, Iannetti F, Polizzi A, et al. Cataracts in three children with a newly recognised neurocutaneous malformation phenotype with ‘cutis tricolor’. Br J Ophthalmol. 2009;93:127–128. 231. Larralde M, Happle R. Cutis tricolor parvimaculata: a distinct neurocutaneous syndrome? Dermatology. 2005;211:149–151. 232. Ruiz-Maldonado R, Orozco-Covarrubias ML. Postinflammatory hypopigmentation and hyperpigmentation. Semin Cutan Med Surg. 1997;16:36–43.

233. Torrelo A, Marrero MD, Mediero IG, et al. Progressive macular leucoderma in a patient with congenital ichthyosiform erythroderma. Br J Dermatol. 2001;144:1280–1282. 234. Rai VM, Balachandran C. Pseudovitiligo in systemic sclerosis. Dermatol Online J. 2005;11:41. 235. Dervis E, Acbay O, Barut G, et al. Association of vitiligo, morphea, and Hashimoto’s thyroiditis. Int J Dermatol. 2004;43:236–237. 236. Bonifati C, Impara G, Morrone A, et al. Simultaneous occurrence of linear scleroderma and homolateral segmental vitiligo. J Eur Acad Dermatol Venereol. 2006;20:63–65. 237. Finkelstein E, Amichai B, Metzker A. Coexistence of vitiligo and morphea: a case report and review of the literature. J Dermatol. 1995;22:351–353. 238. Jenkins RE, Kurwa AR, Atherton DJ, et al. Neonatal lupus erythematosus. Clin Exp Dermatol. 1994;19:409–411. 239. Khaitan BK, Sood A, Mittal R, et al. Chilblain lupus erythematosus mimicking acrofacial vitiligo. Indian J Dermatol Venereol Leprol. 2003;69: 340–342.

Lupus erythematosus

Pigmentary abnormalities

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association with lupus erythematosus.240–242 Chloroquine, commonly used for treatment of lupus erythematosus, may also cause vitiligo-like depigmentation.243

Sarcoidosis

ACQUIRED CIRCUMSCRIBED HYPOMELANOSIS

Hypopigmentation is an uncommon, but well-known manifestation of sarcoidosis, more frequently and easily observed in patients with dark skin of African ancestry.244–247 Lesions are mostly observed as macules without any cutaneous alteration but they may also be seen surrounding classic lesions of sarcoidosis or in coexistence with papules, nodules or infiltrated plaques. Histologically sarcoidal non-caseating granulomas may be present in macular lesions without underlying palpable masses,245,248 and hypopigmentation has also been reported in systemic sarcoidosis with multiple organ involvement but without cutaneous granulomas and with negative skin biopsies.249 On histopathologic examination, a reduction in melanin content with preservation of melanocytes has been described.247,249 On electron microscopic studies, dilatation of the endoplasmic reticulum, cytoplasmic vacuolation, edema and reduction of melanosomes have been found.

Mycosis fungoides

Figure 10.16  Lichen sclerosus. Small multiple achromic lesions showing the Koebner phenomenon.

240. Johnson H, Bossenbroek NM, Rosenman K, et al. Chronic cutaneous lupus erythematosus in vitiligo. Dermatol Online J. 2008;14:10. 241. Laberge G, Mailloux CM, Gowan K, et al. Early disease onset and increased risk of other autoimmune diseases in familial generalized vitiligo. Pigment Cell Res. 2005;18:300–305. 242. Callen JP. Discoid lupus erythematosus in a patient with vitiligo and autoimmune thyroiditis. Int J Dermatol. 1984;23:203–204. 243. Martin-Garcia RF, del RC, Sanchez JL. Chloroquine-induced, vitiligo-like depigmentation. J Am Acad Dermatol. 2003;48:981–983. 244. Tchernev G. Cutaneous sarcoidosis: the ‘great imitator’: etiopathogenesis, morphology, differential diagnosis, and clinical management. Am J Clin Dermatol. 2006;7:375–382. 245. Hall RS, Floro JF, King LE Jr. Hypopigmented lesions in sarcoidosis. J Am Acad Dermatol. 1984;11:1163–1164. 246. Thomas RH, McKee PH, Black MM. Hypopigmented sarcoidosis. J R Soc Med. 1981;74:921–923. 247. Clayton R, Breathnach A, Martin B, et al. Hypopigmented sarcoidosis in the negro. Report of eight cases with ultrastructural observations. Br J Dermatol. 1977;96:119–125. 248. Cornelius CE III, Stein KM, et al. Hypopigmentation and sarcoidosis. Arch Dermatol. 1973;108:249–251. 249. Alexis JB. Sarcoidosis presenting as cutaneous hypopigmentation with repeatedly negative skin biopsies. Int J Dermatol. 1994;33:44–45.

Hypopigmented mycosis fungoides represents an uncommon variant of cutaneous T-cell lymphoma. Hypopigmented macules may be the only manifestation of mycosis fungoides or may be seen in coexistence with characteristic lesions of patch, plaque or tumor stage mycosis fungoides. It is more common in darkskinned children, adolescents and young adults.250–255 Irregular non-atrophic hypopigmented macules of variable size are seen preferentially on the trunk and extremities, although facial lesions have also been reported (Fig. 10.17). Erythema and desquamation may be present. In some instances complete depigmentation mimicking vitiligo may be seen.256 Sézary syndrome and erythrodermic T-cell lymphoma may also develop leukodermic areas, although it has not been described in children.257,258 A high index of suspicion is necessary to diagnose hypopigmented mycosis fungoides. The main differential diagnoses are pityriasis alba and vitiligo. Skin biopsy is necessary for diagnosis and should be considered in any case of atypical persistent hypopigmented macules.

250. Ardigo M, Borroni G, Muscardin L, et al. Hypopigmented mycosis fungoides in Caucasian patients: a clinicopathologic study of 7 cases. J Am Acad Dermatol. 2003;49:264–270. 251. Manzur A, Zaidi ST. Hypopigmented mycosis fungoides in a 10-year-old boy. Dermatol Online J. 2006;12:21. 252. Neuhaus IM, Ramos-Caro FA, Hassanein AM. Hypopigmented mycosis fungoides in childhood and adolescence. Pediatr Dermatol. 2000;17: 403–406. 253. Sezer E, Sezer T, Senayli A, et al. Hypopigmented mycosis fungoides in a Caucasian child. Eur J Dermatol. 2006;16:584. 254. Qari MS, Li N, Demierre MF. Hypopigmented mycosis fungoides: case reports and literature review. J Cutan Med Surg. 2000;4:142–148. 255. Whitmore SE, Simmons-O’Brien E, Rotter FS. Hypopigmented mycosis fungoides. Arch Dermatol. 1994;130:476–480. 256. Das JK, Gangopadhyay AK. Mycosis fungoides with unusual vitiligo-like presentation. Indian J Dermatol Venereol Leprol. 2004;70:304–306. 257. Tang M, Tan SH, Lim LC. Leukoderma associated with Sezary syndrome: a rare presentation. J Am Acad Dermatol. 2003;49:S247–S249. 258. Bouloc A, Grange F, fau-Larue MH, et al. Leucoderma associated with flares of erythrodermic cutaneous T-cell lymphomas: four cases. The French Study Group of Cutaneous Lymphomas. Br J Dermatol. 2000;143:832–836.

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ACQUIRED CIRCUMSCRIBED HYPOMELANOSIS

Figure 10.18  Pityriasis alba on the face. (Courtesy of Dr Antonio Torrelo) Figure 10.17  Hypopigmented macules on the buttock of a 9-year-old boy. Histopathology showed unequivocally mycosis fungoides. (Courtesy of Dr Antonio Torrelo)

On histopathologic examination, there are the same findings of other patch/subtle plaque variants of mycosis fungoides. Epidermotropism with infiltrating lymphocytes with little or no spongiosis and a lymphocytic infiltrate in the upper part of the dermis are seen.259 On electron microscopy decreased numbers of melanocytes and melanosomes within keratinocytes have been reported. Hypopigmented mycosis fungoides usually responds well to therapy, particularly to PUVA. Narrow-band UVB has also been used with success.251,253

Pityriasis alba Pityriasis alba (PA)260 is a skin disorder characterized by asymptomatic, variably hypopigmented, slightly scaling patches, with indistinct margins not preceded by obvious inflammatory lesions (Fig. 10.18). Pityriasis alba occurs predominantly in the faces of children between the ages of 3 and 16 years. However, extensive lesions on trunk and limbs may be seen in atopic patients. Atopy associated pityriasis alba probably represents a form of postinflammatory hypopigmentation.195 Males and darker skin types are more commonly affected and PA is endemic in some areas.261 Sun exposure makes lesions more noticeable. The etiology and pathogenesis of pityriasis alba are still poorly understood. Excessive and unprotected sun exposure, frequent bathing, hot baths, and cutaneous signs of atopy are strongly related to the development of pityriasis alba.261,262

259. Werner B, Brown S, Ackerman AB. ‘Hypopigmented mycosis fungoides’ is not always mycosis fungoides! Am J Dermatopathol. 2005;27:56–67. 260. In SI, Yi SW, Kang HY, et al. Clinical and histopathological characteristics of pityriasis alba. Clin Exp Dermatol. 2008;34:591–597. 261. Blessmann WM, Sponchiado de Avila LG, Albaneze R, et al. Pityriasis alba: a study of pathogenic factors. J Eur Acad Dermatol Venereol. 2002;16:463–468. 262. Lin RL, Janniger CK. Pityriasis alba. Cutis. 2005;76:21–24. 263. Zaynoun ST, Aftimos BG, Tenekjian KK, et al. Extensive pityriasis alba: A histological histochemical and ultrastructural study. Br J Dermatol. 1983;108:83–90. 264. In SI, Yi SW, Kang HY et al. Clinical and histopathological characteristics of pityriasis alba. Clin Esp Dermatopathol. 2009;34:591–597. 265. Relyveld GN, Manke HE, Westerhof W. Progressive macular hypomelanosis: an overview. Am J Clin Dermatol. 2007;8:13-19.

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Histopathologically, spongiosis with exocytosis, hyperkeratosis and acanthosis may be seen, supporting the concept that PA represents a variant of eczema.263 The number of melanocytes has usually been reported to be decreased263; however, it may be normal or variable. Fontana–Masson stain showed significantly reduced pigment in lesional epidermis.260,264 Most cases of pityriasis alba are diagnosed clinically. In some instances it may be difficult to differentiate from resolving pityriasis versicolor or hypopigmented mycosis fungoides. Treatment is often unsatisfactory but lesions often resolve spontaneously within months or years. Hydration and sun avoidance may be helpful. In cases related to atopic dermatitis, mild corticosteroids and topical calcineurin inhibitors may be of some benefit.

Progressive and confluent hypomelanosis Progressive and confluent hypomelanosis is a primary, acquired hypopigmentation observed mostly in females from 18 to 25 years of age of mixed ethnic origin and characterized by hypochromic, non-scaly macules developing on the back and abdomen, increasing in number and progressively coalescing over the whole trunk into larger patches surrounded by smaller well-defined macules (Fig. 10.19).265–268 The resulting hypomelanosis is most apparent in dark-skinned individuals. Some authors have used the name extensive pityriasis alba to describe these cases.269,270 However, this term is a misnomer because true extensive pityriasis alba is usually related to atopy, while in progressive and confluent hypomelanosis there is no history of

266. Guillet G, Helenon R, Gauthier Y, et al. Progressive macular hypomelanosis of the trunk: primary acquired hypopigmentation. J Cutan Pathol. 1988;15:286–289. 267. Guillet G, Helenon R, Guillet MH, et al. Hypomelanose maculeuse confluente et progressive du metis melanoderme. Ann Dermatol Venereol. 1992;119:19–24. 268. Perman M, Sehth P, Lucky A. Progressive macular hypomelanosis in a 16-year old. Pediatr Dermatol. 2008;25:63–65. 269. Wolf R, Sandbank M, Krakowski A. Extensive pityriasis alba and atopic dermatitis. Br J Dermatol. 1985;112:247. 270. Sandhu K, Handa S, Kanwar AJ. Extensive pityriasis alba in a child with atopic dermatitis. Pediatr Dermatol. 2004;21:275–276.

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Pigmentary abnormalities

Figure 10.19  Progressive and confluent hypomelanosis. Hypopigmented macules with ill-defined borders. (Courtesy of Dr Cristina Rubio)

atopic diathesis.271,272 Westerhof et al.273 demonstrated the presence of Propionibacterium acnes in affected hypopigmented skin in a few patients with progressive and confluent hypomelanosis and this observation prompted treatment with anti-acne medications such as benzoyl-peroxide, topical clindamycin and oral doxycycline by some authors.268,274

Kwashiorkor Kwashiorkor is a form of protein-calorie malnutrition that results from a diet poor in protein with an adequate or excessive carbohydrate intake. This condition is more prevalent in developing countries, particularly during times of socioeconomic crisis, although it is also the most common form of nutritional deficiency among hospitalized patients in the USA.275,276 These children are characteristically well until weaned and then develop erythematous plaques that darken and desquamate, constituting the ‘flaky paint dermatitis’ or ‘enamel paint sign’. This finding is helpful for diagnostic purposes275 and may even be present in early-onset kwashiorkor.277 These plaques first appear over pressure points and in the diaper area; in addition, they develop skin pallor that eventually leads to loss of pigment, especially at sites of minor trauma (Fig. 10.20). Hypochromotrichia, presenting as bands of depigmentation, may appear in the hair as well; the breadth of the bands corresponds to the length of time that the child remained malnourished; several of these bands constitute the ‘flag sign.’275 If kwashiorkor persists for a long time, all the

271. Di L, V, Ricci C. On atopic and idiopathic extensive pityriasis alba. Pediatr Dermatol. 2007;24:578–579. 272. Di L, V, Ricci C. Progressive and extensive hypomelanosis and extensive pityriasis alba: same disease, different names? J Eur Acad Dermatol Venereol. 2005;19:370–372. 273. Westerhof W, Relyveld GN, Kingswijk MM, et al. Propionibacterium acnes and the pathogenesis of progressive macular hypomelanosis. Arch Dermatol. 2004;140:210–214. 274. Relyveld GN, Kingswijk MM, Reitsma JB, et al. Benzoyl peroxide/ clindamycin/UVA is more effective than fluticasone/UVA in progressive macular hypomelanosis: a randomized study. J Am Acad Dermatol. 2006;55:836–843. 275. Liu T, Howard RM, Mancini AJ, et al. Kwashiorkor in the United States: fad diets, perceived and true milk allergy, and nutritional ignorance. Arch Dermatol. 2001;137:630–636.

Figure 10.20  Kwashiorkor. Areas of dark desquamation and hypopigmented macules (‘flaking paint’).

scalp hair becomes pale; in patients of skin type VI, a gray-brown or straw-colored hue may be observed.278 Mucocutaneous changes such as periorificial glazed erythema represent one of the common, multisystemic clinical manifestations of kwashiorkor.279 Associated systemic abnormalities include peripheral edema, liver disease, neurologic changes, diarrhea, weight loss, and hypoalbuminemia. Appropriate diet correction eliminates these alterations.

276. Al-Mubarak L, Al-Khenaizan S, Al Goufi T. Cutaneous presentation of kwashiorkor due to infantile Crohn’s disease. Eur J Pediatr. 2009;169: 117–119. 277. Buno IJ, Morelli JG, Weston WL. The enamel paint sign in the dermatologic diagnosis of early-onset kwashiorkor. Arch Dermatol. 1998;134:107–108. 278. McLaren DS. Skin in protein energy malnutrition. Arch Dermatol. 1987;123:1674–1676a. 279. Prendiville JS, Manfredi LN. Skin signs of nutritional disorders. Semin Dermatol. 1992;11:88–97.

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INFECTIOUS HYPOMELANOSIS Tinea versicolor (pityriasis versicolor)

ACQUIRED CIRCUMSCRIBED HYPOMELANOSIS

Tinea versicolor is a superficial skin infection caused by the lipophilic yeast of the genus Malassezia.280 This yeast is part of the normal skin flora in seborrheic areas. The infection results from a change to the mycelial state of dimorphic lipophilic yeasts of the genus Malassezia, which colonize the stratum corneum, under the influence of various factors including moisture, heat, the degree of host immunity and inherited predisposition. The organism produces the dicarboxylic acid, azelaic acid, which is a tyrosinase inhibitor and may contribute to the hypopigmentation noted in this infection.281 The genus Malassezia was previously called Pityrosporum with two species: Pityrosporum ovale and Pityrosporum orbiculare. Malassezia genus was initially separated into two species: the lipophilic yeast Malassezia furfur and the non-lipophilic Malassezia pachydermatis. New species of lipophilic Malassezia besides M. furfur have been delineated: M. sympodialis, M. globosa, M. slooffiae, M. restricta, and M. obtusa. Recently, on the basis of DNA relatedness, four new species, namely, M. dermatis, M. nana, M. japanica, and M. yamatoiensis, have been recognized.282–284 Malassezia globosa, M. sympodialis, and M. furfur seem to be the most common species producing tinea versicolor. The condition is most commonly seen in adolescents and young adults but it may affect infants and even newborns.285–287 Pityriasis versicolor manifests with well-defined, round to oval asymptomatic, or slightly pruritic, minimally scaly hypopigmented macules that may coalesce into larger patches. In some individuals, the lesion may be red–brown or brown. A variant with red macules (pityriasis versicolor rubra) and another with black ones (pityriasis versicolor nigra) has been described.288 The lesions are more prominent in the summer months, not only because of the warm weather but also because normal skin tans while the affected areas often do not. The lesions are distributed over the upper trunk, neck, and proximal upper extremities; facial lesions are not uncommon on the forehead.285 The diagnosis of tinea versicolor is readily made by examination of a KOH preparation of scales from the hypopigmented lesions that show numerous short hyphae and yeast forms. The main differential diagnostic possibilities in tinea versicolor are post-inflammatory hypopigmentation and pityriasis alba. Treatment may be accomplished with one of the antiseborrheic shampoos such as selenium sulfide, or ketoconazole, or topical imidazole antifungal agents. Oral ketoconazole, itraconazole or fluconazole in older children may also be effective, especially in widespread cases.289 Hypopigmentation without

280. Schwartz RA. Superficial fungal infections. Lancet. 2004;364:1173–1182. 281. Jung EG, Bohnert E. Mechanism of depigmentation in pityriasis versicolor alba. Arch Dermatol Res. 1976;256:333–334. 282. Crespo-Erchiga V, Gomez-Moyano E, Crespo M. La pityriasis versicolor y las levaduras del genero Malassezia. Actas Dermosifiliogr. 2008;99:764–771. 283. Crespo-Erchiga V, Florencio VD. Malassezia yeasts and pityriasis versicolor. Curr Opin Infect Dis. 2006;19:139–147. 284. Gaitanis G, Velegraki A, Alexopoulos EC, et al. Distribution of Malassezia species in pityriasis versicolor and seborrhoeic dermatitis in Greece. Typing of the major pityriasis versicolor isolate M. globosa. Br J Dermatol. 2006;154:854–859. 285. Bouassida S, Boudaya S, Ghorbel R, et al. Pityriasis versicolor de l’enfant: etude retrospective de 164 cas. Ann Dermatol Venereol. 1998;125:581–584. 286. Di SA, Zeccara C, Serra F, et al. Pityriasis versicolor in a newborn. Mycoses. 1995;38:227–228.

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any scale may remain for several months after treatment, even though the pathogenic organism has been eradicated. Sun exposure often evens out the pigmentation changes somewhat more quickly after treatment has been completed. Regardless of what therapy is used, recurrences are common.

Leprosy Hypopigmented macules may be the first clinical sign of leprosy.290–292 They are more characteristic of the early indeterminate stage or tuberculoid stage, but in all forms of leprosy, hypopigmented macules may be present.293 Because the incubation period for this disease is 2–5 years, it is rarely seen in children under the age of 1 year. Children with indeterminate leprosy have one or a few asymptomatic, small, ill-defined, not infiltrated hypopigmented macules (Fig. 10.21). The lesions usually spare the warmer parts of the body and are therefore more common on the face, extremities and buttocks. There is usually normal sensation and hair is normal over the patches. At this stage, the diagnosis is difficult to confirm, since there is usually no obvious associated palpable nerve enlargement and lesions may be confused with other noninfectious hypopigmented dermatoses; although at this early stage on histological examination no organisms are found, a mononuclear infiltrate of cutaneous nerves observed in the affected dermis or subcutaneous tissue is an important finding to establish a diagnosis. These lesions may regress spontaneously or evolve into one more definitive forms of leprosy. Lesions of tuberculoid leprosy are well-defined hypopigmnented macules or plaques with sharply marginated, elevated, annular edges. There is loss of hair, decreased sweating, pain, and thermoreception sensation within the plaques themselves. The lesions, usually small (up to 3 cm), are often solitary or only a few in number and as in indeterminate leprosy, they spare the warm areas. Regional cutaneous nerve trunks are often palpably enlarged. In borderline tuberculoid leprosy there are also annular plaques which are less elevated and less scaly than in polar tuberculoid leprosy. The plaques may be larger and are often multiple and asymmetric. As in tuberculoid leprosy, regional nerves are usually palpable. In borderline (dimorphous) leprosy, annular plaques with sharply marginated borders are more common than hypopigmented lesions. This is a very unstable form of leprosy that is rarely seen in clinical practice. In lepromatous leprosy, poorly defined symmetric papules and nodules are more common than hypopigmented plaques. In

287. Nanda A, Kaur S, Bhakoo ON, et al. Pityriasis (tinea) versicolor in infancy. Pediatr Dermatol. 1988;5:260–262. 288. Maeda M, Makimura KC, Yamaguchi H. Pityriasis versicolor rubra. Eur J Dermatol. 2002;12:160–164. 289. Partap R, Kaur I, Chakrabarti A, et al. Single-dose fluconazole versus itraconazole in pityriasis versicolor. Dermatology. 2004;208:55–59. 290. Ramos-e-Silva M, Rebello PF. Leprosy. Recognition and treatment. Am J Clin Dermatol. 2001;2:203–211. 291. Ramos-e-Silva M, Oliveira ML, Munhoz-da-Fontoura GH. Leprosy: uncommon presentations. Clin Dermatol. 2005;23:509–514. 292. Murthy PK. Clinical manifestations, diagnosis and classification of leprosy. J Indian Med Assoc. 2004;102:678–679. 293. Tomimori-Yamashita J, Maeda SM, Sunderkotter C, et al. Leukomelanodermic leprosy. Int J Dermatol. 2002;41:513–515.

Pigmentary abnormalities

Figure 10.21  Indeterminate leprosy. A subtle hypopigmented macule of 2 years’ duration. The macule showed normal sensation. (Courtesy of Dr Fabián Sandoval)

borderline lepromatous leprosy, asymmetric annular plaques coexist with more symmetric papules and nodules. The mechanism of hypopigmentation in leprosy is not well understood. There is no alteration in the number or morphology of melanocytes.294

Treponematoses The treponematoses,295 syphilis and non-venereal treponematoses, can lead to hypopigmentation. All treponematoses are characterized by three stages of disease where, after an initial inoculation lesion, there is a period of latency after which more generalized secondary and tertiary manifestations develop.

294. Shereef PH, Thomas M. Hypopigmented macules in leprosy – a histopathological and histochemical study of melanocytes. Indian J Lepr. 1992;64:189–191. 295. Farnsworth N, Rosen T. Endemic treponematosis: review and update. Clin Dermatol. 2006;24:181–190. 296. Frithz A, Lagerholm B, Kaaman T. Leukoderma syphiliticum: ultrastructural observations on melanocyte function. Acta Derm Venereol. 1982;62:521–525. 297. Dourmishev LA, Dourmishev AL. Syphilis: uncommon presentations in adults. Clin Dermatol. 2005;23:555–564.

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In syphilis, discrete hypopigmented lesions appear in previous sites of secondary lesions after the papular rash of secondary lues, the so-called leukoderma syphiliticum or ‘Venus necklace,’ because it most commonly appears on the neck, back and upper chest. These lesions disappear spontaneously several months after treatment is completed.296,297 Electron microscopic studies have shown that the melanocytes are only slightly reduced in number and have mostly normal outlines. The melanogenesis is impaired and small melanosomes with decreased deposition of melanin are mostly produced at the expense of normal melanin granules. A partial block in the melanin transfer mechanism seems to be in evidence.296 In some cases, Treponema pallidum were demonstrated around vessels and inside nerve fibres in the hypopigmented macules, suggesting that leukoderma in syphilis may represent active infection and not only a post-inflammatory reaction.298 The non-venereal endemic treponematoses (yaws, bejel and pinta) are endemic in certain parts of the world, and can lead to hypopigmentation. In yaws (framboesia, pian or buba) caused by T. pallidum subspecies pertenue, a hypopigmented pitted scar may be seen after spontaneous healing of the primary inoculation lesion. In bejel (endemic syphilis) caused by T. pallidum subspecies endemicum, gummatous nodules of the third stage may leave a depigmented scar as they regress. In pinta (carate or mal de pinto) caused by T. carateum, more extensive pigmentary changes may be seen during the late phase of the disease. Pinta is endemic in small rural areas of Central and South America. After a few months or years of secondary generalized lesions (pintids) that consist of erythemato-violaceous or with a slate blue hue, round, oval to irregular patches, hypopigmented and atrophic macules develop. These lesions progress to extensive generalized pigmentary changes of the late third phase characterized by symmetric hypopigmented or even achromic macules over body prominences with a vitiligo-like distribution. Differentiation from vitiligo may be very difficult at this stage. Clinical diagnosis of non-venereal treponematosis, which should be considered in endemic areas, may be very difficult for clinicians not familiar with these diseases. Serologic test results are used for diagnosis and are identical to those for syphilis, i.e., non-treponemal test (VRDL, RPR) and treponemal tests (TPHA, FTA-Abs).

Onchocerciasis299,300 This condition, also called ‘river blindness,’ is a parasitic infection caused by the filarial nematode, Onchocerca volvulus. It infects 18 million people worldwide, most of them in African nations; it is rarely seen in developed countries except in individuals traveling from endemic areas. Humans, the definitive host, become infected after inoculation of the O. volvulus stage 3 larva into the host during a blood meal of the black fly. The

298. Poulsen A, Secher L, Kobayasi T, et al. Treponema pallidum in leukoderma syphiliticum demonstrated by electron microscopy. Acta Derm Venereol. 1988;68:102–106. 299. Enk CD. Onchocerciasis – river blindness. Clin Dermatol. 2006;24: 176–180. 300. Udall DN. Recent updates on onchocerciasis: diagnosis and treatment. Clin Infect Dis. 2007;44:53–60.

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ACQUIRED CIRCUMSCRIBED HYPOMELANOSIS

inflammatory response to the larva and to its obligate endosymbiotic rickettsial bacteria Wolbachia is responsible for the morbidity of this infection. Onchocerciasis most commonly presents as a diffuse papular dermatitis, often with intense pruritus. Chronic papules and lichenification are associated with strong T helper lymphocyte (Th2) response, whereas depigmentation without itch has been shown to correlate with a milder Th2 reactivity. Onchocercal depigmentation often affects the shins in a symmetrical pattern. It consists of vitiligo-like lesions with hypopigmented patches containing perifollicular spots of normally pigmented skin (‘leopard skin pattern’). Cutaneous nodules (‘onchocercomata’), usually over bony prominences, are another commonly reported manifestation of onchocerciasis. The most important sequela of onchocerciasis is blindness, because Onchocerca microfilariae have particular affinity for the eyes and produce a corneal inflammatory reaction. On histopathologic examination, scanty perivascular inflammatory infiltrates with mononuclear cells, eosinophils, and occasional microfilariae in the papillary dermis are observed. Diagnosis may be difficult. Detection of microfilaria microscopically is not sensitive enough. Several DNA-based diagnostic tests on tissue specimens have been developed as well as antibody based ELISA test.300 The standard treatment for onchocerciasis is ivermectin (150 µg/kg given orally every 6–12 months).301

Post-kala-azar hypopigmentation Post-kala-azar dermal leishmaniasis (PKDL)302 occurs in untreated or insufficiently treated kala-azar. It is characterized by erythematous nodules and plaques and hypopigmentation. Hypopigmented macules are usually generalized and extensive, and often are not completely depigmented. PKDL may resemble leprosy; however in leprosy, the macules show variable sensory loss, are not so extensive, and are usually circular or oval macules that form figurate patterns by coalescence.

CHEMICAL AND DRUG-INDUCED HYPOMELANOSIS A number of chemicals are capable of depigmenting the skin when applied directly on to the cutaneous surface.303 The major primary offending agents are aromatic or aliphatic derivatives of phenols and catechols and benzene derivatives, which are useful as one-

301. Basanez MG, Pion SD, Boakes E, et al. Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis. Lancet Infect Dis. 2008;8:310–322. 302. Ramesh V, Ramam M, Singh R, et al. Hypopigmented post-kala-azar dermal leishmaniasis. Int J Dermatol. 2008;47:414–416. 303. Ghosh S, Mukhopadhyay S. Chemical leucoderma: a clinico-aetiological study of 864 cases in the perspective of a developing country. Br J Dermatol. 2009;160:40–47. 304. O’Malley MA, Mathias CG, Priddy M, et al. Occupational vitiligo due to unsuspected presence of phenolic antioxidant byproducts in commercial bulk rubber. J Occup Med. 1988;30:512–516. 305. Boissy RE, Manga P. On the etiology of contact/occupational vitiligo. Pigment Cell Res. 2004;17:208–214. 306. Jacob SE, Blyumin M. Vitiligo-like hypopigmentation with poliosis following treatment of superficial basal cell carcinoma with imiquimod. Dermatol Surg. 2008;34:844–845. 307. Serrao VV, Paris FR, Feio AB. Genital vitiligo-like depigmentation following use of imiquimod 5% cream. Eur J Dermatol. 2008;18:342–343. 308. Solano F, Briganti S, Picardo M, et al. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects. Pigment Cell Res. 2006;19:550–571.

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step cleansers and antiseptics, or industrial products used in the rubber industry.304 Other contributory toxins are sulfhydryls, mercurials, arsenics, cinnamic aldehyde, p-phenylenediamine, epoxy resins, diphenylcyclopropenone, azelaic acid, corticosteroids, tretinoin, imiquimod, and otic preparations such as eserine and thiotepa.303,305–308 Sometimes, plants used as topical medications may cause hypopigmentation.309 Nowadays, most cases of chemical leukoderma are from household chemical exposure, hair-dye being the most common causative agent.303 Monobenzyl ether of hydroquinone, an antioxidant used in the rubber industry, was one of the first reported offending agents in workers using ‘acid-cured’ rubber gloves. This compound is now being used as a therapeutic depigmenting agent for extensive vitiligo. Chemical leukoderma is more common in adults; however children and even neonates have been reported.303,310 Temporary-henna tattoos may be a relatively common cause in children.311,312 Patients present with localized depigmented patches on the areas exposed to the chemicals, most commonly on the hands. The depigmentation may follow an acute episode of dermatitis or may appear several months after the last exposure without signs of cutaneous irritation. Sites distant from the area of contact may also develop hypopigmentation. Histologic examination of hypopigmented skin reveals only rare melanocytes with few melanosomes and scanty epidermal melanin. Chemical induced hypomelanosis should be differentiated from other congenital and acquired hypomelanotic diseases. It should be considered in the differential diagnosis of any case of idiopathic vitiligo; it may be indistinguishable clinically and histologically, although perifollicular sparing is more suggestive of vitiligo. The diagnosis of chemical leukoderma may only be suspected by exposure to known chemical depigmenting agents. The occurrence in other workers also exposed to the same chemical, distribution of macules corresponding to chemical exposure and the presence of numerous acquired confetti or pea-sized macules may mimic vitiligo and therefore a history of previous exposure to offending agents may be necessary for diagnosis. Certain systemic medications such as chloroquine, imatinib mesylate (Gleevec) and fluphenazine (Prolixin) may also cause hypomelanosis.313–315 The patients may experience hypopigmented vitiligo-like patches or generalized lightening of the skin. Topically applied corticosteroids can also produce hypopigmentation. It is not uncommon to find hypopigmentation in children around lesions of chronic conditions being treated for

309. Liao YL, Chiang YC, Tsai TF, et al. Contact leukomelanosis induced by the leaves of Piper betle L. (Piperaceae): a clinical and histopathologic survey. J Am Acad Dermatol. 1999;40:583–589. 310. Goette DK. Raccoon-like periorbital leukoderma from contact with swim goggles. Contact Dermatitis. 1984;10:129–131. 311. Martin JM, Revert A, Alonso V, et al. Eczema de contacto agudo a parafenilendiamina contenida en tatuajes transitorios con henna. Actas Dermosifiliogr. 2005;96:382–385. 312. Corrente S, Moschese V, Chianca M, et al. Temporary henna tattoo is unsafe in atopic children. Acta Paediatr. 2007;96:469–471. 313. Brazzelli V, Roveda E, Prestinari F, et al. Vitiligo-like lesions and diffuse lightening of the skin in a pediatric patient treated with imatinib mesylate: a noninvasive colorimetric assessment. Pediatr Dermatol. 2006;23:175–178. 314. Grossman WJ, Wilson DB. Hypopigmentation from imatinib mesylate (Gleevec). J Pediatr Hematol Oncol. 2004;26:214. 315. Martin-Garcia RF, del RC, Sanchez JL. Chloroquine-induced, vitiligo-like depigmentation. J Am Acad Dermatol. 2003;48:981–983.

prolonged periods of time with potent or even middle strength topical corticosteroids; this can also occur occasionally when the corticosteroid is delivered under occlusion, as occurs with an occlusive tape; this can produce transient hypopigmented macules, where the diagnosis is often obvious because the hypopigmented area has a shape that is similar to the shape of the tape strip applied, rather than having the configuration of the dermatosis being treated.316 Corticosteroids injected intralesionally when indicated for the treatment of hemangiomas,317 keloids,318–320 and for intra-articular use321,322 can also produce localized hypopigmentation at the infiltration site. Occasionally, intramuscular injections of long-acting corticosteroids may produce a hypopigmented macule of diffuse borders, measuring 2–4 cm2, often observed with a slight depression at the site of injection that can be confused with a patch of morphea; a retrograde migration of the corticosteroid through the hypodermic needle channel, which may occur immediately after the injection, could explain these findings. Spontaneous resolution of all these pigmentary changes induced by corticosteroids usually occurs in a few months. Diphenylcyclopropenone, when used for topical immunotherapy of alopecia areata, has also been reported to induce hypopigmentation323; from a group of 243 patients treated with this molecule, four of them developed localized spotted hypo­ pigmentation on the treated areas (’dyschromia in confetti’), which also occurred at distant sites in one patient.324 The lesions developed several months after treatment was initiated and the hypopigmentation remained unchanged during several months after discontinuation of therapy. A complete history of previously applied topical medications or other chemicals is important in cutaneous hypopigmentation of recent onset. A characteristic disorder of hypopigmentation, called leukoderma punctata, has been reported, consisting of numerous punctate, hypopigmented and achromic lesions on the sunexposed areas of the extremities, following oral 8-methoxy psoralens and sunlight exposure (PUVASOL) for treatment of vitiligo (Fig. 10.22). The lesions were occasionally observed on the face, gluteal regions and upper aspects of the back and chest areas; in a few patients very few and subtle lesions appeared on the dorsum of the hands.325 Histopathologic evaluation of the lesions with Fontana–Masson stain revealed a marked reduction of melanin in five out of six patients. DOPA oxidase stain disclosed a substantial reduction but not complete disappearance of functional melanocytes. Electron microscopic studies of the achromic lesions demonstrated varying degrees of intracellular edema and vacuolar degeneration of the cytoplasm, containing a granular electron-dense material, probably constituted by

316. Kestel JL Jr. Hypopigmentation following the use of Cordran tape. Arch Dermatol. 1971;103:460. 317. Chowdri NA, Darzi MA, Fazili Z, et al. Intralesional corticosteroid therapy for childhood cutaneous hemangiomas. Ann Plast Surg. 1994;33:46–51. 318. Friedman SJ, Butler DF, Pittelkow MR. Perilesional linear atrophy and hypopigmentation after intralesional corticosteroid therapy. Report of two cases and review of the literature. J Am Acad Dermatol. 1988;19: 537–541. 319. Nanda V, Parwaz MA, Handa S. Linear hypopigmentation after triamcinolone injection: a rare complication of a common procedure. Aesthetic Plast Surg. 2006;30:118–119. 320. Kumar P, Adolph S. Hypopigmentation along subcutaneous veins following intrakeloid triamcinolone injection: a case report and review of literature. Burns. 1998;24:487–488. 321. McCormack PC, Ledesma GN, Vaillant JG. Linear hypopigmentation after intra-articular corticosteroid injection. Arch Dermatol. 1984;120:708–709.

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Pigmentary abnormalities

Figure 10.22  Leukoderma punctata. Numerous atrophic, hypopigmented and achromic spots on the upper extremity after therapy with PUVASOL.

aggregates of free cytoplasmic ribosomes; these changes were observed in many keratinocytes of achromic and normally pigmented adjacent skin, most of them in a suprabasal location. Some melanocytes showed similar damage with vacuolar degeneration and intracytoplasmic edema. A possible phototoxic effect provoked by natural UVA-UVB and psoralens (PUVASOL) in predisposed individuals with vitiligo, having therapy on a daily schedule, may have been the cause of this hypopigmentation disorder, especially since methoxsalen phototoxicity peaks at 48–78 h and these patients were treated beyond the two or three doses per week recommended for PUVA or PUVASOL. Avoiding this therapeutic modality in children is strongly recommended. Following this report, a few additional patients developing similar but less numerous lesions without PUVASOL therapy have been observed. Leukoderma punctata has also been reported in children after topical PUVA treatment for vitiligo and in adults after UVB therapy for psoriasis.326 No therapy has been described for this condition, and although its course was unmodified in most of the reported patients, in two of them a slight reduction of lesions was noted.325 Therapy is often not necessary when the toxic effects of chemicals involved are minimal or transient, since the hypopigmentation may resolve spontaneously. When the hypopigmentation is pronounced and permanent, especially if refractory achromic defects develop, melanocyte grafting may be a therapeutic option for this condition.327 Since chronic exposure of these agents, such as occurs in occupational dermatitis, is usually necessary to cause

322. Venkatesan P, Fangman WL. Linear hypopigmentation and cutaneous atrophy following intra-articular steroid injections for de Quervain’s tendonitis. J Drugs Dermatol. 2009;8:492–493. 323. Orecchia G, Stock J. Diphenylcyclopropenone: an important agent known to cause depigmentation. Dermatology. 1999;199:277. 324. van der SP, Happle R. ‘Dyschromia in confetti’ as a side effect of topical immunotherapy with diphenylcyclopropenone. Arch Dermatol. 1992;128: 518–520. 325. Falabella R, Escobar CE, Carrascal E, et al. Leukoderma punctata. J Am Acad Dermatol. 1988;18:485–494. 326. Park JH, Lee MH. Case of leukoderma punctata after topical PUVA treatment. Int J Dermatol. 2004;43:138–139. 327. Falabella R. Repigmentation of stable leukoderma by autologous minigrafting. J Dermatol Surg Oncol. 1986;12:172–179.

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hypopigmentation,328 single exposure of a child to these depigmenting agents usually will not cause cutaneous changes and therefore chemical induced hypopigmentation is not common in children. Nevertheless, this type of depigmentation should always be kept in mind in the differential diagnosis when no other explanation for an acquired and localized hypopigmented lesion occurs.

VITILIGO Joseph Morelli

PHYSICAL EXAMINATION

Vitiligo is macular depigmentation associated with the destruction of melanocytes. The disorder represents a clinical endpoint resulting from a complex interaction of environmental, genetic and immunologic factors. Vitiligo has been recognized for thousands of years. The social stigma associated with vitiligo arose from its confusion with leprosy and other contagious diseases associated with hypopigmentation. Despite the fact that it is now readily distinguishable from other causes of hypopigmentation or depigmentation, these stigma continue in many areas of the world.

GENETICS The genetic epidemiology of vitiligo is part of a broader genetically determined autoimmune and autoinflammatory diathesis. Of patients with generalized vitiligo, 15–20% have one or more affected first-degree relatives. However, this leaves 80–85% of cases which occur sporadically. In those families with multiple members affected, the genetic pattern is suggestive of polygenic, multifactorial inheritance.329

STATISTICS Vitiligo affects 1–2% of the population worldwide.330 Both sexes are affected equally. Vitiligo occurs in all races and geographic regions. Although most people do not think of vitiligo as a childhood disease, 50% of patients develop their first lesions before the age of 20 years and 25% before the age of 10 years.330 Vitiligo has been reported to develop as early in life as 6 months of age.

PRESENTING HISTORY Generalized vitiligo is the most common type of vitiligo and presents as sacral symmetric depigmentation. Many authorities include focal, acral, and acrofacial vitiligo as separate entities from widespread vitiligo, but their shared natural history and response to treatment suggest that they are subsets of generalized vitiligo. Children with vitiligo are also more likely to have a family member with vitiligo and their vitiligo is more likely to have an earlier age of onset.331–333 In contrast, segmental vitiligo

328. Kahn G. Depigmentation caused by phenolic detergent germicides. Arch Dermatol. 1970;102:177–187. 329. Spritz RA. The genetics of generalized vitiligo. Curr Dir Autoimmun. 2008;10:244–257. 330. Huggins RH, Schwartz RA, Janniger CJ. Childhood vitiligo. Cutis. 2007;79:277–280.

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Figure 10.23  Vitiligo covering a large portion of the trunk and upper limbs. (Courtesy of Dr Antonio Torrelo)

is a less common presentation identified by a more rapid progression of segmental depigmentation. Although generalized vitiligo is the most common type of vitiligo seen in both children and adults, the percentage of children with segmental vitiligo is significantly greater than in adults.

PHYSICAL EXAMINATION SKIN The areas of the skin affected by vitiligo are classically devoid of pigmentation and appear as chalk-white macules. They are most common on sacral and sun-exposed areas, but may cover the majority of the cutaneous surface (Fig. 10.23) They may be of any size and shape. Developing vitiligo in dark-skinned people may show various shades of color intermediate between the patient’s normal skin color and the totally depigmented skin, called trichrome vitiligo. Although most vitiligo strictly undergoes a progressive loss of skin color without inflammation, 5% of patients will exhibit a raised inflammatory border at the edge of the depigmented macules. The Koebner phenomenon may be seen, with new areas of vitiligo developing subsequent to skin injury. Halo nevi may also occur (Fig. 10.24). Segmental vitiligo is localized to one area of skin, (Fig. 10.25), although the entire segment is not usually involved. The areas of segmental vitiligo do not correspond to dermatomes.

HAIR, NAILS, TEETH, AND MUCOUS MEMBRANES Areas of hair and mucous membranes may also be depigmented (Fig. 10.26). The teeth are normal.

331. Silverberg NB, Travis L. Childhood vitiligo. Cutis. 2006;77:370–375. 332. Al-Mutairi N, Sharma AK, Al-Sheltawy M, et al. Childhood vitiligo: a prospective hospital-based study. Australas J Dermatol. 2005;46:150–153. 333. Pajvani U, Ahmad N, Wiley A, et al. J Am Acad Dermatol. 2006;55:238–244.

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PATHOPHYSIOLOGY AND HISTOGENESIS

Figure 10.26  Hair depigmentation (poliosis) with vitiligo. (Courtesy of Dr Figure 10.24  Halo nevus in a congenital melanocytic nevus. (Courtesy of Dr

Antonio Torrelo)

Antonio Torrelo)

LABORATORY FINDINGS No laboratory tests are routinely performed. There is debate regarding the utilization of routine screening for thyroid disease versus clinical evaluation and testing if symptomatic. Screening for other autoimmune diseases in childhood should only be performed if there is a positive family history and any clinical signs or symptoms of these disorders.

PATHOPHYSIOLOGY AND HISTOGENESIS MOLECULAR, BIOCHEMICAL, AND IMMUNOLOGIC BASIS

Figure 10.25  Segmental vitiligo in a teenager. (Courtesy of Dr Antonio Torrelo)

SYSTEMIC MANIFESTATIONS Children with vitiligo are usually healthy, although there is an increased incidence of autoimmune disorders in immediate and extended family members.333 Thyroid disease is the most common disorder associated with childhood vitiligo.334,335 Melanocytes are also found in the retinal pigment epithelium, the choroid of the eye and the scala vestibuli of the inner ear; depigmentation has been described in the retinal pigment epithelium and the choroid. Uveitis may also be seen, but eye color does not change. Mild hearing loss may occur. These changes are extremely rare in childhood and routine screening is not necessary.

334. Pagovich OE, Silverberg JI, Freilich E, et al. Thyroid abnormalities in pediatric patients in New York City. Cutis. 2008;81:463–466. 335. Iacovelli P, Sinagra JL, Vidolin AP, et al. Relevance of thyroiditis and of other autoimmune diseases in children with vitiligo. Dermatology. 2005; 210:26–30.

Several theories have been postulated to explain the cause of vitiligo. These include the autoimmune, genetic, autocytotoxic, and neural theories. It is likely that vitiligo is a heterogenous disorder with portions of all theories being correct in a given subset of patients. There is definitely an autoimmune component to vitiligo pathogenesis.336 Antibodies against melanocyte antigens are present in the serum of patients with vitiligo. The extent of vitiligo can be correlated with the incidence and level of these antibodies. Serum from patients with vitiligo is cytotoxic to melanocytes in vitro. Normal melanocytes are also destroyed in people undergoing antigen-specific immunotherapy for melanoma. Melanocyte-specific CD8+ T lymphocytes are also involved in the pathogenesis of vitiligo. These antibodies and T cells recognize a variety of melanocyte enzymatic and structural proteins including tyrosinase, tyrosinase-related protein-1 and 2 (TRP-1, TRP-2), MART1/Melan-A, Pme117/gp100 and gp75.336,337 It is argued that the immunologic response in vitiligo may not be primary, but secondary to an increase in the external or internal phenol/catechol concentration leading to altered immunogenicity of the melanocytes.337

336. Le Poole IC, Luiten RM. Autoimmune etiology of generalized vitiligo. Curr Dir Autoimmune. 1998;111:1103–1108. 337. Westerhof W, d’Ischia M. Vitiligo puzzle: the pieces fall in place. Pigment Cell Res. 2007;20:345–359.

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THERAPEUTICS AND PROGNOSIS

The genetic theory of vitiligo pathogenesis has been clearly related to the autoimmune theory.329 Many authorities believe that the cause of melanocyte death in vitiligo is a primary cell abnormality. Electron microscopic studies of both skin from patients with vitiligo and melanocytes cultured from patients with vitiligo reveal morphologic abnormalities, including cytoplasmic vacuolization, aggregation of melanosomes, autophagic vacuoles, fatty degeneration, and dilatation of the rough endoplasmic reticulum. Others believe that melanocyte death is related to inherent sensitivity to oxidative stress either in response to toxic intermediates of melanin or abnormal production of and/or lack of protection from hydrogen peroxide and other oxygen radicals.337 Melanocytes are derived from the neural crest and related to nerve cells. Nerve endings are in direct contact with epidermal melanocytes in depigmented skin. This is the main basis for the neural theory. An excess of catecholamine metabolites may be seen during active depigmentation,338 although this may be a secondary phenomenon.

HISTOLOGY Early lesions of vitiligo show a decreased number of melanocytes. An inflammatory infiltrate containing cutaneous leukocyte-associated antigen T lymphocytes expressing perforin and granzyme-B is seen clustered in the vicinity of disappearing melanocytes.336 The classic histology of longstanding vitiligo is the absence of melanocytes. Despite this, melanocytes may be identified by electron microscopy in skin of vitiligo that is totally depigmented.339 Since no clinical pigmentation is seen, any melanocytes remaining are either unable to make melanin, have abnormal interactions with neighboring keratinocytes or are too few to make clinically evident pigmentation. No matter what the pathogenesis, the histogenesis of vitiligo is the destruction of melanocytes. The melanocytes present in patches of longstanding vitiligo may either be resistant to destruction or melanocytes that have migrated from the outer root sheath of the hair follicle and are in the process of being destroyed.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of vitiligo depends on the type of vitiligo and the distribution of the depigmentation. Generalized vitiligo must be distinguished from post-inflammatory hypo­ pigmentation, pityriasis alba, tinea versicolor, multiple ash leaf macules, morphea, lichen sclerosus, piebaldism, Waardenburg’s syndrome and linear and whorled nevoid hypomelanosis. In a child with segmental disease, one should also consider nevus depigmentosus and nevus anemicus. The two most important

338. Cucchi ML, Frattini P, Santagostino G, et al. Catecholamines increase in the urine of non-segmental vitiligo especially during its active phase. Pigment Cell Res. 2003;16:111–116. 339. Kim YC, Kim YJ, Sohn S, et al. Histopathologic features in vitiligo. Am J Dermatopathol. 2008;30:112–116. 340. Akimoto S, Suzuki Y, Ishikawa O Multiple actinic keratosies and squamous cell carcinomas on the sun-exposed area of widespread vitiligo. Br J Dermatol. 2000;142:824–825. 341. Lepe V, Moncada B, Castaned-Cazares JP, et al. A double-blind randomized trial of 0.1% tacrolimus vs. 0.05% clobetasol for the treatment of childhood vitiligo. Arch Dermatol. 2003;139:581–585.

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factors that aid in distinguishing vitiligo from the other pigmentation disorders are that the lesions must be acquired after birth and that they are totally depigmented. At times, especially in light-skinned children, it is necessary to use a Wood’s lamp to determine if the skin is truly depigmented. A small proportion of children will have inflammatory vitiligo, which is characterized by an erythematous raised border, making the differential between vitiligo and post-inflammatory hypopigmentation more difficult. Another problem in differential diagnosis arises in darkskinned children with early vitiligo or with trichrome vitiligo. In early vitiligo, some functioning melanocytes may remain and the lesion may not be totally depigmented. In trichrome vitiligo a progression from totally depigmented skin to hypopigmented skin to normal colored skin is observable.

THERAPEUTICS AND PROGNOSIS TOPICAL THERAPY Not all children with vitiligo want active therapy.331 This will depend on the age of the patient, location and extent of the vitiliginous lesions and cultural beliefs. Those patients not wishing treatment must be counseled that the areas of vitiligo are totally lacking in pigment and therefore have no intrinsic sun protection. Unless photoprotected, they are at risk for the development of the sequelae of acute and chronic sun exposure.340 Cover-up cosmetics which match the child’s skin color may be very beneficial for cosmetically sensitive areas. They are somewhat timeconsuming to use; therefore the child must be very motivated. Topical therapy is the first-line of treatment for childhood vitiligo (Fig. 10.27). Topical glucocorticoids, calcineurin inhibitors and calcipotriene alone and in various combinations are effective.330,331 In comparison studies, calcineurin inhibitors are almost as effective as superpotent topical steroids.341 Potent topical steroids are as effective as superpotent topical steroids and have fewer side-effects. For all topical therapies, facial vitiligo demonstrates the best response.330,331

PHOTOTHERAPY Narrowband UVB (NB-UVB, UVB 311 nm) has become the mainstay of phototherapy treatment for children with extensive vitiligo.342,343 It is nearly as effective as oral psoralens with UVA-1 (PUVA), without the side-effects. Unlike PUVA, it may be used in children of any age. Combination phototherapy with topical calcipotriol or topical steroids may be more effective than phototherapy alone.331 Topical pseudocatalase and low dose NB-UVB is another option for therapy.344 Phenylalanine with natural sunlight or UVA has been used in children, but there is concern about possible neurologic side-effects secondary to large doses.

342. Brazzelli V, Prestinari F, Castello M, et al. Useful treatment of vitiligo in 10 children with UV-B narrowband (311 nm). Pediatr Dermatol. 2005;22: 257–261. 343. Kanwar AJ, Dogra S. Narrow-band UVB for the treatment of generalized vitiligo in children. Clin Exp Dermatol. 2005;30:332–336. 344. Schallreuter KU, Kruger C, Wurfel BA, et al. From basic research to the bedside: efficacy of topical treatment with pseudocatalase PC-KUS in 71 children with vitiligo. Int J Dermatol. 2008;47:743–753.

Pigmentary abnormalities

B

VOGT–KOYANAGI–HARADA SYNDROME

A

10

Figure 10.27  (A,B) Re-pigmenting vitiligo due to topical tacrolimus therapy. (Courtesy of Dr Antonio Torrelo)

OTHER THERAPY For small cosmetically significant areas which have not responded to other therapies, melanocyte transplantation is effective. This may be done either by various methods of direct skin transfer or by using cultured autologous melanocytes. Depigmentation therapy is permanent and should only rarely be considered in children with severe (75% body surface involvement), stable vitiligo, which has been unresponsive to therapy.

tant in these children to use vigorous methods of sun protection to prevent acute and chronic photodamage. With advancing age comes an increased knowledge of the differences in skin color, along with an increase in social pressures to be normal. The actual age at which this occurs is quite variable. It is at this time that the child will actively seek treatment. Vitiligo has severe psychosocial effects.347 (An excellent support group exists. It is the National Vitiligo Foundation, PO Box 23226, Cincinnati, OD 45223, USA. Telephone: 513-541-3903. Website: www.vitiligofoundation.org.)

PROGNOSIS Generalized vitiligo is in general a slowly progressive disease, with most people having more skin involved with 3–5 years.345 Spontaneous remission may occur, but is rare. In one large study, only 5% of the patients had >20% of their body surface area covered.346 It is not known if age at onset of disease correlates with eventual proportion of body surface involved. Segmental vitiligo is usually rapidly progressive. It then remains stable and is less responsive to treatment than generalized vitiligo. Patients with segmental vitiligo are not expected to develop generalized vitiligo.

PEDIATRIC ASPECTS OF THE DISEASE Very young children with vitiligo are not bothered by the disease and usually do not wish to participate in treatment. It is impor-

345. Liu J-B, Li M, Yang S, et al. Clinical profiles of vitiligo in China: an analysis of 3742 patients. Clin Exp Dermatol. 2005;30:327–331. 346. Cho S, Kang HC, Hahm JH. Characteristics of vitiligo in Korean children. Pediatr Dermatol. 2000;17:189–193. 347. Ongenae K, Van Geel N, DeSchepper S, et al. Effect of vitiligo on self-reported health-related quality of life. Br J Dermatol. 2005;152:1165–1172.

VOGT–KOYANAGI–HARADA SYNDROME The Vogt–Koyanagi–Harada syndrome is an acute multisystem inflammatory disease that is thought to represent an autoimmune response to pigment cells. The disease is rare in childhood.348 The disease usually begins with an acute febrile illness, often accompanied by meningoencephalitis, uveitis and dysacusis. Vitiligo is the cutaneous finding and presents after the other signs. The eye disease can be severe with cataract formation, retinal pigment atrophy, and glaucoma. Treatment with systemic glucocorticosteroids and other immunomodulatory agents is often required. Vitiligo vulgaris can affect the eyes and ears as well as the skin. What distinguishes this acute severe disease from the chronic and milder changes in vitiligo vulgaris is unknown.

348. Berker N, Ozdamar Y, Soykan E, et al. Vogt–Koyanagi–Harada syndrome in children: a report of a case and review of the literature. Ocul Immunol Inflamm. 2007;15:351–357.

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NEOPLASTIC DISORDERS OF MELANOCYTES Khanh Thieu and Hensin Tsao

CHILDHOOD MELANOMA

FAMM/dysplastic nevus syndrome

Xeroderma pigmentosum (XP) refers to a set of autosomal recessive disorders characterized by defects in the cellular repair of UV-induced DNA damage. The prevalence of XP is about one in 1 million in North America and Europe but has been reported to be more common in Japan (1 in 100 000).352 Affected patients have exquisite photosensitivity, experience degenerative changes in the sun-exposed skin and eyes, and are predisposed to early onset cancers, including cutaneous and ocular melanoma. Melanomas develop in about 5% of patients with XP.352 The estimated median age of onset is about 19 years,353 although one study reports that up to 40% of XP-associated melanomas occur in children 12 years old and younger.354 Overall, XP patients 100) melanocytic nevi, which are often clinically atypical. Atypical nevi are usually 5–10 mm in diameter, are often multicolored, with shades ranging from tan to dark brown, are round or oval in shape, and possess irregular, ill-defined borders. The moles often possess a ‘fried egg’ appearance (i.e. a central elevation within a flat lesion). Atypical nevi are most commonly found on the posterior trunk, and also occur frequently on the scalp and sun-protected areas such as the buttocks and breasts. Early in childhood, the nevi may appear relatively normal, as the atypical nevi phenotype does not usually become fully expressed until puberty.349 Germline mutations in CDKN2A have been identified in a subset of patients with FAMM. This gene encodes two distinct protein products p16 and p14ARF through alternative splicing that exert inhibitory effects on cell growth through distinct pathways involving the retinoblastoma (Rb) and p53 proteins.355 The prevalence of germline CDKN2A mutations among familial melanoma kindreds varies widely, ranging from 20% in Australia to 45% in North America and 57% in Europe.356 The lifetime cumulative risk of melanoma in patients with very strong FAMM pedigree can approach 100%,357 especially in high risk areas such as Australia. A study of 23 families believed to have this syndrome revealed the median age at diagnosis to be 33 years old.358 Only 9% of FAMM melanoma cases occurred before age 20, compared with 2% in the general population.358 While this represents only a modest increase in risk during the pediatric years, the eventual onset of melanoma during adult life merits minimizing of controllable risk factors, such as sun exposure, at an early age. Children diagnosed with FAMM should undergo a thorough skin examination every 6–12 months. The patient and the family should be taught how to detect changing moles, including potentially hidden ones on the scalp. The children also should be encouraged to use sunscreen daily and avoid excessive sun exposure. All first-degree relatives of the patient should also be encouraged to undergo regular screening exams after 10 years of

349. Ceballos PI, Ruiz-Maldonado R, Mihm MC, Jr. Melanoma in children. N Engl J Med. 1995;332:656–662. 350. Strouse JJ, Fears TR, Tucker MA, et al. Pediatric melanoma: risk factor and survival analysis of the surveillance, epidemiology and end results database. J Clin Oncol. 2005;23:4735–4741. 351. Huynh PM, Grant-Kels JM, Grin CM. Childhood melanoma: update and treatment. Int J Dermatol. 2005;44:715–723. 352. Bootsma D, Kraemer KH, Cleaver JE, et al. Nucleotide excision repair syndromes: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. In: Vogelstein BV, Kinzler K, eds. The genetic basis of human cancer. New York: McGraw Hill; 2002:211–237. 353. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol. 1987;123:241–250.

354. Lynch HT, Anderson DE, Smith JL, Jr, et al. Xeroderma pigmentosum, malignant melanoma, and congenital ichthyosis. A family study. Arch Dermatol. 1967;96:625–635. 355. Tsao H. Update on familial cancer syndromes and the skin. J Am Acad Dermatol. 2000;42:939–969; quiz 970–972. 356. Goldstein AM, Chan M, Harland M, et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. 2007;44:99–106. 357. Kanzler MH, Swetter SM. Malignant melanoma. J Am Acad Dermatol. 2003;48:780–783. 358. Goldstein AM, Fraser MC, Clark WH, Jr, et al. Age at diagnosis and transmission of invasive melanoma in 23 families with cutaneous malignant melanoma/dysplastic nevi. J Natl Cancer Inst. 1994;86:1385–1390.

EPIDEMIOLOGY

CHILDHOOD MELANOMA

Pediatric melanoma is a rare and potentially fatal disease. In the USA, melanoma in patients under 20 years of age comprises approximately 2% of all melanomas, and cases occurring in prepubertal children (> Ankyloblepharon, ectodermal dysplasia and clefting syndrome (AEC, Hay Wells) and Rapp–Hodgkin syndrome

>> Bazex–Dupre–Christol syndrome >> Congenital atrichia with nail dystrophy, abnormal facies and retarded psychomotor development

also the limbs and trunk. Study of a large pedigree suggests X-linked dominant inheritance.18

HYPOTRICHOSIS WITH JUVENILE MACULAR DYSTROPHY Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder, characterized by sparse and short scalp hair from birth, followed within a few years by progressive macular degeneration leading to blindness. It is shown to result from a mutation in a CDH3 encoding P-cadherin.19

HYPOTRICHOSIS WITH ECTODERMAL DYSPLASIAS Hypotrichosis is an important feature in many of the ectodermal dysplasia syndromes but often becomes obvious only after the neonatal period. A selection of conditions in which there may be congenital severe atrichia or hypotrichosis is listed in Box 11.1. Ectodermal dysplasias will be discussed in more detail in Chapter 7.

HYPOTRICHOSIS WITH ICHTHYOSES

Congenital hypotrichosis and milia

Ichthyoses presenting as the ‘collodion baby’ phenotype

This condition bears some clinical similarity to atrichia with papular lesions. There is hypotrichosis with sparse, coarse hair. Multiple milia are present at birth on the face and sometimes

The hair is often either absent or shed in the early weeks of life with the membrane in this group of conditions, which includes autosomal recessive and autosomal dominant forms of lamellar

8.

14. Wang J, Malloy PJ, Feldman D. Interactions of the vitamin D receptor with the corepressor hairless: Analysis of hairless mutants in atrichia with papular lesions. J Biol Chem. 2007;282:25231–25239. 15. O’Regan GM, Zurada J, Martinez-Mir A, et al. A recurrent splice-site mutation in the human hairless gene underlies congenital atrichia in Irish families. Br J Dermatol. 2007;156:744–747. 16. Wali A, Ansar M, Khan MN, et al. Atrichia with papular lesions resulting from a novel insertion mutation in the human hairless gene. Clin Exp Dermatol. 2006;31:695–698. 17. Zlotogorski A, Hochberg Z, Mirmirani P, et al. Clinical and pathologic correlations in genetically distinct forms of atrichia. Arch Dermatol. 2003;139:1591–1596. 18. Rapelanoro R, Taieb A, Lacombe D. Congenital hypotrichosis and milia: report of a large family suggesting X-linked dominant inheritance. Am J Med Genet. 1994;52:487–490. 19. Indelman M, Leibu R, Jammal A, et al. Molecular basis of hypotrichosis with juvenile macular dystrophy in two siblings. Br J Dermatol. 2005;153:635–638.

9. 10. 11. 12. 13.

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BOX 11.1 ECTODERMAL DYSPLASIAS IN WHICH THERE IS SEVERE NEONATAL HYPOTRICHOSIS

Yan KL, He PP, Yang LM, et al. Marie Unna hereditary hypotrichosis: Report of a Chinese family and evidence for genetic heterogeneity. Clin Exp Dermatol. 2004;29:460–463. He PP, Zhang XJ, Yang LM, et al. Refinement of a locus for Marie Unna hereditary hypotrichosis to a 1.1cM interval at 8p21.3. Br J Dermatol. 2004;150:837–842. Yang S, Gao Y, Yan KL, et al. Identification of a novel locus for Marie Unna hereditary hypotrichosis to a 17.5cM interval at 1p21.1–1q21.3. J Invest Dermatol. 2005;125:711–714. Kraemer L, Wajid M, Shimomura Y, et al. Mutations in the hairless gene underlie APL in three families of Pakistani origin. J Dermatol Sci. 2008;50:25–30. Betz RC, Indelman M, Pforr J, et al. Identification of mutations in the human hairless gene in two new families with congenital atrichia. Arch Dermatol Res. 2007;299:157–161. Michailidis E, Theos A, Zlotogorski A, et al. Atrichia with papular lesions resulting from novel compound heterozygous mutations in the human hairless gene. Pediatr Dermatol. 2007;24:E79–E82.

Hair disorders

11

plaques, nail dystrophy, gingival erythema and recurrent infections suggesting that this condition and hereditary mucoepithelial dysplasia may be the same condition.24 However, hereditary mucoepithelial dysplasia is believed to be autosomal-dominant, whereas the finding of Blaschko-distributed lesions in mothers and sisters of boys with IFAP suggests that this is, in at least some pedigrees, an X-linked trait.25 In other pedigrees, an autosomaldominant inheritance seems to be operating.26 Oral retinoids may improve the cutaneous features but not the alopecia or photophobia.27 IFAP is thought now to be a cell-to-cell adhesion disorder.28

Peeling skin syndrome

secondary infection and scarring.

ichthyosis, congenital ichthyosiform erythroderma, and lamellar ichthyosis of the newborn (self-healing collodion baby).

Keratitis, ichthyosis and deafness syndrome (KID syndrome)

From birth, these individuals demonstrate atrichia or severe hypotrichosis, keratotic follicular papules, corneal vascularization, loss of vision and photophobia.20–23 Retinal vascular tortuosity may be a clinical sign of carrier status in females.22 There are reports in some cases of periorificial erosions and keratotic

KID syndrome is a congenital ectodermal defect. Severe hypo­ trichosis of scalp, eyebrows, and eyelashes may be evident at birth and persists through life. There is a spiny follicular plugging as well as widespread, thickened erythematous plaques, perioral furrowing, reticulate hyperkeratosis of palms and soles, keratitis and sensorineural hearing loss. There is a rare fatal form described which is lethal in the first year of life as a result of overwhelming infections.31 KID syndrome appears to be genetically heterogeneous and may be caused by mutations in the GJB2 (connexin 26) or the connexin 30 (connexin 30) genes.31–34 GJB2 mutations are the main cause of disease. Most of the cases caused by GJB2 mutations are sporadic but dominant transmission has also been described. Dominant mutations in GJB2 have also been shown to cause various forms of palmoplantar keratoderma associated with hearing loss.35

20. Cambiaghi S, Barbareschi M, Tadini G. Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome in two unrelated female patients. J Am Acad Dermatol. 2002;46:S156-S158. 21. Bibas-Bonet H, Fauze R, Boente MC, et al. IFAP syndrome ‘plus’ seizures, mental retardation, and callosal hypoplasia. Pediatr Neurol. 2001;24: 228–231. 22. Traboulsi EI, Waked N, Megarbane H, et al. Ocular findings in ichthyosis follicularis-alopecia-photophobia (IFAP) syndrome. Ophthalmic Genet. 2004;25:153–156. 23. Sato-Matsumara KC, Matsumara T, Kumakiri M, et al. Ichthyosis follicularis with alopecia and photophobia in a mother and daughter. Br J Dermatol. 2000;142:157–162. 24. Rothe MJ, Lucky AW. Are ichthyosis follicularis and hereditary mucoepithelial dystrophy related diseases? Pediatr Dermatol. 1995;12:195. 25. König A, Happle R. Linear lesions reflecting lyonization in women heterozygous for IFAP syndrome (ichthyosis follicularis with atrichia and photophobia). Am J Med Genet. 1999;85:365–368. 26. Sato-Matsumara KC, Matsumara T, Kumakiri M, et al. Ichthyosis follicularis with alopecia and photophobia in a mother and daughter. Br J Dermatol. 2000;142:157–162. 27. Khandpur S, Bhat R, Ramam M. Ichthyosis follicularis, alopecia and photophobia (IFAP) treated with acitretin. J Eur Acad Dermatovenereol. 2005;19:759–762.

28. Tsolia MN, Aroni K, Konstantopoulou I, et al. Ichthyosis follicularis with alopecia and photophobia in a girl with cataract: Histological and electron microscopy findings. Acta Dermatovenereol. 2005;85:51–55. 29. Al-Ghamdi F, Al-Raddadi A, Satti M. Peeling skin syndrome: 11 cases from Saudi Arabia. Ann Saudi Med. 2006;26:352–357. 30. Mevorah B, Orion E, de Viragh P, et al. Peeling skin syndrome with hair changes. Dermatology. 1998;197:373–376. 31. Jonard L, Geldmann D, Parsy C, et al. A familial case of KeratitisIchthyosis-Deafness (KID) syndrome with the GJB2 mutation G45E. Eur J Med Genet. 2008;51:35–43. 32. Jan AY, Amin S, Ratajczak P, et al. Genetic heterogeneity of KID syndrome: Identification of a Cx30 gene (GJB6) mutation in a patient with KID syndrome and congenital atrichia. J Invest Dermatol. 2004;122:1108–1113. 33. Mazereeuw-Hautier J, Bitoun E, Chevrant-Breton J, et al. Disease expression and spectrum of connexin 26 (GJB2) mutations in 14 patients. Br J Dermatol. 2007;156:1015–1019. 34. Arita K, Akiyama M, Aizawa T, et al. A novel N14Y mutation in connexin 26 in keratitis-ichthyosis-deafness syndrome: Analyses of altered gap junctional communication and molecular structure of N terminus of mutated connexin 26. Am J Pathol. 2006;169:416–423. 35. De Zwart-Storm EA, Hamm H, Stoevesandt J, et al. A novel missense mutation in GJB2 disturbs gap junction protein transport and causes focal palmoplantar keratoderma with deafness. J Med Genet. 2008;45:161–166.

Lamellar ichthyosis Alopecia often occurs in this condition as a result of hair being caught up in and shed with the large plates of scale which exfoliate from the scalp. Hair loss may also occur as a result of secondary bacterial infection (Fig. 11.1).

Ichthyosis follicularis, congenital atrichia and photophobia (IFAP)

DIFFUSE CONGENITAL ATRICHIA OR HYPOTRICHOSIS

Figure 11.1  Alopecia in a child with lamellar ichthyosis, subsequent to

Peeling skin syndrome is a rare genodermatosis of probable autosomal recessive inheritance.29 There is a single report of a child with the inflammatory variant of the peeling skin syndrome who in addition, had hair abnormalities30 with what were designated trichorrhexis invaginata-like changes, irregular twisting of the hair, and areas of hair shaft narrowing.

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Congenital ichthyosis, follicular atrophoderma, hypotrichosis and hypohidrosis This combination of traits has been described as a new autosomalrecessive genodermatosis,36 and all of the features are present from the neonatal period.

Autosomal recessive ichthyosis with hypotrichosis (ARIH) syndrome ARIH syndrome is characterized by congenital ichthyosis, abnormal hair and corneal involvement. It is caused by a mutation in the ST14 gene which encodes the serine protease matriptase.37 CONGENITAL LOCALIZED OR PATCHY ALOPECIA

HYPOTRICHOSIS WITH PREMATURE AGING SYNDROMES While the onset of obvious hypotrichosis is often delayed until several years of age in these conditions, sparse hair is evident in early infancy in some cases of Hutchison–Gilford progeria, Rothmund–Thomson syndrome and Cockayne syndrome. A severe neonatal progeroid syndrome has been described in which sparse anterior scalp hair, thin eyebrows, and absent eyelashes were evident at birth, along with redundant skin, absent subcutaneous fat, and prominent blood vessels.38

HYPOTRICHOSIS WITH IMMUNODEFICIENCY SYNDROMES Alopecia is often a striking feature of a heterogeneous group of congenital immunodeficiency conditions presenting in early infancy with erythroderma, failure to thrive, and diarrhea, which includes severe combined immunodeficiency-associated congenital graft-versus-host disease and Omenn syndrome.39–41 In cartilage hair hypoplasia syndrome, sparsity of scalp, eyebrow, and eyelash hair is often evident in the neonatal period, together with short limbs and prenatal growth failure.42

HYPOTRICHOSIS WITH GENETIC DISORDERS OF THE HAIR SHAFT Increased fragility of hair in many of the genetic disorders of the hair shaft leads to early alopecia. These will be discussed in detail later in this chapter.

36. Lestringant GG, Kuster W, Frossard PM, et al. Congenital ichthyosis, follicular atrophoderma, hypotrichosis and hypohidrosis. Am J Med Genet. 1998;75:186–189. 37. Avrahami L, Maas, S, Pasmanik-Chor M, et al. Autosomal recessive ichthyosis with hypotrichosis syndrome: Further delineation of the phenotype. Clin Genet. 2008;74:47–53. 38. Arboleda G, Ramirez N, Arboleda H. The neonatal progeroid syndrome (Wiedemann–Rautenstrauch): A model for the study of human aging? Exp Gerontol. 2007;42:939–943. 39. Kroft EBM, Weemaes CMR, Seyger MMB. An infant with erythroderma and immunodeficiency. Ned Tijdsc Dermatovenereol. 2007;17:178–180.

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Figure 11.2  Temporal triangular alopecia.

CONGENITAL LOCALIZED OR PATCHY ALOPECIA NEONATAL OCCIPITAL ALOPECIA A well-defined patch of alopecia commonly develops in the occipital area in the early months of life. This has previously been attributed entirely to rubbing the back of the head on the bedding surface but it is explained more fully by an understanding of the patterns of hair cycle evolution in fetal and early neonatal life, covered in Chapter 6.

SCALP INJURY Alopecia, which is usually temporary, may occur in areas of scalp damaged by instrumentation such as forceps, vacuum extractor, or scalp monitors and also over cephalhematomas (see Ch. 6).

TEMPORAL TRIANGULAR ALOPECIA This is a well-circumscribed triangular or lance-shaped area of non-cicatricial hypotrichosis positioned in the fronto-temporal area, with the anterior margin either at the hairline or sometimes separated from it by a small fringe of normal hair (Fig. 11.2).43 It is unilateral in 80% of cases. Vellus hairs are present in the affected area and occasionally a few terminal hairs are retained.43,44 Histopathologic examination of transverse sections of a biopsy

40. Kato M, Kimura H, Seki M, et al. Omenn syndrome. Review of several phenotypes of Omenn syndrome and RAG1/RAG2 mutations in Japan. Allergol Int. 2006;55:115–119. 41. Farrell A, Scerri L, Stevens A, et al. Acute graft-versus-host disease with unusual cutaneous intracellular vacuolation in an infant with severe combined immunodeficiency. Pediatr Dermatol. 1995;12:311–313. 42. Makitie O, Sulisalo T, de la Chapelle A, et al. Cartilage-hair hypoplasia. J Med Genet. 1995;32:39–43. 43. Tan E, Ng M, Giam YC. Temporal triangular alopecia: Report of five cases in Asian children. Pediatr Dermatol. 2002;19:127–128. 44. Patrizi A, Morrone P, Fiorentini C, et al. An additional familial case of temporal triangular alopecia. Pediatr Dermatol. 2001;18:263–264.

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Figure 11.3  Alopecia over grossly folded congenital melanocytic nevus, with CONGENITAL LOCALIZED OR PATCHY ALOPECIA

cutis verticis gyrata appearance. (Courtesy Dr Marcelo Ruvertoni, British Hospital, Montevideo, Uruguay.).

Figure 11.4  Linear area of alopecia at the site of a sebaceous nevus specimen demonstrates that the majority of follicles are vellus; a normal number of follicles is present but the follicular size is abnormal for the scalp. The condition may be congenital and may be noted in the neonatal period in infants with abundant scalp hair, in whom it is often erroneously ascribed to forceps trauma. It is more often first noted in early childhood and adult onset has been reported.45 A report of the condition in a mother and daughter, in both of whom there was also developmental delay and seizures, suggests that in at least some cases, the condition may occur as part of a syndrome with autosomal-dominant inheritance.46

LOCALIZED ALOPECIA ASSOCIATED WITH OTHER NEVOID CONDITIONS Congenital melanocytic nevus These lesions are usually associated with hypertrichosis but large folded lesions on the scalp causing a cutis verticis gyrata appearance may have sparse covering hair or in some extreme cases, complete absence of hair (Fig. 11.3).47

Sebaceous nevus (of Jadassohn) (Fig. 11.4) These nevi are characteristically hairless. Sometimes, the nevus is so flat and subtle that it is only recognized as such later, and the presentation is as a linear or oval-shaped patch of congenital alopecia.

Aplastic nevus (syn. minus nevus) This is a nevoid condition in which there is a complete absence of skin appendages in an area of otherwise normal skin.48

45. Trakimas C, Sperling LC. Temporal triangular alopecia acquired in adulthood. J Am Acad Dermatol. 1999;40:842–844. 46. Ruggieri M, Rizzo R, Happle R. Temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. Arch Dermatol. 2000;136:426–427. 47. Yazici AC, Ikizoglu G, Baz K, et al. Cerebriform intradermal nevus. Pediatr Dermatol. 2007;24:141–143.

(Courtesy Dr A. Torrelo).

Aplasia cutis This condition is dealt with in detail in Chapters 6 and 18. Alopecia is a feature of both the common form of aplasia cutis congenita, with an irregularly shaped erosion which eventually heals, often with hypertrophic scarring, and of membranous aplasia cutis where there is an oval or round, hairless area covered by a smooth membrane and occasionally surrounded by a hair collar. The latter condition is probably a forme fruste of heterotopic brain tissue. Aplasia cutis producing a localized congenital alopecia may be a feature also of a number of syndromes including Adams–Oliver syndrome (Fig. 11.5) and Toriello oculoectodermal syndrome.

Cranial meningoceles, encephaloceles and heterotopic meningeal or brain tissue These present characteristically as tumors or cysts, which are either hairless or have sparse overlying hair. There is often, however, a surrounding collar of long hair producing the ‘hair collar sign.’

HYPOTRICHOSIS WITH CONGENITAL FORMS OF CUTIS VERTICIS GYRATA A marked folding of the scalp associated with sparse hair over the folds can occur at birth with melanocytic nevi, as mentioned above. In addition, it may be a feature of certain syndromes. When it occurs in Turner syndrome it is postulated that the redundant skin results from resolved intrauterine lymphedema.49

48. Schoenfeld RJ, Mehregan AH. Aplastic nevus – the ‘minus nevus’. Cutis. 1973;12:386–389. 49. Larralde M, Gardner SS, Torado M, et al. Lymphedema as a postulated cause of cutis verticis gyrata in Turner syndrome. Pediatr Dermatol. 1998;15:18–22.

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LOCALIZED ALOPECIA ASSOCIATED WITH SYNDROMES Hallermann–Streiff syndrome The hair may be normal at birth but in some cases, the typical alopecia, located in the frontal and parietal areas over the cranial sutures, may be evident in early months, together with atrophic facial skin and multiple craniofacial and ocular abnormalities.52

X-linked dominant conditions

HAIR SHAFT ABNORMALITIES

Several rare syndromes, caused by X-linked dominant genes which interfere with hair growth, produce a mosaic pattern of alopecia in affected females as a result of functional X-chromosome mosaicism.53 The hemizygous males with these conditions rarely survive. The conditions include focal dermal hypoplasia (Goltz syndrome),54 incontinentia pigmenti,53 oral facial digital syndrome,55 and X-linked dominant chondro­ dysplasia punctata.56 The alopecia in these conditions has a patchy distribution, sometimes obviously linear or spiral as it follows the lines of Blaschko. The pattern of these lines on the scalp has recently been further delineated.57 Figure 11.5  Alopecia in area of aplasia cutis in an infant with Adams–Oliver syndrome.

HAIR SHAFT ABNORMALITIES These conditions have been reviewed in detail by Whiting,58 Price,59 and Rogers.60,61

MONILETHRIX

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In Beare–Stevenson syndrome, which is due to a mutation in a fibroblast growth factor receptor gene,50 it occurs in association with acanthosis nigricans, craniofacial and anogenital anomalies and developmental delay. In the Michelin-tire baby syndrome there is a generalized folding of the skin due to an excess of various types of connective tissue; while there may be hyper­ trichosis elsewhere, there may be a marked hypotrichosis of the scalp.51 Multiple folds of redundant skin, all over the body, due to an accumulation of hyaluronic acid occurs in the so-called Shar Pei dog syndrome,51 and again there is scalp hypotrichosis. Most other forms of cutis verticis gyrata develop later in life.

This is an autosomal-dominant condition producing a beaded appearance of the hair.60 On microscopy, spindle-shaped ‘nodes’ separated by constricted internodes are seen. The nodes have the diameter of normal hair and may be medullated, whereas the internodes are narrower and usually non-medullated and are the sites of fracture. The abnormality may affect the whole length of the hair or there may be only a few areas of narrowing in an otherwise apparently normal hair (Fig. 11.6). Recently, mutations in the human basic hair keratins hHb1 and hHb6 have been reported.62 However, the failure to demonstrate these mutations in one family suggests the possibility of genetic heterogeneity.63 The hair is usually normal at birth but

50. Zhang Y, Gorry MC, Post JC, et al. Genomic organization of the human fibroblast growth factor receptor gene (FGFR2) and comparative analysis of the human FGFR gene family. Gene. 1999;230:69–79. 51. Sinclair R, de Berker D. Hereditary and congenital alopecia and hypotrichosis. In: Dawber R, ed. Diseases of the hair and scalp. Oxford: Blackwell Science; 1997:151–238. 52. Cohen JJ. Hallermann–Streiff syndrome: a review. Am J Med Genet. 1991;41:488–489. 53. Traupe H. Functional X-chromosome mosaicism of the skin: Rudolf Happle and the lines of Alfred Blaschko. Am J Med Genet. 1999;85: 324–329. 54. Terashi H, Kurata S, Hashimoto H, et al. A case of Goltz syndrome presenting as congenital incomplete alopecia. J Dermatol. 1994;21: 122–124. 55. Boente M, Primc N, Veliche H, et al. A mosaic pattern of alopecia in the oral-facial-digital syndrome type I (Papillon-League and Psaume syndrome). Pediatr Dermatol. 1999;16:367–370.

56. Braverman N, Lin P, Moebius FF, et al. Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi–Hunnermann syndrome. Nat Genet. 1999;22:291–294. 57. Happle R, Assim A. The lines of Blaschko on the head and neck. J Am Acad Dermatol. 2001;44:612–615. 58. Whiting D. Structural abnormalities of the hair shaft. J Am Acad Dermatol. 1987;16:1–25. 59. Price VH. Structural abnormalities of the hair shaft. In: Orfanos C, Happle R, eds. Hair and hair diseases. Berlin: Springer Verlag; 1990:363–422. 60. Rogers M. Hair shaft abnormalities: Part I. Australas J Dermatol. 1995;36: 179–186. 61. Rogers M. Hair shaft abnormalities: Part II. Australas J Dermatol. 1996;37: 1–11. 62. Horev L, Glaser B, Metzker A, et al. Monilethrix: mutational hotspot in the helix termination motif of the human hair basic keratin 6. Human Hered. 2000;50:325–330. 63. Richard G, Itin P, Lin JP, et al. Evidence for genetic heterogeneity in monilethrix. J Invest Dermatol. 1996;107:812–814.

Figure 11.6  Microscopy of monilethrix demonstrating the beaded appearance.

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Figure 11.8  Pseudomonilethrix. Irregularly spaced nodes, wider than the normal shaft, occurring near the site of overlap of the hairs.

Figure 11.9  Pseudomonilethrix. Denting of the hair at the site of pressure from an overlapping hair.

Figure 11.7  Monilethrix. Most hairs are broken almost flush with the scalp, with some coarse longer hairs and follicular keratosis (Courtesy Dr A. Torrelo).

PSEUDOMONILETHRIX is replaced within weeks by affected hairs which are dry, dull, and brittle, breaking spontaneously to leave a stubble-like appearance. The hairs may break almost flush with the scalp or may attain lengths of 0.5–2.5 cm, or occasionally longer (Fig. 11.7). Follicular keratosis is associated in some pedigrees and may involve scalp, face, and limbs. Koilonychia is sometimes found. The condition tends to improve significantly with age, particularly in girls, perhaps in relation to hormonal influences.64 An acute loss of hair following a fever is a feature of this condition. The hair is lost within days of the fever, and may be of such a severity that it is misdiagnosed as severe alopecia areata. However, the onset of regrowth is immediate. Some residual long hairs may have an unusual coarse texture.

64. Gebhart M, Fischer T, Claussen U, et al. Monilethrix – improvement by hormonal influences? Pediatr Dermatol. 1999;16:297–300.

This condition was originally described in 1973 as a developmental defect characterized by fragile hair with irregular nodes along the shaft when seen on microscopy.65 Autosomal-dominant inheritance with variable penetrance was postulated. Large pedigrees were described in which almost 100% of members demonstrated the abnormality. The nodes are 0.75–1 mm in length, and wider than the normal shaft. The zones between the nodes are of normal thickness. Scanning electron microscopy demonstrates the nodes to be optical illusions, representing indentations of hair with the sides of the depressions protruding beyond the normal diameter of the shaft (Figs 11.8, 11.9). The cuticular pattern is normal over both ‘nodes’ and ‘internode’. In 1986, Zitelli66 nicely demonstrated that the condition is, in fact, an artifact, caused by the

65. Bentley-Phillips B, Bayles MAH. A previously undescribed hair anomaly (pseudomonilethrix). Br J Dermatol. 1973;89:159–167. 66. Zitelli JA. Pseudomonilethrix: an artifact. Arch Dermatol. 1986;122:688.

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Figure 11.10  Pili torti. Microscopy showing the series of twists. Figure 11.11  Pili torti. Scanning electron microscopy demonstrating the flattening of the shaft at the site of twisting.

pressure between glass-slides of overlapping hairs. He noted that the length of the swelling correlated with the diameter of overlapped hair and the width of the swelling and the depth of the indentation are proportional to the pressure applied. This artifact is seen almost routinely when mounting the fair, fine hair of patients with certain ectodermal dysplasias, if hairs are allowed to overlap. It is often temporary, with the deformation disappearing in a few minutes. Similar deformities are seen in fine hair handled with forceps. It is likely that the early reported pedigrees were examples of ectodermal dysplasias.

PILI TORTI This is characterized by a twisting of the hair shaft on its own axis.60 On microscopy, groups of three or four regularly spaced twists, each of 0.4–0.9 mm in width, are seen occurring at irregular intervals along the shaft (Figs 11.10, 11.11). Twists are almost always through 180°, although some are through 90° or 360°. The hair shaft is somewhat flattened at the site of the twist. Pili torti may occur as an inherited, isolated phenomenon with the onset at birth or in the early months of life. The hair is usually fairer than expected and is spangled, dry, and brittle, breaking at different lengths. It may stand out from the scalp and it tends to be short, especially in areas subject to trauma (Fig. 11.12). Both autosomal-dominant and autosomal-recessive pedigrees have been reported.59 There is a late onset form of pili torti in which alopecia develops after puberty. It is an autosomal-dominant condition in which affected hair is coarse, stiff and jet black. Eyebrow hairs and lashes break off during childhood. After puberty, the scalp hair becomes more brittle and a patchy alopecia may develop. Body hair is sparse and may be seen broken off almost flush with the skin surface. Mental retardation has been associated in some pedigrees.59,60

67. Kodama H, Murata Y. Molecular genetics and pathophysiology of Menkes disease. Pediatr Int. 1999;41:430–435. 68. Kodama H, Murata Y, Kobayashi M. Clinical manifestations and treatment of Menkes disease and its variants. Pediatr Int. 1999;41:423–429.

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Figure 11.12  Sparse, spangled hair in pili torti. Pili torti occurs as a feature of several other defined syndromes.

Menkes Syndrome Menkes syndrome is an X-linked recessive condition characterized by progressive neurodegeneration and connective tissue manifestations and is usually lethal in the early years of life. The unusual, twisted hair, demonstrating pili torti on microscopy, has led to the terminology ‘kinky hair syndrome’ or ‘steely hair syndrome.’ The basis of the disorder has been found to relate to a defect in copper transport.67,68 In 1993, the genes for both Menkes disease69 and Wilson disease70 were isolated, and they were found to encode

69. Vulpe C, Levinson B, Whitney S, et al. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nat Genet. 1993;3:7–13. 70. Bull PC, Thomas GR, Rommens JM, et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993;5:327–337.

homologous cation copper-transporting P-type ATPase proteins. The Menkes disease protein (ATP7A) is expressed in most tissues except liver, while the Wilson disease protein (ATP7B) is well expressed in the liver, explaining the clinical differences between these two conditions.71 The Menkes gene is on chromosome X13.3 and mutations in this gene in patients with Menkes disease show great variety, including missense, nonsense, deletion, and insertion mutations.67 Mutations in the Menkes gene have also been identified in patients with mild Menkes disease, which shows features similar to, but less severe than, classical Menkes disease, and in the occipital horn syndrome (X-linked cutis laxa, Ehlers–Danlos type 9), mainly characterized by connective tissue features, indicating that these conditions represent allelic forms of Menkes disease.67 The loss of Menkes protein activity blocks the export of dietary copper from the gastrointestinal tract leading to a decreased bioavailability of copper with resultant functional deficiencies of copper-dependent enzymes.68,72 In the classic form, the scalp hair is often sparse at birth and may remain so. It is hypopigmented, sometimes with a silvery sheen, and is twisted or kinked in appearance. It may be rather coarse in texture. It is fragile and breaks easily in areas of trauma, such as the occipital area (Figs 11.13, 11.14). The eyebrows are usually sparse and disordered. Microscopically, pili torti is demonstrated. The skin is pale and lax with a doughy consistency and may be mottled. The hypopigmentation of hair and skin is explained by a deficiency in the copper-dependent enzyme, tyrosinase. Lyonization leads to a Blaschko-distributed hypopigmentation and areas of pili torti noted in some obligate female carriers.73 These infants are hypotonic and hypothermic and develop early seizures. There is microcephaly and progressive developmental delay. Imaging studies demonstrate osteoporosis, metaphyseal flaring, particularly of ribs and femora, and tortuous blood vessels in the brain and elsewhere. The tortuosity of the vessels results from a defect in elastin crosslinking due to deficiency of another copper-dependent enzyme, lysyl oxidase. If untreated, most infants die within the first year, but longerterm survivors are now being reported as a result of early treatment.74 Parenteral administration of copper, if commenced in the neonatal period, may prevent neurological deterioration but this advantage is lost after the first 2 months of life and early treatment does not improve the non-neurological features such as connective tissue laxity.68 Prenatal testing is now available by mutational analysis.

Other syndromes with pili torti In Bazex syndrome, inherited as an X-linked dominant trait, congenital hypotrichosis with pili torti is associated with follicular atrophoderma, multiple facia milia, and an increased suscep71. Suzuki M, Gitlin JD. Intracellular localization of the Menkes and Wilson’s disease proteins and their role in intracellular copper transport. Pediatr Int. 1999;41:436–442. 72. Harrison MD, Dameron CT. Molecular mechanisms of copper metabolism and the role of the Menkes disease protein. J Biochem Mol Toxicol. 1999;13:93–106. 73. Lorette G, Toutain A, Barthes M, et al. Maladie de Menkes. Anomalie particulière de la pigmentation chez la mère et trois soeurs. Ann de Pediatr. 1992;39:453–456.

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Figure 11.13  Steely, sparse hair in a patient with Menkes syndrome.

Figure 11.14  Spangled and twisted appearance of the hair in a boy with Menkes syndrome. (Courtesy Dr A Lucky.)

tibility to development of basal cell carcinomas.75 In Bjornstad syndrome, there is an associated sensori-neural deafness and in some cases, mental retardation.76,77 In later childhood, normal hair may replace the affected hairs, with considerable improvement in appearance. Mental retardation has been reported in 74. Christodoulou J, Danks DM, Sarkar B, et al. Early treatment of Menkes disease with parenteral copper histidine: long term follow up of four treated patients. Am J Med Genet. 1998;76:154–164. 75. Goetyn M, Geerts M-L, Kint A, et al. The Bazex–Dupre–Christol syndrome. Arch Dermatol. 1994;130:337–342. 76. Loche F, Bayle-Lebey P, Carriere JP, et al. Pili torti with congenital deafness (Bjornstad syndrome): a case report. Pediatr Dermatol. 1999;16:220–221. 77. Selvaag E. Pili torti and sensorineural hearing loss. A follow-up of Bjornstad’s original patients and a review of the literature. Eur J Dermatol. 2000;10:91–97.

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Figure 11.16  Trichorrhexis nodosa. Scanning electron microscopy of the HAIR SHAFT ABNORMALITIES

node demonstrating the disruption of the cuticle and the splaying out of the cortical cells.

Figure 11.15  Trichorrhexis nodosa. Microscopy demonstrating the node which appears like two brushes pushed together.

one case.78 Bjornstad syndrome is autosomal-recessive and has been mapped to chromosome 2.79 In Crandall syndrome, probably inherited as an X-linked recessive trait, congenital hypotrichosis with pili torti is associated with sensorineural deafness and hypopituitarism.80 Pili torti may occur also in Rapp–Hodgkin syndrome, although pili canaliculi is the more characteristic finding.81

TRICHORRHEXIS NODOSA (TN)

756

Trichorrhexis nodosa with arginosuccinicaciduria (ASAU) There is a neonatal form of ASAU that is fatal in early life and a later-onset form. Most children with late-onset ASAU show trichorrhexis nodosa.82 The hair may be normal at birth but becomes fragile by 1–2 years. There is a dull, dry, matted appearance especially in the occipital area. The condition reverts to normal with dietary treatment of the metabolic condition but it recurs quickly if the diet is abandoned. An acquired TN has also been described in association with severe nutritional deficiency.

This term refers to the light microscopic appearance of a fracture with splaying out and release of individual cortical cells from the main body of the hair shaft producing an appearance suggestive of the ends of two brushes pushed together (Fig. 11.15).59,60 When the break occurs, the brush-like end is clearly seen. Electron microscopy shows the disrupted cuticle and splaying of cortical cells (Fig. 11.16). The defect renders the hair very fragile and it breaks readily with trauma or sometimes almost spontaneously. In congenital trichorrhexis nodosa, inherited as an autosomaldominant trait, the hair is usually normal at birth but is replaced within a few months with abnormal, fragile hair. The condition tends to improve with time. Acquired trichorrhexis nodosa is a distinctive response of the hair shaft to external injury. In adolescents it may be seen as a result of the use of hot combs, excessively hot hair dryers, hairstraightening procedures, and other chemical treatments. In younger children, it may be a feature of hair injured by traction, twisting (as in trichotillomania), and rubbing. Trichorrhexis nodosa may occur in hair weakened by other hair shaft abnormalities, in particular monilethrix and trichothiodystrophy.

Sulfur-deficient brittle hair is a marker for a neuroectodermal symptom complex occurring in a group of autosomal-recessive genetic disorders.61,83 Named syndromes in this spectrum include Pollitt syndrome, Tay syndrome, Sabinas brittle hair syndrome, and Marinesco–Sjögren syndrome.84 The words describing the various clinical features of the condition have led to other mnemonic names, including BIDS, IBIDS, and PIBIDS.83 The clinical features found in this group of conditions are brittle hair (Fig. 11.17), ichthyosis, short stature, decreased fertility, intellectual impairment, photosensitivity, and osteosclerosis (Fig. 11.18). Mental retardation of varying degrees is present in almost all cases but there have been reports of individuals with typical hair findings and normal development.85 Photosensitivity is present in about 50% of patients. Photosensitive trichothiodystrophy, along with xeroderma pigmentosum (XP) and Cockayne syndrome, are explained by mutations in genes involved in

78. Van Buggenhout G, Trommelen J, Hamel B, et al. Bjornstad syndrome in a patient with mental retardation. Genet Counsel. 1998;9:201–204. 79. Lubianca Neto JF, Lu L, Eavey RD, et al. The Bjornstad syndrome (sensorineural hearing loss and pili torti) disease gene maps to chromosome 2q34–2q36. Am J Hum Genet. 1998;62:1107–1112. 80. Crandall B, Samec L, Sparkes RS, et al. A familial syndrome of deafness, alopecia and hypogonadism. J Pediatr. 1973;82:461–465. 81. Camacho F, Ferrando J, Pichardo AR, et al. Rapp–Hodgkin syndrome with pili canaliculi. Pediatr Dermatol. 1993;10:54–57.

82. Potter JL, Timmons GD, et al. Arginosuccinicaciduria: The hair shaft abnormality revisited. Am J Dis Child. 1980;134:1095–1096. 83. Itin PH, Pittelkow MR. Trichothiodystrophy: review of sulfur-deficient brittle hair syndromes and association with the ectodermal dysplasias: J Am Acad Dermatol. 1990;22:705–717. 84. Tolmie JL, de Berker D, Dawber R, et al. Syndromes associated with trichothiodystrophy: Clin Dysmorphol. 1994;3:1–14. 85. Peter C, Tomczok J, Hoting E, et al. Trichothiodystrophy without associated neuroectodermal defects. Br J Dermatol. 1998;139:137–140.

TRICHOTHIODYSTROPHY

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HAIR SHAFT ABNORMALITIES

Figure 11.19  Trichothiodystrophy. Microscopy demonstrating flattened hair shafts, one twisting like a ribbon. Several areas of trichoschisis.

Figure 11.17  Trichothiodystrophy. Short, disordered sparse hair. (Courtesy Dr A. Torrelo.)

Figure 11.20  Trichothiodystrophy. Microscopy demonstrating flattened shaft twisted through 360°.

Figure 11.18  Trichothiodystrophy. X-ray demonstrating osteosclerosis of skull.

nucleotide excision repair. In most patients with photosensitive trichodystrophy the defect is indistinguishable from that of XP complementation type D but two other repair-deficient complementation groups have been described, XP-B and TTD-A.86,87 Surprisingly, an increased tendency to skin cancer is rarely a feature in these patients.88,89 Individuals with trichothiodystrophy may present with a collodion baby phenotype and intrauterine growth retardation may occur. Other features include facial dysmorphism, congenital cataracts, and nail dystrophy. A

86. Taylor EM, Broughton BC, Botta E, et al. Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD(ERCC2) repair/transcription gene. Proc Nat Acad Sci USA. 1997;94:8658–8663. 87. Weeda G, Eveno E, Donker I, et al. A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. Am J Hum Genet. 1997;60:320–329. 88. de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis. 2000;21:453–460.

rare variant is reported with severe recurrent infections, failure to thrive, and death in early infancy.90 On light microscopy the hair has a wavy, irregular outline and a flattened shaft in which twists like a folded ribbon occur (Figs 11.19, 11.20). Two types of fracture are seen – trichoschisis, a clean, transverse fracture, and an atypical trichorrhexis nodosa with less splaying out of the cortical cells than is usually seen. Using crossed polarizers, bright and dark bands are seen when the hair is aligned in one of the polarizer directions, the so-called tiger-tail appearance (Fig. 11.21). This may be absent at birth and is not fully developed until 3 months of age.91 Scanning electron microscopy shows irregular ridging and fluting and disordered, reduced, or absent cuticle scale pattern (Fig. 11.22).

WOOLY HAIR This is tight, curly hair, which differs considerably from that of other areas of scalp and that of family members (Fig. 11.23).61

89. Charles CA, Connelly EA, Aber CG, et al. A rare presentation of squamous cell carcinoma in a patient with PIBIDS-type trichothiodystrophy. Pediatr Dermatol. 2008;25(2):264–267. 90. Petrin JH, Meckler KA, Sybert VP. A new variant of trichothiodystrophy with recurrent infections, failure to thrive and death. Pediatr Dermatol. 1998;15:31–34. 91. Brusasco A. The typical ‘tiger-tail’ pattern of the hair shaft in trichothiodystrophy may not be evident at birth: Arch Dermatol. 1997;133:249.

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Figure 11.21  Trichothiodystrophy. Hair viewed microscopically using crossed polarizers, demonstrating the banded ‘tiger tail’ appearance.

Figure 11.23  Wooly hair. (Courtesy Dr A. Torrelo.)

in the plakoglobin and desmoplakin gene;95 giant axonal neuropathy;96 and primary osteoma cutis.97 Wooly hair nevus has been associated with ocular abnormalities92 and with epidermal nevi, usually away from the site of the wooly hair nevus and sometimes quite extensive.98

UNCOMBABLE HAIR

It is usually abnormal from birth. The hair is not fragile in this condition. A wide variety of changes are described in shaft crosssectional shape, follicle morphology, and cuticular appearance on scanning electron microscopy. The pathogenesis is unclear and may vary from case to case. There are three main groups. Two are diffuse and inherited, one autosomal-recessive and one autosomal-dominant. The other is localized and sporadic, the woolly hair nevus. The condition is important because there are many associations. Diffuse wooly hair has been associated with ocular abnormalities, some present at birth;92 keratosis pilaris atrophicans;93 Noonan syndrome;93 palmoplantar keratoderma and cardiac conduction defects;94 recently linked with a deletion

Uncombable hair (syn. spun glass hair, pili canaliculi, pili trianguli et canaliculi) is a condition defined by its clinical features.61,99 In the classical clinical form, the hair is a light silvery-blond, paler than expected. It is frizzy, stands away from the scalp, and cannot be combed flat (Fig. 11.24). It is often glistening or ‘spangled.’ It is usually normal in length, quantity, and tensile strength. The onset may be with the first terminal growth or soon after. Eyebrows, lashes, and body hair are normal. There are reports suggesting both dominant and recessive inheritance patterns. Scanning electron microscopy best demonstrates the characteristic shallow grooving or flattening of the surface (Fig. 11.25),99 although the grooves can be seen with routine microscopy of hairs prepared with mineral oil or mounting media on glass slides. These areas are often discontinuous and change orientation many times along the length of the hair, occurring on different faces of the hair at different points. Crosssectional microscopy shows triangular, reniform, quadrangular, and other unusual shapes (Fig. 11.26). It is now clear that longitudinal grooving of hair shafts and/or irregular cross-section is not specific for the clinical entity of uncombable hair. It has been demonstrated in a variety of other syndromes including progeria, Marie Unna hypotrichosis, Rapp–Hodgkin syndrome,81,100

92. Taylor A. Hereditary woolly hair with ocular involvement. Br J Dermatol. 1990;123:523–526. 93. Neild VS, Pegum JS, Wells RS. The association of keratosis pilaris atrophicans and woolly hair, with or without Noonan’s syndrome. Br J Dermatol. 1984;110:357–362. 94. Carvajal-Huerta L. Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol. 1998;39: 418–421. 95. Protonotarios N, Tsatsopoulou A. Naxos disease: Cardiocutaneous syndrome due to cell adhesion defect. Orphanet J Rare Dis. 2006;1:4.

96. Ouvrier RA. Giant axonal neuropathy. Brain Dev. 1989;11:207–214. 97. Ruggieri M, Pavone V, Smilari P, et al. Primary osteoma cutis – multiple cafe-au-lait spots and woolly hair abnormality. Pediatr Radiol. 1995;25:34–36. 98. Wright S, Lemoine NR, Leigh IM. Woolly hair naevi with systematized linear epidermal naevus. Clin Exp Dermatol. 1986;11:179–182. 99. Matis WL, Baden H, Green R, et al. Un-combable hair syndrome. Pediatr Dermatol. 1987;4:215–219. 100. Micali GM, Cook B, Blekys I, et al. Structural hair abnormalities in ectodermal dysplasia. Pediatr Dermatol. 1990;7:27–32.

Figure 11.22  Trichothiodystrophy. Scanning electron microscopy demonstrating the irregular ridging and fluting and disordered cuticle scale pattern.

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Hair disorders

Figure 11.26  Uncombable hair (pili canaliculi). Cross-sectional microscopy demonstrating reniform and other abnormal shapes.

Figure 11.24  Uncombable hair (pili canaliculi) in two sisters.

Figure 11.25  Uncombable hair (pili canaliculi). Scanning electron microscopy demonstrating discontinuous grooving on different faces of the hair shaft.

oral facial digital syndrome type I,55 ectrodactyly ectodermal dysplasia and clefting syndrome,100 hypohidrotic ectodermal dysplasia (Fig. 11.27),100 and angel-shaped phalango-epiphyseal dysplasia.101 The classical clinical appearance of spun glass or uncombable hair would seem to depend on a certain proportion of abnormal hairs. The typical spangled appearance as found in the classical patient with no other abnormalities has been seen also in patients with Rapp–Hodgkin syndrome81 and in hypohidrotic ectodermal dysplasia.102

PILI ANNULATI This hair shaft abnormality, which may be congenital, does not render the hair fragile. The hair looks normally shiny but on close observation, alternating bright and dark bands are seen

101. Fritz TM, Trueb RM. Uncombable hair with angel shaped phalangoepiphyseal dysplasia. Pediatr Dermatol. 2000;17:21–24.

Figure 11.27  Uncombable hair (pili canaliculi). Spangled hair in a patient with hypohidrotic ectodermal dysplasia.

(Fig. 11.28).61 There are usually no associated abnormalities. The condition may be sporadic or inherited, usually as a dominant characteristic. The bright areas are due to light scattered from clusters of air-filled cavities within the cortex and in a hair mount, viewed with transmitted light, the light areas appear as dark patches (Fig. 11.29). Scanning electron microscopy shows longitudinal wrinkling and folding in bands corresponding to the abnormal areas, possibly due to the evaporation of air in the spaces when the hair is coated in the vacuum. Transmission electron microscopy demonstrates multiple holes within the cortex.

102. Shelley WB, Shelley ED. Uncombable hair syndrome: observations on response to biotin and occurrence in siblings with ectodermal dysplasia. J Am Acad Dermatol. 1985;13:97–102.

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HAIR SHAFT ABNORMALITIES

Figure 11.28  Pili annulati. Banded appearance of hair viewed with reflected light.

Figure 11.30  Total alopecia in an infant with Netherton syndrome.

Figure 11.29  Pili annulati. Microscopy demonstrating air spaces in the cortex of the hair.

PSEUDOPILI ANNULATI In this condition, which may simply represent an unusual variant of normal hair, there is a periodic reflection of light along the shaft giving an appearance of light and dark bands with reflected light, as in pili annulati.59,103 The banding is due to superficial optical effects stemming from the geometry of the hair, which is elliptical in cross section and partially twisted in an oscillating fashion along its axis. On examination with transmitted light, the hair appears to vary periodically in thickness. However, the thick and thin segments are not constant and alternate when the hair is rotated, indicating that the appearance is due to twisting. The internal structure of the hair is normal. The banding is seen only when the light strikes the hair at right angles to the hair’s long axis and only when the hair is rotated in certain positions about its long axis and not others. The flattened, twisted surfaces of the fiber act as reflective mirrors that preferentially reflect the light at certain angles and not others, and the elliptical hair acts as a variable cylindrical lens to refract 103. Lee S-SJ, Lee Y-S, Giam Y-C. Pseudopili annulati in a dark-haired individual. Pediatr Dermatol. 2001;18:27–30.

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Figure 11.31  Sparse, dull hair in a 10-year-old child with Netherton syndrome.

and focus the incident light on to the posterior wall of the hair from which it is internally reflected.

TRICHORRHEXIS INVAGINATA This is the characteristic hair shaft abnormality of Netherton syndrome for which the gene (SPINK 5) has recently been mapped to chromosome 5.104 Although the severity varies considerably, the clinical and microscopic findings61 are present 104. Chavanas S, Garner C, Bodemer C, et al. Localization of the Netherton syndrome gene to chromosome q32, by linkage analysis and homozygosity mapping. Am J Hum Genet. 2000;66:914–921.

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Figure 11.32  Trichorrhexis invaginata. Microscopy demonstrating the

DIFFUSE HYPERTRICHOSIS

bamboo-like appearance of the invagination.

Figure 11.34  Netherton syndrome. Microscopy demonstrating the ‘golf tee hair’ appearance due to the expanded proximal end of an invaginate node after a break has occurred.

tions has been described107 and should not be mistaken for pili torti. Figure 11.33  Trichorrhexis invaginata. Scanning electron microscopy demonstrating a tulip-like appearance at the site of invagination.

from birth. In the severely affected neonate the hair may be extremely sparse or even absent (Fig. 11.30). What hair is present is fragile, short, and dull (Fig. 11.31). The changes may affect eyebrows, eyelashes, and general body hair also. Sometimes the scalp hair is so minimally affected that the diagnosis cannot be made on sampling from this area but the eyebrows are almost always short and broken and these should be sampled in a suspected case in which the abnormality cannot be demonstrated on scalp hair. Microscopically, a ball and socket configuration with various patterns is seen. The classical ‘bamboo hair’ occurs when the soft, abnormal hair shaft wraps around a firmer distal shaft, producing the appearance of a shallow invagination of the distal into the proximal shaft (Fig. 11.32). There is a tulip-like form with a deeper invagination and hence longer sides of the ‘cup’ (Fig. 11.33).59 The earliest stage of the invagination may be seen as a circumferential stricture. The term ‘golf tee hair’ has been given to the expanded proximal end of an invaginate node after a break has occurred (Fig. 11.34).105 Thin vellus hairs may show multiple invaginations, the so-called ‘canestick hairs.’106 A helical pattern of twisting with obliquely running, parallel invagina-

105. de Berker D, Paige D, Harper J, et al. Golf tee hairs: a new sign in Netherton syndrome. Br J Dermatol. 1992;127(Suppl 40):30. 106. Menne T, Weisman K. Canestick lesions of vellus hair in Netherton’s syndrome. Arch Dermatol. 1985;121:451. 107. Lurie R, Ben-Zion G. Helical hairs: A new hair anomaly in a patient with Netherton’s syndrome. Cutis. 1995;55:349–352.

ACQUIRED PROGRESSIVE KINKING OF THE HAIR This condition, in which section of hair, usually frontal, hair becomes progressively more curly, frizzy and dull, usually has its onset in early adult life, involves androgen-dependent scalp hair, leads to hair thinning, and is probably in the spectrum of androgenetic alopecia.108 However, a reversible form, unassociated with hair thinning, has been reported in a prepubertal boy.109

HYPERTRICHOSIS Li-Chuen Wong Hypertrichosis refers to diffuse or localized patterns of excessive hair growth without evidence of masculinization.

DIFFUSE HYPERTRICHOSIS PRIMARY HYPERTRICHOSIS Because of the wide variety of designations given and the poor clinical descriptions in the early literature there is much confusion surrounding the classification of congenital hypertrichosis

108. Tosti A, Piraccini BM, Pazzaglia M, et al. Acquired progressive kinking of the hair. Arch Dermatol. 1999;135:1223–1226. 109. Rigopoulos D, Katoulis AC, Stavrianeas NG, et al. Acquired progressive kinking of the hair in a prepubertal boy. Br J Dermatol. 1997;137: 832–833.

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occurring alone or with only occasional associations. However, several individual entities can probably be separated out.110–112

Hypertrichosis lanuginosa

DIFFUSE HYPERTRICHOSIS

This is a very rare condition characterized by retention of lanugo hair. At birth there is a coat of profuse, usually fair, silky, fine hair up to 10 cm in length, involving all the usual hair-bearing areas of skin and blending with the hair of scalp and eyebrows.110,111 There may be accentuation over the spine and on the pinnae and profuse growth in the ear canal may lead to infection and a hearing deficit. Matted hair in the diaper area is particularly troublesome.113 The prognosis varies, with many authors reporting improvement while others report persistence or even worsening.113 At puberty there may be no conversion to terminal hair in secondary sexual hair areas, with long, fine, lanugo hairs persisting in pubic and axillary areas and in the beard. While about one-third of cases are sporadic, both autosomal-dominant and autosomal-recessive inheritance patterns are reported.110 Most patients have no other abnormalities, but congenital glaucoma and dental abnormalities including neonatal teeth have been observed.113 Management involves cutting or shaving the hair and there is one report of successful removal of hair using a neodymium-YAG laser.114

Ambras syndrome This condition, so designated in reference to the first documented case, has been subsequently reported under a variety of names. It appears to be a unique form of diffuse congenital hypertrichosis in which the hair, which may demonstrate pigmentation and medullation, is said to be vellus rather than lanugo hair.110,115,116 This syndrome is associated with a pericentric inversion of chromosome 8.115,117 The hypertrichosis is most marked on face, ears, and shoulders and persists through life. On the face the long hair uniformly covers brow, eyelids, nose, and cheeks. A number of dysmorphic facial features have occurred in these patients.

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terminal hair hypertrichosis present at birth and most severe over the face, pubic area, back, and upper chest.110 (In some cases, there was an improvement on the trunk and limbs after puberty.) This condition has recently been mapped to chromosome Xq24–q27.1.118

X-linked recessive hypertrichosis A large Mexican kindred showed a congenital universal hyper­ trichosis inherited in an apparent X-linked recessive manner. Affected individuals also had dental malformations and deafness.119

Prepubertal hypertrichosis A series is reported of children with generalized hypertrichosis present from birth and increasing in severity in early childhood, but no other abnormal clinical findings.120 There is profuse terminal hair growth on the back and proximal limbs and also on the temples, spreading across the brow and merging with bushy eyebrows. The pattern does not resemble hirsutism. There was a patterning of the hair growth on the back with an inverted fir tree distribution centering on the spine. It is not clear whether this condition represents an abnormality or whether it is an extreme form of the normal range of hair growth, as it resembles the patterns of hair growth seen in some racial groups.120 However, a study has demonstrated elevated plasma dihydrotestosterone levels in several patients, suggesting that indeed an endocrine abnormality may be the basis for this condition.121

HYPERTRICHOSIS AS PART OF OTHER GENETICALLY DETERMINED DISORDERS Hypertrichosis, with the onset in the neonatal period or in childhood, is a feature of a number of genetically determined syndromes. A selection of these122–124 is covered in Table 11.1.

X-linked dominant hypertrichosis

DRUG-INDUCED HYPERTRICHOSIS

A pedigree has been reported with probable X-linked dominant inheritance in which affected individuals had a generalized

Neonatal hypertrichosis is an occasional feature of the fetal alcohol syndrome125 and also can occur with maternal use of

110. Garcia-Cruz D, Figuera LE, Cantu JM. Inherited hypertrichoses. Clin Genet. 2002;61:321–329. 111. Wendelin DS, Pope DN, Mallory SB. Hypertrichosis. J Am Acad Dermatol. 2003;48:S161–S179. 112. Vashi R, Mancini A, Paller AS. Primary generalized and localized hypertrichosis in children. Arch Dermatol. 2001;137:877–884. 113. Partridge JW. Congenital hypertrichosis lanuginosa: neonatal shaving. Arch Dis Child. 1987;62:623–625. 114. Littler CM. Laser hair removal in a patient with hypertrichosis lanuginosa congenita. Dermatol Surg. 1997;23:705–707. 115. Tadin-Strapps M, Warburton D, Baumeister FAM. Cloning of the breakpoints of a de novo inversion of chromosome 8, inv (8)(p11.2q23.1) in a patient with Ambras syndrome. Cytogenet Genome Res. 2004;107:68–76. 116. Baumeister FAM. Differentiation of Ambras syndrome from hypertrichosis universalis. Clin Genet. 2000;57:157–158. 117. Rashid RM, White LE. A hairy development in hypertrichosis: A brief review of Ambras syndrome. Dermatol Online J. 2007;13:8. 118. Figuera LE, Pandolfo M, Dunne PW, et al. Mapping of the congenital generalized hypertrichosis locus to chromosome Xq24–q27.1. Nat Genet. 1995;10:202–207.

119. Tadin-Strapps M, Salas-Alanis JC, Moreno L, et al. Congenital universal hypertrichosis with deafness and dental anomalies inherited as an X-linked trait. Clin Genet. 2003;63:418–422. 120. Barth JH, Wilkinson JD, Dawber R. Prepubertal hypertrichosis: normal or abnormal? Arch Dis Childh. 1988;63:666–668. 121. Balducci R, Toscano V. Bioactive and peripheral androgens in prepubertal simple hypertrichosis. Clin Endocrinol. 1990;33:407–414. 122. Lee IJ, Im SB, Kim D-K. Hypertrichosis universalis congenita: a separate entity, or the same disease as gingival fibromatosis? Pediatr Dermatol. 1993;10:263–266. 123. Lacombe D, Bioulac-Sage P, Sibout M, et al. Congenital marked hypertrichosis and Laband syndrome in a child: overlap between the gingival fibromatosis-hypertrichosis and Laband syndromes. Genet Counsel. 1994;5:251–256. 124. Ostergaard E, Bradinova I, Ravn SH, et al. Hypertrichosis in patients with SURF1 mutations. Am J Med Genet. 2005;138:384–388. 125. Hanson JW, Jones KL, Smith DW. Fetal alcohol syndrome: experience with 41 patients. J Am Med Assoc. 1976;235:1458–1460.

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Table 11.1  Syndromes featuring hypertrichosis

Hypertrichosis with gingival fibromatosis   There are three syndromes which may represent parts of a single spectrum:   1. Gingival fibromatosis122   2. Gingival fibromatosis and epilepsy122

  3. Laband syndrome123

Hypertrichosis with hereditary porphyrias   1. Congenital erythropoietic porphyria   2. Familial porphyria cutanea tarda

  3. Hepatoerythropoietic porphyria

HYPERTRICHOSIS

OTHER FEATURES

Relatively mild congenital hypertrichosis Severe congenital hypertrichosis. Hair is pigmented. Most severe on face, arms, and lumbosacral area Marked congenital hypertrichosis reported in one patient

Gingival fibromatosis Gingival fibromatosis and epilepsy

Gingival hyperplasia, dysplasia of the terminal phalanges, hepatosplenomegaly, facial dysmorphism

Hypertrichosis occurs particularly on light exposed areas A marked, diffuse facial hypertrichosis may occur in early childhood; less often limb involvement A variable, sometimes severe hypertrichosis

Hypertrichosis with osteochondrodysplasia (Cantu syndrome)110,111

Diffuse hypertrichosis

Congenital macrosomia, coarse facial features, cardiomegaly, narrow thorax, broad ribs, coxa valga, and short phalanges. Recently described megaepiphyses

Cornelia de Lange syndrome

Mild generalized hypertrichosis with low frontal and occipital hairlines, thick eyebrows, synophrys and long, upturned lashes. The hair on the lateral elbows and sacral area may be very long and fine

Low birth weight congenital livedo, increased susceptibility to infection, growling cry, distinctive facies with hypertelorism, an anti-Mongoloid slant of the palpebral fissures, long philtrum, and thin lips. Rare features are micromelia, phocomelia, gastrointestinal, and urogenital malformations

Coffin Siris syndrome

Hypertrichosis, particularly of face and back. Low frontal hairline, bushy eyebrows, and long eyelashes, but often sparse scalp hair

Absence or hypoplasia of the nails and distal phalanges of 5th fingers and toes, microcephaly, facial dysmorphism, growth failure, and mental retardation

Leprechaunism

Coarse curly scalp hair. Extensive body and facial hypertrichosis in 75% of cases

Low birth weight, wrinkled loose skin with decrease of subcutaneous fat, acanthosis nigricans, periorificial rugosity of skin, thick lips, gingival hypertrophy, large low-set ears, and hypertrophic external genitalia

Seip–Berardinelli syndrome (congenital generalized lipodystrophy)

Congenital hypertrichosis of face, neck and limbs, increasing with age. Low frontal hairline and thick, curly scalp hair

Deficient subcutaneous fat, acanthosis nigricans, organomegaly, hypertrophy of genitalia. Insulin resistant diabetes

Mucopolysaccharidoses: Hunter, Hurler and Sanfilippo forms

Hypertrichosis is an occasional feature of these

Barber–Say syndrome

Extensive generalized hypertrichosis, most marked over the back

Redundant atrophic skin, telecanthus, ectropion, macrostomia, a broad bulbous nose, and abnormal pinnae

Rubinstein–Taybi syndrome

Hypertrichosis of trunk, limbs and face in two-thirds of cases. The eyebrows are highly arched and the eyelashes unusually long

Capillary vascular malformations, beaked nose, hypertelorism, high arched palate, cryptorchidism and broad thumbs and great toes and sometimes other digits. Pilomatricomas

Leigh syndrome and SURF1 mutation124

Hypertrichosis begins in first year

Psychomotor retardation

DIFFUSE HYPERTRICHOSIS

SYNDROME

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minoxidil126 and valproic acid.127 A dose-dependent hypertrichosis of the brow, limbs, and back becomes obvious in the first 4 weeks of treatment with diazoxide, which is used in neonates with hyperinsulinemia. Other drugs that may be responsible for hypertrichosis in infants and children include ciclosporin, penicillamine, diphenylhydantoin, and minoxidil. An excellent result is reported from the use of a chemical depilatory cream in ciclosporin-induced hypertrichosis in a 6-month-old infant.128

HYPERTRICHOSIS WITH SYSTEMIC DISEASES Systemic illnesses in children in which diffuse hypertrichosis may develop include anorexia nervosa129 and other causes of malnutrition, dermatomyositis,130 congenital and primary hypothyroidism131,132 and congenital adrenal hyperplasia.133 LOCALIZED HYPERTRICHOSIS

LOCALIZED HYPERTRICHOSIS

Figure 11.35  Nevoid hypertrichosis consisting of a single patch of terminal hair on the back. (Courtesy Dr A. Lucky.)

NEVOID HYPERTRICHOSIS Several patients have been reported with single or multiple localized patches of terminal hair growing from skin of normal color and texture (Fig. 11.35).111,134,135 In one case, underlying lipo­ atrophy was found in some patches.135 Additional abnormalities in one patient included areas of lipoatrophy and streaky depigmentation away from the areas of hypertrichosis, developmental delay and seizures, congenital lung cyst, congenital malrotation of the gut, multiple skeletal, dental, and ocular abnormalities.134 This constellation of findings did not fit into any recognized syndrome. It is likely that these represent mosaic disorders. A case has been recently reported of a definitely Blaschkodistributed pattern of depigmented hypertrichosis in a patient who also had short stature, scoliosis, developmental delay and seizures, structural brain malformations demonstrated on imaging, microphthalmia, eyelid coloboma, and other structural ocular abnormalities.136 In another case with multiple patches of congenital nevoid hypertrichosis, there was an associated epidermal nevus, hypopigmented hairless streaks, and a retinal pigmentary abnormality; surprisingly, the hypertrichosis spontaneously resolved by the age of 2 years.137 Nevoid hypertrichosis responds well to laser therapy with the Alexandrite laser, since the target is terminal hair.138 126. Kaler SG, Patrinos ME, Lambert GH, et al. Hypertrichosis and congenital anomalies associated with maternal use of minoxidil. Pediatrics. 1987;79; 434–436. 127. Stoll C, Audeoud F, Gaugler C, et al. Multiple congenital malformations including generalized hypertrichosis with gum hypertrophy in a child exposed to valproic acid in utero. Genet Counsel. 2003;14:289–298. 128. Wendelin DS, Mallory GB, Mallory SB. Depilation in a 6-month-old with hypertrichosis: a case report. Pediatr Dermatol. 1999;16:311–313. 129. Schultze UM, Pettke-Rank CV, Kreienkamp M, et al. Dermatologic findings in anorexia and bulimia nervosa of childhood and adolescence. Pediatr Dermatol. 1999;16:90–94. 130. Pope DN, Strimling RB, Mallory SB. Hypertrichosis in juvenile dermatomyositis. J Am Acad Dermatol. 1994;31:383–387. 131. Stern SR, Kelnar CHJ. Hypertrichosis due to hypothyroidism. Arch Dis Childh. 1985;60:763–766. 132. Akcakus M, Koklu E, Kutoglu S, et al. Neonatal hypertrichosis in an infant of a diabetic mother with congenital hypothyroidism. J Perinatol. 2006;26: 256–258. 133. Barbaro M, Lajic S, Baldazzi L, et al. Functional analysis of two recurrent amino acid substitutions in the CYP21 gene from Italian patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2004;89: 2402–2407. 134. Rogers M. Naevoid hypertrichosis. Clin Exp Dermatol. 1981;16:74.

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FAMILIAL CERVICAL HYPERTRICHOSIS WITH KYPHOSCOLIOSIS A family has been reported with congenital localized hypertrichosis of the cervical area overlying a kyphoscoliosis, without other spinal or cutaneous abnormalities.139 The inheritance pattern was autosomal dominant.

ANTERIOR CERVICAL HYPERTRICHOSIS A congenital patch of hypertrichosis on the front of the neck has been described as an isolated phenomenon,140 and in association with peripheral sensory and motor neuropathy,141 retinal abnormalities,142 and mental retardation.143

HAIRY CUTANEOUS MALFORMATIONS OF PALMS AND SOLES There have been reports of the familial occurrence of hair growth on circumscribed areas of the palms and soles.111 In one family, the skin in the area showed exaggerated skin markings in a geometric pattern. The condition was present at birth and persisted 135. Vergani R, Betti R, Martino P, et al. Giant nevoid hypertrichosis in an Iranian girl. Pediatr Dermatol. 2002;19:64–66. 136. Schauder S, Hanefeld F, Noske UM, et al. Depigmented hypertrichosis following Blaschko’s lines associated with cerebral and ocular malformations: a new neurocutaneous autosomal lethal gene syndrome from the group of epidermal naevus syndromes? Br J Dermatol. 2000;142: 1204–1207. 137. Dudding TE, Rogers M, Roddick LG, et al. Nevoid hypertrichosis with multiple patches of hair that underwent almost complete spontaneous resolution. Am J Med Genet. 1998;79:195–196. 138. Cheung ST, Lanigan SW. Naevoid hypertrichosis treated with alexandrite laser. Clin Exp Dermatol. 2004;29:435–436. 139. Reed OM, Mellette JR, Fitzpatrick JE. Familial cervical hypertrichosis with underlying kyphoscoliosis. J Am Acad Dermatol. 1989;20:1069–1072. 140. Braddock SR, Jones KL, Bird LM, et al. Anterior cervical hypertrichosis: a dominantly inherited isolated defect. Am J Med Genet. 1995;55:498–499. 141. Trattner A, Hodak E, Sagie-Lerman T, et al. Familial congenital anterior cervical hypertrichosis associated with peripheral sensory and motor neuropathy – A new syndrome? J Am Acad Dermatol. 1991;25:767–770. 142. Garty BZ, Snir M, Kremer I, et al. Retinal changes in familial peripheral sensory and motor neuropathy associated with anterior cervical hypertrichosis. J Pediatr Ophthalmol Strabismus. 1997;34:309–312. 143. Corona-Rivera JR, Gonzalez-Abarca S, et al. Mental retardation in a boy with anterior cervical hypertrichosis. Am J Med Genet. 2005;135:69–71.

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through life. Histopathology demonstrated the presence of ectopic hair follicles and some increase in the amount of elastic fibers in the dermis.

SCROTAL HAIR Several infant boys have been reported to have developed scrotal hair within the first 3 months of life, in the absence of clinical or biochemical evidence of excessive androgen production.144 The condition was non-progressive and the hair usually disappeared by the age of 18 months.

This is an uncommon condition in which profuse vellus hair is localized on the extensor aspects of the arms, particularly around the elbow area.111,112 It is likely that the few associated abnormalities reported represent chance associations. Both dominant and recessive inheritance patterns have been reported but some cases are apparently sporadic. The condition appears in infancy, increases in early childhood and improves spontaneously at puberty.

HYPERTRICHOSIS WITH SPINAL FUSION ABNORMALITIES These occur mainly in the lumbosacral area (creating a so-called ‘faun tail’ but can occur elsewhere over the spine. A tuft of long, silky hair often marks the abnormal area, with or without other cutaneous markers, such as dimple, sinus tract, collagenoma, aplasia cutis, capillary malformation, hemangioma, lipoma, or pigmented nevus.111,145,146 These cutaneous lesions may be found in the presence of clinical spina bifida with myelomeningocele but are particularly helpful as markers for occult spinal dysraphism.

HYPERTRICHOSIS WITH CRANIAL MENINGOCELES, ENCEPHALOCELES AND HETEROTOPIC MENINGEAL OR BRAIN TISSUE These are often marked by a peripheral collar of hair, a tuft of hair nearby or overlying hair, with at times a vascular stain (Fig. 11.36). Prominent or patulous hair follicle orifices may also be a feature (see Ch. 6). The membranous form of aplasia cutis, which may also demonstrate a hair collar, is now recognized as a forme fruste of a neural tube closure defect. For scalp lesions, the hair is longer, thicker, and often darker than the surrounding normal hair. With lesions away from the scalp, the presence of hair may be an indication that one is dealing with a neural lesion. A patient has been reported with a congenital patch of hypertrichosis over the lumbar area, well away from the spine, overlying what was demonstrated histologically to be meningeal

144. Slyper AH, Esterly NB. Nonprogressive scrotal hair growth in two infants. Pediatr Dermatol. 1993;10:34–35. 145. Davis DA, Cohen PR, George RE. Cutaneous stigmata of occult spinal dysraphism. J Am Acad Dermatol. 1994;31:892–896. 146. Senayli A, Sezer E, Sezer T, et al. Coexistence of sacral dimple, solitary collagenoma and mid-dorsal hypertrichosis in a child with occult spinal dysraphism. Br J Dermatol. 2007;156:1065–1066.

LOCALIZED HYPERTRICHOSIS

HYPERTRICHOSIS CUBITI Figure 11.36  Localized hypertrichosis at the site of a small area of heterotopic brain tissue.

tissue.147 The mechanism of this type of case may be displacement of meningeal cells along nerves during embryogenesis rather than the entrapment of meningeal membranes at the time of closure of the neural tube.148

HYPERTRICHOSIS WITH FOCAL FACIAL DERMAL DYSPLASIA A patient is reported with what is designated as an unusual variant of focal facial dermal dysplasia with symmetrical skin defects at both temples and extending on to the cheeks.149 These were scar-like, circular, atrophic lesions, each surrounded by a fine rim of hair. These lesions are believed to follow an embryological fusion line. It was suggested that perhaps they would be better described under the broader term of bilateral aplasia cutis.

HEMIHYPERTROPHY WITH HYPERTRICHOSIS Hemihypertrophy is a rare congenital disorder in which the whole, or less commonly, part of one side of the body is enlarged. Serious associated malformations include Wilms tumor and tumors of brain and adrenals. The skin is often normal but cutaneous abnormalities reported include pigmentation, telangiectasia, abnormal nail growth, and hypertrichosis, which can be very striking.111,150

LOCALIZED HYPERTRICHOSIS IN ASSOCIATION WITH OTHER NEVI OR TUMORS Congenital melanocytic nevus Congenital melanocytic nevi may be covered at birth with dense, dark terminal hair over part or all of their surface.111 On the

147. Penas PF, Jones-Caballero M, Amigo A, et al. Cutaneous meningioma underlying congenital localised hypertrichosis. J Am Acad Dermatol. 1994;30:363–366. 148. Penas PF, Jones-Caballero M, Garcia-Diez A. Cutaneous heterotopic meningeal nodules. Arch Dermatol. 1995;131:731. 149. Stone N, Burge S. Focal facial dermal dysplasia with a hair collar. Br J Dermatol. 1998;139:1111–1137. 150. Akarsu S, Coskun BK, Aydin AM, et al. Congenital hemihypertrophy with hemihypertrichosis. J Dermatol. 2005;32:478–481.

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scalp, even very flat lesions often have a dense covering of hair which is longer, darker, and coarser than the surrounding scalp hair. In areas other than the scalp, the degree of hairiness of the lesion is usually proportional to its degree of elevation.

Congenital smooth muscle hamartoma and Becker’s nevus

ERUPTIVE VELLUS HAIR CYSTS

Congenital smooth muscle hamartomas present most commonly at birth as slightly raised, firm, pebbly plaques, of background skin color or slightly pigmented, with a varying degree of hypertrichosis.111,151 They most often occur on the trunk or the proximal limbs but may involve other areas, including the scalp. A transient piloerection or elevation of the lesion after it is rubbed (the pseudo-Darier sign) or exposed to cold temperatures is a characteristic feature. Extensive hypertrichosis overlying extensive, widespread smooth muscle hamartomas has been reported.152 Becker’s nevus usually presents in late childhood or adolescence as a patch of thickened, pigmented, hypertrichotic skin but congenital cases have been reported, although usually lacking hypertrichosis in the neonatal period.153 An unusual presentation with congenital bilaterally symmetrical lesions, hypertrichotic at birth, has been reported.154 Controversy remains as to whether Becker’s nevus and congenital smooth muscle hamartoma are in one spectrum151 or are distinct entities.155

Eccrine angiomatous hamartoma Eccrine angiomatous hamartoma presents as a blue-purple, painful nodule or plaque, usually located on a distal extremity.156 Hypertrichosis is a common feature.156

Plexiform neurofibroma There is often hyperpigmentation with irregular outlines over these lesions and hypertrichosis of varying degree may also occur.157 A prominent paraspinal hair whorl has been reported at the site of a deep mediastinal plexiform neurofibroma158 and a similar paraspinal whorl has been described in a neurofibromatosis patient with a posterior mediastinal ganglioneuroma.159

Sclerosing tufted angioma A tufted angioma is a rare congenital or acquired vascular proliferation histologically characterized by multiple separated

151. Holland KE, Galbraith SS. Generalized congenital smooth muscle hamartoma presenting with hypertrichosis, excess skin folds, and follicular dimpling. Pediatr Dermatol. 2008;25:236–239. 152. Glover MT, Malone M, Atherton DJ. Michelin-tire baby syndrome resulting from diffuse smooth muscle hamartoma. Pediatr Dermatol. 1989;6:329–331. 153. Danarti R, Konig A, Salhi A, et al. Becker’s nevus syndrome revisited. J Am Acad Dermatol. 2004;51:965–969. 154. Ferreira MJ, Bajanca R, Fiadeiro T. Congenital melanosis and hypertrichosis in a bilateral distribution. Pediatr Dermatol. 1998;15:290–292. 155. Gagne EJ, Su WPD. Congenital smooth muscle hamartoma of the skin. Pediatr Dermatol. 1993;10:142–145. 156. Pelle MT, Pride HB, Tyler WB. Eccrine angiomatous hamartoma. J Am Acad Dermatol. 2002;47:429–435. 157. Ettl A, Marinkovic M, Koornneef L. Localised hypertrichosis associated with periorbital neurofibroma; clinical findings and differential diagnosis. Ophthalmol. 1996;103:942–948.

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cellular nodules within dermis and subcutaneous fat.160 Each lobule comprises masses of endothelial cells whorled around a pre-existing vascular plexus, and sometimes bulging into the walls of dilated thin-walled vascular spaces giving a tufted appearance. They usually appear clinically as red to brown plaques, or occasionally, as nodules.160 There is a rare clinical variant, preferentially localized to the lower limbs, which progresses to sclerosis.161 The lesions are present at birth or develop in the first weeks of life as erythematous plaques, which extend and become progressively indurated. On microscopic examination, there is fibrosis in addition to the usual histological features. Several of these lesions demonstrated hypertrichosis and increased sweating.

LINEAR MELORHEOSTOTIC SCLERODERMA Melorheostosis is a rare bone dysplasia characterized by eccentric cortical hyperostosis. It has been associated with soft-tissue abnormalities, including vascular lesions and marked dermal thickening, producing a sclerodermoid change.162 Histologically, the dermis contains excessive normal collagen fibers lacking the hyalinization seen in a true linear scleroderma. There may be significant overlying hypertrichosis. Cases are reported with the cutaneous changes of linear melorheostotic scleroderma but with no skeletal changes demonstrable.163

HYPERTRICHOSIS DUE TO LOCAL HEAT AND CUTANEOUS HYPEREMIA There are various situations in which hypertrichosis occurs where the likely pathogenesis is related to local heat and cutaneous hyperemia.164 Examples include sites of PUVA therapy,111 chickenpox scars, insect bites, at the edges of burns, areas of chronic excoriation, under a plaster cast, and over inflamed joints.

ERUPTIVE VELLUS HAIR CYSTS Li-Chuen Wong Eruptive vellus hair cysts are discrete bluish, pale or skin-colored smooth surfaced, soft papules ranging in diameter from 1 to 4 mm, most commonly found on the anterior chest, but also on the upper and lower extremities, the face, neck, posterior trunk and/or buttocks of children and young adults.165,166 The usual

158. Pivnik EK, Lobe TE, Fitch SJ, et al. Hair whorl as an indicator of a mediastinal plexiform neurofibroma. Pediatr Dermatol. 1997;14:196–198. 159. Flannery DB, Howell CG. Confirmation of the Riccardi sign. Proc Greenwood Genet Centre. 1986;6:161. 160. Herron MD, Coffin CM, Vanderhooft SL. Tufted angiomas: Variability of the clinical morphology. Pediatr Dermatol. 2002;19:394–401. 161. Catteau B, Enjolras O, Delaporte E, et al. Angiome en touffes sclerosant. A propos de 4 observations aux membres inferieurs. Ann Dermatol Venereol. 1998;125:682–687. 162. Miyachi Y, Horio T, Yamada A, et al. Linear melorheostotic scleroderma with hypertrichosis. Arch Dermatol. 1979;115:1233–1234. 163. Fimiani M, Rubengi P, de Aloe G, et al. Linear melorheostotic scleroderma with hypertrichosis sine melorheostosis. Br J Dermatol. 1999;141:747–776. 164. Kara A, Kanra G, Alanay Y. Localized acquired hypertrichosis following cast application. Pediatr Dermatol. 2001;18:57–59. 165. Reep MD, Robson KJ. Eruptive vellus hair cysts presenting as multiple periorbital papules in a 13-year-old boy. Pediatr Dermatol. 2002;19:26–27. 166. Baums K, Blume-Peytavi U, Dippel E, et al. Guess what: Eruptive vellus hair cysts. Europ J Dermatol. 2000;10:487–489.

Hair disorders

Table 11.2  Conditions with a primary absence or reduction of color CONDITION

HAIR COLOR

Tyrosinase negative albinism

Hair has no color

Tyrosinase positive albinism

Hair color is diluted, often yellowish

Chediak–Higashi

Silvery color

Griscelli syndrome

Silvery color

Elejalde syndrome

Silvery color

Isolated pili torti

Fairer than expected

Menkes syndrome

Fairer than expected, sometimes silvery

Uncombable hair

Fairer than expected

Phenylketonuria

Alternating light and darker when on and off treatment (flag sign)

Homocystinuria

Probably due to keratinization changes

Oast house disease

Very light, almost white hair

DIFFUSE HYPOPIGMENTATION OF HAIR

age at onset is between ages 4 and 18 years but presence at birth and adult onset are both reported. The development is usually quite fast and then, following a static period, in some cases, spontaneous clearing takes place after several years. On histopathology, there is a cystic structure in the middermis lined by four or five layers of squamous epithelium with a discrete granular layer and filled with laminated and amorphous keratinous material as well as fragments of vellus hairs.166,167 There are no sebaceous glands in the cyst wall as are seen in steatocystoma multiplex. A case has been reported with some umbilicated papules with histological evidence of transepithelial elimination, which may explain the spontaneous disappearance of lesions.168 Kindreds with an autosomal-dominant inheritance pattern have been reported.169 There are reports of families in which milia, eruptive vellus hair cysts, and steatocystoma multiplex all occurred,170 with some individuals showing more than one type of lesion. Hybrid cysts with features of steatocystoma multiplex in one part and eruptive vellus hair cysts in another have also been reported.167 This led to the conclusion that these three disorders should be considered as subtypes of multiple pilosebaceous cysts that may all present overlapping histologic features, with the different level of the sebaceous duct from which the cyst originates explaining the different clinical manifestations. However, this concept is challenged by studies reporting the finding of expression of both keratin 10 and keratin 17 in steatocystoma multiplex but only keratin 17 in eruptive vellus hair cysts.171 Lesions are usually fairly subtle cosmetically and there is a chance of spontaneous involution. However, successful treatment is reported with needle evacuation172 and by the use of an erbium:YAG laser.173 Laser treatment may not be so successful on the face, as depth of ablation is limited by the risk of atrophy or scarring.174 There are anecdotal reports of success with topical retinoids (personal communications, Dr. A. Lucky and Dr. L. Schachner).

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occurs, as a result of nutritional deficiencies, as an acquired reversible condition.

PRIMARY DIFFUSE HYPOPIGMENTATION OF THE HAIR Hair that is hypopigmented from birth is found in a wide range of genetic conditions.175 In some, it is simply fairer than expected but in others it may have a silvery aspect. Some of these conditions are listed in Table 11.2.

PREMATURE CANITIES

ABNORMALITIES OF HAIR COLOR Li-Chuen Wong

DIFFUSE HYPOPIGMENTATION OF HAIR This may be primary and present from birth, particularly in certain genetic conditions; it may appear later as premature graying (premature canities) due to autoimmune diseases and certain syndromes and is usually permanent; and it usually

167. Hurlimann AF, Panizzon RG, Burg G. Eruptive vellus hair cyst and steatocystoma multiplex: Hybrid cysts. Dermatology. 1996;192:64–66. 168. Bovenmeyer DA. Eruptive vellus hair cysts. Arch Dermatol. 1979;115:338–339. 169. Piepkorn MW, Clark L, Lombardi DI. A kindred with congenital vellus hair cysts. J Am Acad Dermatol. 1981;5:661–665. 170. Patrizi A, Neri I, Guerrini V, et al. Persistent milia, steatocystoma multiplex and eruptive vellus hair cysts: variable expression of multiple pilosebaceous cysts within an affected family. Dermatology. 1998;196: 392–396. 171. Tomkova H, Fujimoto W, Arata J. Expressions of keratins (K10 and K17) in steatocystoma multiplex, eruptive vellus hair cysts and epidermoid and trichilemmal cysts. Am J Dermatopathol. 1997;19:250–253.

Canities, or graying of human hair, is caused by a reduction in the activity of melanocytes within hair follicles and is a normal part of the aging process. Premature canities refers to a diffuse loss of color, especially of scalp hair, at an age earlier than that generally accepted as physiologic, before the age of 20 in whites and before age 30 in blacks.175,176 Occasionally, children develop a few gray or white hairs in the apparent absence of any other dermatological or systemic condition but there are some recognized causes of this phenomenon.175,176 Some of the causes of premature canities are listed in Box 11.2. Canities, once established, is usually permanent.

172. Sardy M, Karpati S. Needle evacuation of eruptive vellus hair cysts. Br J Dermatol. 1999;141:594–595. 173. Kageyama N, Tope WD. Treatment of multiple eruptive hair cysts with erbium:YAG laser. Dermatol Surg. 1999;25:819–822. 174. Coras B, Hohenieutner U, Landthaler M, et al. Early recurrence of eruptive vellus hair cysts after Er: YAG laser therapy: case report and review of the literature. Dermatol Surg. 2005;31:1741–1744. 175. Dawber R, Gummer CL. The colour of hair. In: Dawber R, ed. Diseases of the hair and scalp. Oxford: Blackwell Science; 1997:397–417. 176. Tobin D, Cargnello JA. Partial reversal of canities in a 22-year-old normal Chinese male. Arch Dermatol 1992;129:789–791.

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BOX 11.2 PREMATURE CANITIES

Autoimmune diseases

>> Generalized vitiligo >> Widespread alopecia areata >> Pernicious anemia >> Addison disease >> Hypothyroidism >> Hyperthyroidism Syndromes

NON-SCARRING ALOPECIA

>> Progeria >> Werner >> Rothmund–Thomson >> Dyskeratosis congenita >> Down >> Cri du chat >> Book

ACQUIRED REVERSIBLE DIFFUSE HYPOPIGMENTATION Various deficiency states may lead to acquired reversible diffuse hypopigmentation of hair. In protein malnutrition, or kwashiorkor, the hair is lighter than expected. If periods of malnutrition alternate with periods of adequate diet, alternating lighter and darker areas may occur, the so-called flag sign. Lightening of hair is also an occasional feature of severe iron deficiency.177

LOCALIZED HYPOPIGMENTATION (POLIOSIS) Poliosis is defined as a localized patch of white hair due to the absence or deficiency of melanin in a group of neighboring follicles. Some of the causes are covered in Table 11.3.

ALTERATION OF HAIR COLOR DUE TO EXOGENOUS AGENTS There are various drugs which lead to reversible alterations in hair color, but few of these are regularly used in children. Chloroquine interferes with pheomelanin synthesis and, in blond and red-haired individuals, can cause a progressive lightening and silvery coloration.175,178 A similar change has been noted with alpha-interferon.178 Lightening of normally dark hair has also been reported during etretinate therapy.179 There have been no reports of this change with acitretin. There are various chemicals, usually encountered in an industrial setting, which can cause hair discoloration, but the one most relevant to children is copper used as an algae retardant in swimming pools. This causes a green discoloration in blond 177. Sato S, Jitsukawa K, Sato H, et al. Segmented heterochromia in black scalp hair associated with iron deficiency anemia. Arch Dermatol. 1989;125:531–535. 178. Fleming CJ, MacKie RM. Alpha interferon-induced hair discoloration. Br J Dermatol. 1996;135:337–338.

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Table 11.3  Poliosis CONDITION

SYMPTOM

Piebaldism

White forelock

Waardenburg syndrome

White forelock

Tietz syndrome

Multiple white patches

Vitiligo

Patchy

Vogt–Koyanagi–Harada syndrome

Patchy/vitiligo

Alezzandrini syndrome

Patchy/vitiligo

Alopecia areata

Regrowing hair, reversible

Tuberous sclerosis Halo nevus Halo around neurofibroma

Table 11.4  Classification of hair loss NON-SCARRING ALOPECIA

SCARRING ALOPECIA

Telogen effluvium Anagen effluvium Alopecia areata Androgenetic alopecia Hair shaft abnormalities Trauma (e.g., traction) Infectious disorders (e.g., dermatophyte, syphilis) Systemic diseases (e.g., thyroid, systemic lupus erythematosus, iron-deficiency anemia) Intoxications (e.g., vitamin A, bismuth) Nutritional deficiencies   (e.g., zinc, biotin) Medications

Developmental defects   (e.g., aplasia cutis) Infections (bacterial, viral, fungal) Trauma (irradiation, thermal or caustic burns) Neoplastic disorders Lichen planus (lichen planopilaris), lupus erythematosus, morphea, scleroderma, sarcoidosis Keratosis pilaris atrophicans Folliculitis decalvans Dissecting cellulitis of the scalp Acne keloidals Pseudopelade Alopecia mucinosa

hair, which may be reversed with a penicillamine shampoo or the application of a 1-hydroxyethyl diphosphonic acidcontaining solution.180

NON-SCARRING ALOPECIA Yong-Kwang Tay Hair loss disorders can be divided into non-scarring (noncicatricial) and scarring (cicatricial) alopecia (Table 11.4). Causes of non-scarring alopecia include alteration of the hair growth cycle, structural abnormalities of the hair, and trauma. 179. Vesper JL, Fenske NA. Hair darkening and new growth associated with etretinate therapy. J Am Acad Dermatol. 1996;34:860. 180. Melnik BC, Plewig G, Daldrup T, et al. Green hair: guidelines for diagnosis and therapy. J Am Acad Dermatol. 1986;15:1065–1068.

Hair disorders

Physiologic

>> Physiologic effluvium of the newborn >> Postpartum effluvium Injury or stress

>> Emotional stress >> High fever >> Severe infection >> Syphilis >> Severe chronic illness, e.g. chronic renal failure, hepatic failure, advanced malignancy

>> Systemic lupus erythematosus >> Major surgery >> Hypo- or hyperthyroidism >> Crash diets, precipitous decrease of calories or protein >> Iron deficiency >> Zinc deficiency >> Essential fatty acid deficiency >> Biotin deficiency >> Drugs (Box 11.4) >> Idiopathic: In about one-third of cases of acute telogen effluvium, no trigger can be identified186

BOX 11.4 DRUGS ASSOCIATED WITH TELOGEN EFFLUVIUM (INCLUDING BUT NOT LIMITED TO)

>> ACE inhibitors, e.g., captopril,187 enalapril188 >> Albendazole189 >> Amphetamine190 >> Aminosalicylic acid191 >> Anticoagulants e.g., heparin,186 warfarin192 >> Antidepressants,193 e.g., fluoxetine, tricyclic antidepressants >> Antiepileptics, e.g., carbamazepine,194 valproic acid,186 lamotrigine195

>> Antiretrovirals,196,197 e.g., indinavir, ritonavir, lopinavir >> Beta blockers, e.g., metoprolol,198 propranolol199 >> Bromocriptine200 >> Cimetidine201 >> Danazol202 >> Interferons,203 e.g., interferon α >> Levodopa204 >> Lithium205 >> Oral contraceptive pills – during or up to 3 months after discontinuation193

>> Retinoids,206 e.g., etretinate and excess vitamin A >> Pramipexole207 >> Pyridostigmine208

It is calculated that the average human scalp contains 100 000 hairs. The average growth rate of terminal hair is about 2.5 mm/ week (1 cm/month). The human hair follicle has a fairly long phase of growth, the anagen phase, which lasts for a period of 2–6 years, average 3 years. The hairs then undergo a period of involution, the catagen phase lasting about 3 weeks, followed by a resting telogen or club phase, lasting about 3 months. At the end of this period, new growth is initiated. In healthy persons, 80–90% of the scalp is in the actively growing, anagen stage; 5% is in the catagen stage; 10–15% is in the resting, telogen stage; and 50–100 hairs are shed and simultaneously replaced each day.181

During the period of hair growth, the normal cyclic pattern may be interrupted by a variety of different stimuli, resulting in abnormally large numbers of scalp anagen hairs suddenly moving in concert to enter telogen. The resulting increase in hair shedding occurs diffusely over the scalp, usually 6 weeks to 4 months after an inciting event (Fig. 11.37). Second in incidence only to androgenetic alopecia in adults, this disorder likely represents the most common type of alopecia in children.182 The diagnosis of telogen effluvium can often be suspected by history alone. Etiologic factors fall into two groups (Boxes 11.3, 11.4).183,184 In the first group, the effluvium is physiologic in nature and there is no injury to the follicle. Abnormally large numbers of hairs enter telogen because they are programmed to

181. Kligman AM. Pathologic dynamics of human hair loss: 1, Telogen effluvium. Arch Dermatol. 1961;83:175–198. 182. Bedocs LA, Bruckner AL. Adolescent hair loss. Curr Opin Pediatr. 2008; 20:431–435. 183. Sperling LC. Evaluation of hair loss. Curr Probl Dermatol. 1996;8:97. 184. Harrison S, Sinclair R. Telogen effluvium. Clin Exp Dermatol. 2002;27:389–395. 185. Peters EMJ, Liotiri S, Bodo E, et al. Probing the effects of stress mediators on the human hair follicle. Substance P holds central position. Am J Pathol. 2007;171:1872–1886. 186. Headington JT. Telogen effluvium. New concepts and review. Arch Dermatol. 1993;129:356–363. 187. Leaker B, Withworth JA. Alopecia associated with captopril treatment. Aust NZ J Med. 1984;14:866. 188. Ahmad S. Enalapril and reversible alopecia. Arch Intern Med. 1991;151:404. 189. Garcia-Muret MP, Sitjas D, Tuneu L, et al. Telogen effluvium associated with albendazole therapy. Int J Dermatol. 1990;29:669–670. 190. Voron DA. Alopecia and amphetamine use. JAMA. 1988;260:183–184. 191. Kutty PK, Raman KRK, Hawken K, et al. Hair loss and 5-aminosalicylic acid enemas. Ann Intern Med. 1982;97:785–786. 192. Umlas J, Harken DE. Warfarin induced alopecia. Cutis. 1988;42:63–64. 193. Tosti A, Pazzaglia M. Drug reactions affecting hair: Diagnosis. Dermatol Clin. 2007;25:223–231. 194. Shuper A, Stahl B, Weitz R. Carbamazepine-induced hair loss. Drug Intell Clin Pharm. 1985;19:924–925. 195. Patrizi A, Savoia F, Negosanti F, et al. Telogen effluvium caused by magnesium valproate and lamotrigine. Acta Derm Venereol. 2005;85:77–78.

196. Ginarte M, Losada E, Prieto A, et al. Generalized hair loss induced by indinavir plus ritonavir therapy. AIDS. 2002;16:1695–1696. 197. Bongiovanni M, Chiesa E, Monforte A, et al. Hair loss is an HIV-1 infected woman receiving lopinavir plus ritonavir therapy as first line HAART. Dermatol Online J. 2003;9:28. 198. Graeber CW, Lapkin RA. Metoprolol and alopecia. Cutis. 1981;28:633–634. 199. Scribner MD. Propranolol therapy. Arch Dermatol. 1977;113:1303. 200. Blum I, Leiba S. Increased hair loss as a side-effect of bromocriptine treatment. N Engl J Med. 1980;303:1418. 201. Kalsha JH, Praham CF, Jones JK. Cimetidine-associated alopecia. Int J Dermatol. 1983;22:202–204. 202. Duff P, Mayer AR. Generalized alopecia: an unusual complication of danazol therapy. Am J Obstet Gynecol. 1981;141:349–350. 203. Tosti A, Misciali C, Bardazzi F, et al. Telogen effluvium due to recombinant interferon α-2b. Dermatology. 1992;184:124–125. 204. Marshall A, Williams MJ. Alopecia and levodopa. BMJ. 1971;2:47. 205. Dawber R. Hair loss during lithium treatment. Br J Dermatol. 1982;107:124–125. 206. Berth-Jones J, Shuttleworth D, Hutchinson PE. A study of etretinate alopecia. Br J Dermatol. 1990;122:751–755. 207. Katz KA, Cotsarelis G, Gupta R, et al. Telogen effluvium associated with the dopamine agonist pramipexole in a 55-year-old woman with Parkinson’s disease. J Am Acad Dermatol. 2006;55:S103–S104. 208. Field LM. Toxic alopecia caused by pyridostigmine bromide. Arch Dermatol. 1980;116:1103.

TELOGEN EFFLUVIUM

TELOGEN EFFLUVIUM

BOX 11.3 CAUSES OF TELOGEN EFFLUVIUM183,184

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ANAGEN EFFLUVIUM

Figure 11.37  Telogen effluvium. Temporary diffuse alopecia initiated by crash dieting.

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of the dermal papilla adherent to the tip of the root. Telogen hair roots have uniform shaft diameters, contain no pigment, and are club-shaped. The ratio of telogen to anagen hairs varies from one person to another with an average telogen count of 13%.181 A telogen count of ≥25% is abnormal. In the typical case of telogen effluvium, the telogen count does not usually exceed 50%.181 Telogen counts exceeding 70% or 80% do not represent simple telogen effluvium and such cases result from sudden and severe metabolic arrest affecting the actively growing hairs (anagen effluvium).183 The scalp biopsy in the active phase of acute telogen effluvium will show >12–15% of terminal follicles in telogen. However, in the recovery phase of telogen effluvium, the telogen counts may be normal or even low normal.186 If a patient is suspected of having a telogen effluvium and a precipitating factor is not evident from the history or physical examination, a search for an occult disease is justified. A complete blood count, chemistry profile, serum iron/ferritin, and thyroid function tests constitute an acceptable screening panel.183 If indicated, rapid plasma reagin (RPR) to rule out syphilis should be obtained and any abnormalities corrected. There is no effective treatment for telogen effluvium. Spontaneous regrowth occurs and, unless the stressful event is repeated, complete regrowth takes place within 6 months. Careful explanation of the cause of this disorder and its favorable prognosis with strong psychological support and instructions to avoid manipulation, such as vigorous shampooing, combing, and brushing, until new growth has occurred, is generally all that is required.

do so. Telogen effluvium of the newborn and postpartum telogen effluvium are examples. The second category of factors resulting in telogen effluvium involves some sort of injury or stress to the follicles, in response to which many hairs prematurely enter catagen and then telogen phases. Emotional stress has long been implicated as one of the factors involved in hair loss. Recently, substance P, a stress associated neuropeptide, has been shown to cause catagen-inducing and hair damaging pro-inflammatory effects, providing a biological explanation for how stress may trigger or aggravate telogen effluvium and alopecia areata.185 Chronic telogen effluvium refers to telogen shedding lasting >6 months and is common in women between 30 and 50 years of age.209 Affected women commonly present with persistent shedding that runs a fluctuating course over several years and often report a high hair density prior to the onset of hair loss, suggestive of a long anagen phase. The diagnosis of telogen effluvium is suggested by finding a positive hair pull: a lock of hair is grasped between the thumb and forefinger with firm, steady traction applied along the lengths of the hairs. More than six extractable hairs is indicative of active shedding.183 Loss can be estimated by counting the number of hairs shed each day. Loss of >100 hairs/day can be considered excessive. The ratio of resting to growing hairs (the telogen:anagen ratio) can be determined by gently plucking approximately 50 hairs from the patient’s scalp and examining them under a low-power microscope. This can be done by clamping about 50 hairs about 1 cm from the skin surface with a hemostat (the jaws of which have been covered by rubber tubing to prevent trauma to the hair shafts), followed by a gentle but short tug. Anagen hair roots are recognized by the presence of intact outer and inner hair sheaths, with or without a portion

In anagen effluvium, there is marked inhibition of anagen hairmatrix metabolism, such that hair shaft production is greatly diminished.183 Hair loss is profound, since over 80% of scalp hair is normally in anagen at any given time. Causes of anagen effluvium are radiation therapy and chemotherapy and are usually associated with telogen hair loss.193 As follicular metabolism ceases under the influence of chemical toxins or ionizing radiation, the hair shaft tapers to a point and is shed. Hair loss is usually noted from 10 days to 1 month after starting chemotherapy and may be more prominent over the frontal, vertex and parietal areas.210 Chemotherapeutic agents implicated include cyclophosphamide, methotrexate, 6-mercaptopurine, vincristine and doxorubicin.211,212 Alopecia has also been reported after therapeutic doses of colchicine.213 Anagen effluvium has been reported after toxic exposure to boric acid,214 thallium,215 arsenic, and mercury.216 The change in the hair bulb is characteristic and early in the course. A gentle hair pull will yield numerous ‘pencil-point’ dystrophic hairs with proximal tips that taper to a point.183 As hairs are rapidly shed, fewer and fewer anagen shafts are left in the scalp. A hair pluck performed late in the course of the disease

209. Whiting DA. Chronic telogen effluvium: Increased scalp hair shedding in middle aged women. J Am Acad Dermatol. 1996;35:899–906. 210. Chadha V, Shenoi SD. Hair loss in cancer chemotherapeutic patients. IJDVL. 2003;69:131–132. 211. Brien R, Zelson JH, Schwartz AO, et al. Scalp tourniquet to lessen alopecia after vincristine. N Engl J Med. 1970;238:1496. 212. Dean JC, Salmon SE, Griffith KS. Prevention of doxorubicin-induced hair loss with scalp hypothermia. N Engl J Med. 1974;301:1427–1429.

213. Malkinson ED, Lynfield YL. Colchicine alopecia. J Invest Dermatol. 1959; 33:371–374. 214. Stein KM, Odom RB, Justice GR, et al. Toxic alopecia form ingestion of boric acid. Arch Dermatol. 1973;108:95–97. 215. Feldman J, Levisohn DR. Acute alopecia: clue to thallium toxicity. Pediatr Dermatol. 1993;10:29–31. 216. Pierard GE. Toxic effects of metals from the environment on hair growth and structure. J Cutan Pathol. 1979;6:237–242.

ANAGEN EFFLUVIUM

Hair disorders

ALOPECIA AREATA Alopecia areata is characterized by the sudden appearance of sharply defined round or oval patches of hair loss. It is a common disorder, with an incidence of 20.2/100 000 person-years.218 About 1% of the population will have had alopecia areata by the age of 50.219 The condition occurs at all ages, with between 11% and 20% reported to start before the age of 16.220,221 One prospective study of 10 000 children in a pediatric dermatology clinic demonstrated a prevalence of 6.7%, with peak onset between 2 and 6 years of age.222 The female to male ratio is 1 : 1 until adolescence when the disease becomes more common in females.218,223,224 There is a history of familial occurrence in 10– 20% of affected persons.225 Although there are reports of simultaneous occurrence in identical twins,226 and autosomal dominance with incomplete penetrance has been suggested, the genetic status of this disorder is unclear, but a multifactorial mode of inheritance has been proposed.227 In one study, the estimated lifetime risks were 7.1% in siblings, 7.8% in parents and 5.7% in offspring.227

Clinical features The typical picture of alopecia areata consists of a sudden appearance of one or more round, lanceolate or oval well-circumscribed patches of hair loss (Fig. 11.38).228 Patients often report increased hair shedding. The primary patch may appear on any hairy cutaneous surface, e.g., eyebrows (Fig. 11.39), beard area, but it usually occurs on the scalp. The skin is smooth, soft, occasionally slightly pink and almost totally devoid of hair. Short hairs that taper as they approach the scalp are called ‘exclamation-mark hairs’ and, if present, are very characteristic of alopecia areata.183

217. Duvic M, Lemak NA, Valero V, et al. A randomized trial of minoxidil in chemotherapy-induced alopecia. J Am Acad Dermatol. 1996;35:74–78. 218. Safavi KH, Muller SA, Suman VJ, et al. Incidence of alopecia areata in Olmsted county, Minnesota, 1975 through 1989. Mayo Clin Proc. 1995;70: 628–633. 219. Sahn EE. Alopecia areata in childhood. Semin Dermatol. 1995;14:9–14. 220. Tan E, Tay YK, Giam YC. A clinical study of childhood alopecia areata in Singapore. Pediatr Dermatol. 2002;19:298–301. 221. Sharma VK, Kumar B, Dawn G. A clinical study of childhood alopecia areata in Chandigarh, India. Pediatr Dermatol. 1996;13:372–377. 222. Nanda A, Al-Hasawi F, Alsaleh QA. A prospective survey of pediatric dermatology clinic patients in Kuwait: an analysis of 10,000 cases. Pediatr Dermatol. 1999;16:6–11.

Figure 11.38  Alopecia areata with sharply defined oval patches of hair loss.

ALOPECIA AREATA

will consist almost exclusively of telogen hairs (which are spared from the metabolic insult). When the telogen count approaches 100%, a form of anagen effluvium is almost certainly the cause. There is no effective treatment for anagen effluvium. Cessation of the responsible drug or toxin generally results in regrowth of hair. When cytostatic drugs are indicated, the expected hair loss can be minimized to some degree by scalp hypothermia, e.g., by applying ice packs to the scalp for 30 min before the drug is injected.212 Another approach is to use a specially constructed scalp tourniquet placed around the head just above the ears and inflated to 10 mmHg above systolic pressure immediately before injection of the cytostatic drug. This helps to minimize the toxic effects of the drug on the hair follicles.211 Topical minoxidil has been used to inhibit chemotherapy-induced alopecia to some degree.217

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(Courtesy Dr A. Torrelo.)

Figure 11.39  Alopecia areata affecting the lower lid.

These loose hairs are easily plucked out of the scalp and when examined under low power, most will be telogen hairs with a frayed distal tip. Hair regrowth in alopecia areata may occur as depigmented hairs, which may repigment with time, or may remain white. Ophiasis, a term derived from the Greek word ophis for serpent, refers to a pattern of alopecia seen mostly in children. It begins as a bald spot on the posterior occiput, extending anteriorly and bilaterally in a 2.5–5 cm wide band above the ear (Fig. 11.40) and sometimes extending to meet on the anterior aspect of the scalp. This occurs in 80% are loose anagen hairs devoid of sheaths.328 A gentle hair pull performed on a normal scalp will yield telogen hairs and the presence of anagen hairs on a gentle hair pull is abnormal.330 If loose anagen hair syndrome is suspected clinically, and the hair pull test is negative, the diagnosis is not excluded as there are periods where no hairs can be obtained on hair pull and serial re-examination by hair pull is recommended.331 When the bulbs of these shafts are examined microscopically, most or all of the hairs are anagen hairs and the bulbs do not have outer root sheaths, but show a ruffling of the hair shaft.328 This is because the extracted shafts tear away from their root sheaths at the cuticular zone, where the hair shaft cuticle interlocks with the inner root sheath cuticle.330 In loose anagen hair syndrome, the normally tenacious bond between the lower hair shaft and the inner root sheath is pathologically weak, allowing trivial amounts of traction to separate the shaft from the sheath. On scanning electron microscopy, the distal part of the hair shaft shows axial twisting, ridging and fluting with distorted bulbs

320. Keuthen NJ, O’Sullivan RL, Sprich-Buckminster S. Trichotillomania: current issues in conceptualization and treatment. Psychother Psychosom. 1998;67:202–213. 321. Azrin NH, Nunn RG, Frantz SE. Treatment of hair pulling (trichotillomania): a comparative study of habit reversal and negative practice training. Behav Ther Exp Psychiatry. 1980;11:13–20. 322. Van Minnen A, Hoogduin KAL, Keijsers GPJ, et al. Treatment of trichotillomania with behavioral therapy or fluoxetine: a randomized, waiting-list controlled study. Arch Gen Psychiatry. 2003;60:517–522. 323. Swedo SE, Leonard HL, Rapoport JL, et al. A double-blind comparison of clomipramine and desipramine in the treatment of trichotillomania (hair pulling). N Engl J Med. 1989;321:497–501. 324. Baden HP, Kvedar JC, Magro CM. Loose anagen hair as a cause of hereditary hair loss in children. Arch Dermatol. 1992;128:1349–1353.

325. Chapalain V, Winter H, Langbein L, et al. Is the loose anagen syndrome a keratin disorder? Arch Dermatol. 2002;138:501–506. 326. Price VH, Gummer CL. Loose anagen syndrome. J Am Acad Dermatol. 1989;20:249–256. 327. Tosti A, Misciali C, Borrello P, et al. Loose anagen hair in a child with Noonan’s syndrome. Dermatologica. 1991;182:247–249. 328. Tosti A, Peluso AM, Misciali C, et al. Loose anagen hair. Arch Dermatol. 1997;133:1089–1093. 329. Sadick NS. Clinical and laboratory evaluation of AIDS trichopathy. Int J Dermatol. 1993;32:33–38. 330. O’Donnell BP, Sperling LC, James WD. Loose anagen hair syndrome. Int J Dermatol. 1992;31:107–109. 331. Chong AH, Sinclair R. Loose anagen syndrome: a prospective study of three families. Australas J Dermatol. 2002;43:120–124.

LOOSE ANAGEN HAIR SYNDROME

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lacking inner and outer root sheaths, with cuticle scales present distal to the bulb.326,332 The pathological shaft findings observed on micro­scopy are not specific and can also be seen in patients with uncombable hair syndrome.333,334 However, hair cannot be extracted easily in uncombable hair syndrome and typical loose anagen bulbs are not observed. No treatment is available for loose anagen hair syndrome. It is reassuring for patients and their families to know that the appearance of the hair improves with time, with length and density of the hair gradually increasing with age in both children and adults.326,328,331

ANDROGENETIC ALOPECIA ANDROGENETIC ALOPECIA

780

Androgenetic alopecia, also known as common balding or malepattern baldness in men and hereditary thinning or femalepattern baldness in women, is the most common cause of hair loss. It is characterized by progressive, patterned hair loss from the scalp and is caused by circulating androgens in genetically susceptible men and women. It begins in the teens, 20s, or 30s in both sexes and is usually fully expressed by the 40s.335 Malepattern baldness affects up to 70% of all males in later life and female androgenetic alopecia up to 30% of older women.336 Mean age of onset in adolescence is 16.8 years with a male predominance.337 Limited prevalence data suggest that 15% of adolescent men may be affected with androgenetic alopecia.338 These adolescent patients show milder symptoms than adults, have normal serum levels of testosterone and dehydroepiandrosterone sulfate, and a family history of alopecia was found in 72%, which is greater than that reported in adults, which ranges from 30.9% to 64.5%.338 Inheritance of androgenetic alopecia is probably a polygenic trait with heritability from both maternal and paternal sides.339 Therefore, a history of baldness in grandparents and first-degree relatives on both sides of the family should be sought. Dihydrotestosterone is the primary androgen implicated in the pathogenesis of androgenetic alopecia.340 It is formed by the conversion of testosterone by the enzyme 5α-reductase. Androgens gradually transform large scalp hair follicles to smaller follicles over many cycles, resulting in progressively shorter, finer, miniaturized hairs with fewer hair follicles per unit area, which ultimately do not cover the scalp effectively. Most patients with androgenetic alopecia complain of thinning rather than shedding of hair, although early in the course of androgenetic alopecia, hair loss may occur and this has features of a telogen effluvium.183 This is because the duration of anagen growth shortens and hairs cycle through the telogen phase more frequently. In men, the pattern of androgenetic alopecia varies from accentuation of the bitemporal recession,

to frontal and/or vertex thinning, to loss of all hair, except hair along the occipital and temporal margins (Fig. 11.45). Women have diffuse thinning, often worse centrally with the central part appearing widened and the scalp becoming visible. In women, there is often retention of hair along the frontal hairline that may be straight or M-shaped. In fact, there is considerable overlap between the sexes, with many women demonstrating a male pattern of hair loss,341 and some men showing a female pattern with diffuse crown thinning and retention of the frontal hairline. On histology, androgenetic alopecia is characterized by a mixture of hairs with various bulb depths and shaft diameters. Below each miniaturized follicle is a ‘streamer,’ the collapsed connective tissue sheath that once surrounded the formerly deep-seated, terminal hair.342 Miniaturized follicles can be identified on horizontal sections of scalp biopsies and sebaceous lobules appear large in relation to the miniaturized follicles.343 Other features are an increased ratio of telogen to anagen hairs and, in advanced cases, there is an increase in the percentage of vellus and indeterminate hairs compared with terminal hairs. Many biopsy specimens of androgenetic alopecia show mild perifollicular, lymphohistiocytic, upper dermal inflammation. These changes are non-specific and can be found in a high percentage of normal controls.342

332. Dicle O, Velipasaoglu S, Ozenci CC, et al. Report of a new case with loose anagen hair syndrome and scanning electron microscopy findings. Int J Dermatol. 2008;47:936–938. 333. Boyer J, Cobb M, Sperling L, et al. LAHS mimicking the uncombable hair syndrome. Cutis. 1996;57:111–112. 334. Lee AJ, Maino KL, Cohen B, et al. A girl with loose anagen hair syndrome and uncombable, spun-glass hair. Pediatr Dermatol. 2005;22:230–233. 335. Price VH. Androgenetic alopecia and hair growth promotion state of the art: present and future. Clin Dermatol. 1988;6:218–227. 336. Norwood OT. Incidence of female androgenetic alopecia (female pattern alopecia). Dermatol Surg. 2001;27:53–54.

337. Kim BJ, Kim JY, Eun HC, et al. Androgenetic alopecia in adolescents: a report of 43 cases. J Dermatol. 2006;33:696–699. 338. Price VH. Androgenetic alopecia in adolescents. Cutis. 2003;71:115–121. 339. Ellis JA, Stebbing M, Harrap SB. Genetic analysis of male pattern baldness and the 5α-reductase genes. J Invest Dermatol. 1998;110:849–853. 340. Kaufman DK. Androgen metabolism as it affects hair growth in androgenetic alopecia. Dermatol Clin. 1996;14:697–711. 341. Venning VA, Dawber RPR. Patterned androgenetic alopecia in women. J Am Acad Dermatol. 1988;18:1073–1077. 342. Kligman AM. The comparative histopathology of male pattern baldness and senescent baldness. Clin Dermatol. 1988;6:108–118.

Figure 11.45  Androgenetic alopecia in a child. (Courtesy Dr A. Torrelo.)

Men with androgenetic alopecia do not require a laboratory evaluation. In women, hormonal abnormalities of adrenal or ovarian origin, e.g., polycystic ovary syndrome, are less likely if the patient has no menstrual irregularities, infertility, hirsutism, truncal obesity, acanthosis nigricans, acne, virilization, or galactorrhea.344,345 If one or more of the above symptoms is present, it may be useful to evaluate total and free testosterone, dehydroepiandrosterone sulfate, LH, FSH and prolactin.346 Referral to an endocrinologist may be indicated. Without treatment, androgenetic alopecia is progressive.347 Because of the psychosocial impact of hair loss, it is important to explain to the patient the nature of the condition, assess his or her expectations, stress that response to any therapy may be slow, and emphasize that treatment will need to be used long term. The aim of treatment is to retard further thinning of the hair and to promote hair regrowth. Topical minoxidil has been shown to promote hair growth in large controlled clinical studies. The mechanism of action of minoxidil on hair growth promotion is unclear. The hair follicle dermal papilla controls hair growth and minoxidil may be involved in the development of dermal papilla vascularization via stimulation of vascular endothelial growth factor expression.348 Other proposed mechanisms of action include induction of anagen or an increase in anagen duration and enlargement of miniaturized follicules.346 Minoxidil solutions of 2% and 5% have been studied in adults (≥18 years old), and promotes moderate to dense growth in about one-third of subjects.349,350 Minoxidil works equally well on vertex and frontal scalp thinning.349 The 5% topical minoxidil solution is superior to the 2% formulation and works more rapidly in men with androgenetic alopecia.351 Recently, minoxidil was developed into a 5% foam formula which, compared with the 5% minoxidil solution, was noted to be easier to use with lack of dripping, quick absorption and drying.352 A randomized, placebo controlled trial of 5% foam showed a statistically significant increase in hair counts over placebo during a 16-week period of twice-daily usage in men with androgenetic alopecia.352 A 5% topical minoxidil solution has been evaluated in women with female pattern hair loss and was found to be significantly more effective than placebo.353 There was also a trend towards superior efficacy of 5% topical minoxidil solution over the 2% formulation, but this was not consistently

statistically significant.353 Topical minoxidil solution works in women with female pattern hair loss, both with and without hyperandrogenism and in pre- and postmenopausal women alike.346 Minoxidil is applied directly on to the dry scalp, twice daily. Care should be taken to avoid deposition of the drug on hair as this can impart a greasy, flaky appearance, reducing compliance. Hair grooming products can be used subsequently. The drug should be left on the scalp for at least 4 h to maximize absorption.354 Topical minoxidil may initially cause a telogen effluvium beginning 2–8 weeks after treatment initiation. This temporary shedding, resulting from the minoxidil initiated release of telogen hairs as anagen promotion begins, is selflimiting with continued treatment.346 Patients should be forewarned so that treatment is not interrupted. It should be used for at least 1 year before assessing efficacy.349 It has to be used indefinitely to maintain its effect; after stopping treatment, the newly regrown hair is shed within 4–6 months of drug discontinuation.355 Side-effects of topical minoxidil include irritation (itching, dryness, erythema), primarily due to propylene glycol and occasionally allergic contact dermatitis.267 Irritation is common with the 5% minoxidil formulation, which contains more propylene glycol than the 2% minoxidil solution. The use of a tar shampoo, topical steroid scalp lotion, or 2% minoxidil, which contains less propylene glycol, may control the problem.267 Facial and limb hypertrichosis may occur through local transfer of the drug or via a systemic effect.356 The side-effect of hypertrichosis appears to be dose-related (5% > 2% formulation).357 The hypertrichosis disappears after discontinuing the drug and may occur in 3–5% of women, who should be aware of this possibility.349 Minimal systemic absorption of minoxidil can occur with topical use, but serum levels are well below those that produce hemodynamic effects. A large-scale 1 year study on patients who used 2% or 5% topical minoxidil showed no increased risk of cardiovascular events compared with controls.358 There are two isoforms of the human 5α-reductase enzyme. Type I predominates in the sebaceous glands, whereas type II is present in hair follicles and prostate. Oral finasteride, a specific inhibitor of the human type II 5α-reductase that decreases the conversion of testosterone to dihydrotestosterone, has been shown to reduce both serum and scalp skin dihydrotestosterone levels in balding men.359,360

343. Eudy G, Solomon AR. The histopathology of noncicatricial alopecia. Semin Cutan Med Surg. 2006;25:35–40. 344. Price VH, Baden H, DeVillez RL, et al. Guidelines of care for androgenetic alopecia. J Am Acad Dermatol. 1996;35:465–469. 345. Lee AT, Zane LT. Dermatologic manifestations of polycystic ovary syndrome. Am J Clin Dermatol. 2007;8:201–219. 346. Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol. 2005;52:301–311. 347. Rushton DH, Ramsay ID, Norris MJ, et al. Natural progression of male pattern baldness in young men. Clin Exp Dermatol. 1991;16:188–192. 348. Lachgar S, Charveron M, Gall Y, et al. Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells. Br J Dermatol. 1998;138:407–411. 349. Shapiro J, Price VH. Hair regrowth. Therapeutic agents. Dermatol Clin. 1998;16:341–356. 350. DeVillez RL, Jacobs JP, Szpunar CA, et al. Androgenetic alopecia in the female. Treatment with 2% topical minoxidil solution. Arch Dermatol. 1994;130:303–307. 351. Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2002;47:377–385. 352. Olsen EA, Whiting D, Bergfeld W, et al. A multicenter, randomized, placebo-controlled, double-blind clinical trial of a novel formulation of

5% minoxidil topical foam versus placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol. 2007;57:767–774. 353. Lucky AW, Piacquadio DJ, Ditre CM, et al. A randomized, placebocontrolled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004;50:541–553. 354. Ross EK, Shapiro J. Management of hair loss. Dermatol Clin. 2005;23: 227–243. 355. Olsen EA, Weiner MS. Topical minoxidil in male pattern baldness: Effects of discontinuation of treatment. J Am Acad Dermatol. 1987;17:97–101. 356. Peluso AM, Misciali C, Vincenzi C, et al. Diffuse hypertrichosis during treatment with 5% topical minoxidil. Br J Dermatol. 1997;136:118–120. 357. Dawber RP, Rundegren J. Hypertrichosis in females applying minoxidil topical solution and in normal controls. J Eur Acad Dermatol Venereol. 2003;17:271–275. 358. Shapiro J. Safety of topical minoxidil solution: a one-year, prospective, observational study. J Cutan Med Surg. 2003;7:322–329. 359. Waldstreicher J, Fiedler V, Hordinsky M, et al. Effects of finasteride on dihydrotestosterone content of scalp skin in men with male pattern baldness. J Invest Dermatol. 1994;102:615. 360. Ryu HK, Kim KM, Yoo EA, et al. Evaluation of androgens in the scalp hair and plasma of patients with male-pattern baldness before and after finasteride administration. Br J Dermatol. 2006;154:730–734.

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Finasteride 1 mg/day is effective in the treatment of men (≥18 years old) with vertex and frontal male-pattern hair loss in studies up to 2 years in length.361,362 A response to finasteride may be seen as early as 3 months, but patients should be encouraged to continue the treatment for at least 24 months before evaluating it.362 Although there are studies of finasteride in adults,362–368 there are no data on the use of finasteride in subjects under age 18. Continued daily use of 1 mg oral finasteride is needed for sustained benefit, otherwise the benefits are lost in 12 months.361 The incidence of side-effects in the finasteride group was similar to placebo, and the only important side-effect was sexual dysfunction (e.g. decreased libido, decreased semen volume, erectile dysfunction) in 4.2% of men receiving finasteride versus 2.2% on placebo.361 This returned to normal in all cases in which the drug was stopped and in many cases with continued treatment. Finasteride is contraindicated in women who are or may potentially be pregnant, because of the risk that inhibition of conversion of fetal testosterone to dihydrotestosterone could impair virilization of a male fetus. In one open, randomized, comparative trial of 65 men, finasteride therapy was found to be more effective than topical 5% minoxidil in treating androgenetic alopecia.366 Combination therapy with topical 5% minoxidil and finasteride daily has been reported367 and small scale studies suggest that combination therapy may be more effective than monotherapy, but further investigation is needed.368 Men who wish to switch from one treatment to another should continue the original medication in addition to the new agent for at least 3 months before discontinuing it to allow time for the newer drug to reach a point of effectiveness to avoid excessive shedding.346 In certain selected cases, some other treatments may be helpful in women. Spironolactone, an aldosterone antagonist, has been used to treat acne, hirsutism, and androgenetic alopecia. Small open trials have shown some benefit in andro­genetic alopecia with doses of 50–200 mg/day.369 Side-effects of spironolactone are breast soreness and menstrual irregularities.370 Periodic monitoring of serum potassium and blood pressure is recommended. Cyproterone acetate in doses of 50–100 mg/day together with ethinyl estradiol is not available in the USA, but has been successful in preventing progression of hair loss and inducing regrowth.370,371 In exceptional cases, excision of bald scalp with or without tissue expansion, scalp flaps and hair transplantation are options

361. Kaufman KD, Olsen EA, Whiting D, et al. Finasteride in the treatment of men with androgenetic alopecia. J Am Acad Dermatol. 1998;39:578–589. 362. Leyden J, Dunlap F, Miller B, et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol. 1999;40:930–937. 363. The Finasteride Male Pattern Hair Loss Study Group. Long-term (5-year) multinational experience with finasteride 1mg in the treatment of men with androgenetic alopecia. Eur J Dermatol. 2002;12:38–49. 364. Rogers NE, Avram MR. Medical treatments for male and female pattern hair loss. J Am Acad Dermatol. 2008;59:547–566. 365. Price VH, Roberts JL, Hordinsky M, et al. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol. 2000;43:768–776. 366. Arca E, Acikgoz G, Tastan HB, et al. An open, randomized, comparative study of oral finasteride and 5% topical minoxidil in male androgenetic alopecia. Dermatology. 2004;209:117–125. 367. Walsh DS, Dunn CL, James WD. Improvement in androgenetic alopecia (stage V) using topical minoxidil in a retinoid vehicle and oral finasteride. Arch Dermatol. 1995;131:1373–1375.

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in patients with advanced androgenetic alopecia. Hair prostheses are also an option in advanced stages of hair loss.

SCARRING ALOPECIA Yong-Kwang Tay Scarring or cicatricial alopecia is the end result of a wide number of inflammatory processes affecting the pilosebaceous units, resulting in destruction of tissue and consequent permanent scarring alopecia of the affected areas. The scarring may be the result of a developmental defect (aplasia cutis), due to infections (e.g., severe bacterial, viral, or fungal infection), physical trauma (e.g., thermal or caustic burns), neoplastic disorders; various dermatoses (e.g., lichen planus, lupus erythematosus, morphea), keratosis pilaris atrophicans, folliculitis decalvans, dissecting cellulitis of the scalp, acne keloidalis, pseudopelade, and alopecia mucinosa.

KERATOSIS PILARIS ATROPHICANS Keratosis pilaris is a common skin condition characterized by keratinous plugs in the follicular orifices surrounded by a variable degree of erythema over the face, arms and thighs. When rarely atrophy occurs, the condition is called keratosis pilaris atrophicans (KPA). KPA is a group of cutaneous disorders characterized by follicular hyperkeratosis and scarring.372 There are three distinct clinical entities that show KPA: ulerythema ophryogenes (keratosis pilaris atrophicans faciei), atrophoderma vermiculata, and keratosis follicularis spinulosa decalvans (Table 11.5).373 Some authors, however, consider atrophoderma vermiculata the final stage of the inflammatory disorders of ulerythema ophryogenes and keratosis follicularis spinulosa decalvans. Ulerythema ophryogenes, which literally means scarring erythema of the eyebrows, is characterized by redness, keratotic follicular papules and atrophic scarring of the eyebrows, classically involving the outer half. The disorder may extend to include the cheeks, forehead and scalp with resulting scarring, atrophy and occasionally alopecia.374 Ulerythema ophryogenes is frequently accompanied by keratosis pilaris of the arms and thighs. The symptoms present from birth or infancy and inheritance is autosomal dominant. Progression of the disease usually ceases after puberty. Association of ulerythema ophryogenes with

368. Khandpur S, Suman M, Reddy BS. Comparative efficacy of various treatment regimens for androgenetic alopecia in men. J Dermatol. 2002;29:489–498. 369. Burke BM, Cunliffe WJ. Oral spironolactone therapy for female patients with acne, hirsutism or androgenic alopecia. Br J Dermatol. 1985;112:124–125. 370. Birch MP, Lalla SC, Messenger AG. Female pattern hair loss. Clin Exp Dermatol. 2002;27:383–388. 371. Vexiau P, Chaspoux C, Boudou P, et al. Effects of minoxidil 2% vs. cyproterone acetate treatment on female androgenetic alopecia: a controlled, 12-month randomized trial. Br J Dermatol. 2002;146:992–999. 372. Baden HP, Byers HR. Clinical findings, cutaneous pathology and response to therapy in 21 patients with keratosis pilaris atrophicans. Arch Dermatol. 1994;130:469–475. 373. Bassioukas K, Fragidou M, Nakuci M, et al. Atrophoderma vermiculata. Cutis. 1997;59:337–340. 374. Callaway SR, Lesher JL. Keratosis pilaris atrophicans: case series and review. Pediatr Dermatol. 2004;21:14–17.

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Table 11.5  Classification of keratosis pilaris atrophicans ATROPHODERMA VERMICULATA

ULERYTHEMA OPHRYOGENES

KERATOSIS FOLLICULARIS SPINULOSA DECALVANS

Skin lesions

Erythematous papules, follicular plugs, horn cysts, atrophic scars

Follicular papules, plugging, scarring

Milia, thornlike follicular projections, atrophic scars

Sites

Cheeks, neck, limbs

Lateral eyebrows, extending medially

Scalp, eyebrows, eyelashes, cheeks, nose, neck, dorsal hands, fingers

Alopecia

Absent

Minimal, eyebrows

Scarring alopecia of the scalp

Absent

Absent

Marked, corneal opacities

Inheritance

Sporadic or autosomal dominant

Sporadic or autosomal dominant

Sporadic or X-linked recessive

Noonan syndrome,375,376 wooly hair,377,378 Cornelia de Large syndrome379 and Rubinstein–Taybi syndrome380 has been described. Atrophoderma vermiculata has its onset between 5 and 12 years of age, occasionally later. It starts with erythema and inflammatory follicular hyperkeratosis on the cheeks leading to pit-like honeycomb scarring.373 Generally measuring 1–2 mm across and 1 mm deep, these cribriform lesions with sharp edges are separated by narrow ridges of normal-appearing skin (Fig. 11.46). Other sites of involvement are the neck and the extensor surface of the limbs. It is thought to be of either sporadic or autosomal-dominant inheritance.373 Keratosis follicularis spinulosa decalvans is characterized by follicular hyperkeratosis of the skin, corneal dystrophy, photophobia, scarring alopecia of the scalp, and absent eyebrows and eyelashes.381 Other findings are hyperkeratosis of the calcaneal region of the soles and a high cuticle on the nails. Symptoms usually improve spontaneously at puberty. Inheritance of keratosis follicularis spinulosa decalvans is X-linked recessive, and the gene has been localized to Xp21.2–p22.2,382 which has subsequently been narrowed down to Xp22.13–p22.2.383,384 Aminoaciduria has been associated with keratosis follicularis spinulosa decalvans.385 The primary defect of keratosis pilaris atrophicans appears to be abnormal keratinization of the follicular infundibulum, which results in obstruction of the growing hair shaft, pro­ ducing a chronic inflammatory infiltrate with scarring below that level.372 It is not surprising that topical therapies are unsuccessful, as the abnormality is present deep in the follicle. Scarring may also limit penetration. Keratolytics and topical corticosteroids are of some help in reducing the keratotic and inflammatory components of keratosis pilaris atrophicans, but the effect is only partial. Other treatments used have 375. Pierini DO, Pierini AM. Keratosis pilaris atrophicans faciei (ulerythema ophryogenes): a cutaneous marker in the Noonan syndrome. Br J Dermatol. 1979;100:409–416. 376. Snell JA, Mallory SB. Ulerythema ophryogenes in Noonan syndrome. Pediatr Dermatol. 1990;7:77–78. 377. Neild VS, Pegum JS, Wells RS. The association of keratosis pilaris atrophicans and woolly hair, with and without Noonan’s syndrome. Br J Dermatol. 1984;110:357–362. 378. McHenry PM, Nevin NC, Bingham EA. The association of keratosis pilaris atrophicans with hereditary woolly hair. Pediatr Dermatol. 1990;7:202–204. 379. Florez A, Fernandez-Redondo V, Toribio J. Ulerythema ophryogenes in Cornelia de Lange syndrome. Pediatr Dermatol. 2002;19:42–45. 380. Gomez Centeno P, Roson E, Peteiro C, et al. Rubinstein-Taybi syndrome and ulerythema ophryogenes in a 9-year-old boy. Pediatr Dermatol. 1999;16:134–136.

KERATOSIS PILARIS ATROPHICANS

Photophobia

Figure 11.46  Atrophoderma vermiculata in a child with Bazex–Dupré– Christol syndrome. (Courtesy Dr A. Torrelo.)

included antibiotics, dapsone, intralesional steroids, tretinoin, and ultraviolet radiation. There has not been any consistent benefit with any of these modalities.386 In stable atropho­ derma vermiculata, dermabrasion, laser resurfacing and collagen implants have been used to improve the cosmetic appearance. Pulsed dye laser treatment may help to lighten 381. Oranje AP, Molewaterplein LDM, Van Osch LDM, et al. Keratosis pilaris atrophicans. Arch Dermatol. 1994;130:500–502. 382. Oosterwijk JC, Nelen M, van Zandvoort PM, et al. Linkage analysis of keratosis follicularis spinulosa decalvans and regional assignment to human chromosome Xp21.2–p22.2. Am J Hum Genet. 1992;50:801–807. 383. Oosterwijk JC, Richard G, van der Wielen MJ, et al. Molecular genetic analysis of two families with keratosis follicularis spinulosa decalvans: refinement of gene localization and evidence for genetic heterogeneity. Human Genet. 1997;100:520–524. 384. Porteous MEM, Strain L, Logie LJ, et al. Keratosis follicularis spinulosa decalvans: confirmation of linkage to Xp22.13–p22.2. J Med Genet. 1998;35:336–337. 385. Rand R, Baden HP. Keratosis follicularis spinulosa decalvans – report of two cases and literature review. Arch Dermatol. 1983;199:22–26. 386. Arreita E, Milgram-Sterngerg Y. Honeycomb atrophy on the right cheek. Arch Dermatol. 1988;124:1101–1104.

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the erythema associated with keratosis pilaris atrophicans but does not improve the associated skin roughness.387 One case report has demonstrated long-term suppression of atropho­ derma vermiculata with oral isotretinoin, provided that it is given during the active inflammatory stage before scarring develops,388 although others have reported only a transient remission of the inflammatory changes on the scalp with isotretinoin.389

FOLLICULITIS DECALVANS

FOLLICULITIS DECALVANS

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Folliculitis decalvans is a rare form of recurrent, patchy, painful neutrophilic folliculitis of the scalp causing scarring and resultant hair loss. The scalp alone may be involved or it may extend to the axillae, pubic region, and trunk.390 There are multiple rounded or irregular bald atrophic patches, each surrounded by crops of follicular pustules with crusting (Fig. 11.47). Successive crops of pustules continue peripherally, each followed by destruction of the affected follicles, producing slow extension of the alopecia. Folliculitis decalvans affects both sexes, typically affecting women aged 30–60 years and men from adolescence onwards. Familial disease has been described in identical twins.391 Tufted folliculitis is a variant of this entity in which there is progressive folliculitis of the scalp that resolves with irregular areas of scarring alopecia in which numerous hair tufts emerge from dilated follicular openings.392,393 Other authors consider tufted folliculitis to be a non-specific form of cicatricial alopecia because of its occurrence in a wide range of unrelated cicatrizing disorders.394,395 The cause of folliculitis decalvans is still uncertain. Staphylococcus aureus can nearly always be grown from the pustules and it is possible that folliculitis decalvans may be the result of an abnormal host response to toxins released from S. aureus.393 The early histopathologic features include acneiform infundibular dilatation and an intrafollicular and perifollicular neutrophilic infiltrate affecting the upper and middle parts of the follicle. With disease progression, the infiltrate becomes mixed, with neutrophils, lymphocytes, plasma cells and foreign-body giant cells. Late-stage disease is characterized by follicular and adventitial dermal fibrosis.396 Early folliculitis decalvans lesions are characterized by an infiltration of activated T-helper cells with a mixed TH1/TH2 pattern. Interleukin (IL)-8 and intercellular adhesion molecule (ICAM)-1 may contribute to the infiltration of neutrophils, whereas basic fibroblast growth factor (b-FGF) and transforming growth factor (TGF)-β may be important mediators of the fibrosis that characterizes late-phase disease.397

Bacterial cultures should be taken from an intact pustule and antibiotic sensitivities determined. A nasal swab should be performed to identify an occult S. aureus reservoir.398 The patient should be advised to shampoo daily with an antiseptic cleanser, e.g., triclosan, and intranasal eradication of S. aureus with topical antibacterial agents may be useful.398 Systemic antibiotics (such as cloxacillin, erythromycin, tetracycline, doxycycline, minocycline or co-trimoxazole) starting at the doses used to treat acne vulgaris with gradual tapering over several months will often prevent extension of the disease.398,399 There is often rapid relapse after stopping treatment and the patient may have to stay on low dose antibiotics for many years. Oral antibiotics may be combined with topical antibiotics such as 2% mupirocin, 1% clindamycin or 2% erythromycin and topical antibiotics alone may be sufficient for very mild cases.398 Oral fusidic acid and oral zinc sulfate together with topical fusidic acid have helped some patients.400 Rifampicin 600 mg daily for 10 weeks led to resolution of the symptoms and no recurrence for 1 year.401 A combination of oral rifampicin 300 mg twice daily and oral clindamycin 300 mg twice daily for 10 weeks has been reported to produce

387. Clark SM, Mills CM, Lanigan SW. Treatment of keratosis pilaris atrophicans with the pulsed tunable dye laser. J Cutan Laser Ther. 2000;2: 151–156. 388. Weightmann W. A case of atrophoderma vermiculata responding to isotretinoin. Clin Exp Dermatol. 1998;23:89–91. 389. Lernia VD, Ricci C. Folliculitis spinulosa decalvans: an uncommon entity within the keratosis pilaris atrophicans spectrum. Pediatr Dermatol. 2006; 23:255–258. 390. Bogg A. Folliculitis decalvans. Acta Derm Venereol (Stockh). 1963;43:14–24. 391. Douwes KE, Landthaler M, Szeimies RM. Simultaneous occurrence of folliculitis decalvans capillitis in identical twins. Br J Dermatol. 2000;143:195–197. 392. Annessi G. Tufted folliculitis of the scalp: a distinctive clinicohistological variant of folliculitis decalvans. Br J Dermatol. 1998;138:799–805. 393. Powell JJ, Dawber RPR, Gatter K. Folliculitis decalvans including tufted folliculitis: Clinical, histological and therapeutic findings. Br J Dermatol. 1999;140:328–333.

394. Pujol RM, Garcia-Patos V, Ravella-Mateu A, et al. Tufted hair folliculitis: a specific disease? Br J Dermatol. 1994;130:259–260. 395. Petronic-Rosic V, Krunic A, Mijuskovic M, et al. Tufted hair folliculitis: a pattern of scarring alopecia? J Am Acad Dermatol. 1999;41:112–114. 396. Ross EK, Tan E, Shapiro J. Update on primary cicatricial alopecias. J Am Acad Dermatol. 2005;53:1–37. 397. Chiarini C, Torchia D, Bianchi B, et al. Immunopathogenesis of folliculitis decalvans: clues in early lesions. Am J Clin Pathol. 2008;130:526–534. 398. Otberg N, Kang H, Alzolibani AA, et al. Folliculitis decalvans. Dermatol Ther. 2008;21:238–244. 399. Tan E, Martinka M, Ball N, et al. Primary cicatricial alopecias: Clinicopathology of 112 cases. J Am Acad Dermatol. 2004;50:25–32. 400. Abeck D, Korting HC, Braun-Falco O. Folliculitis decalvans. Long-lasting response to combined therapy with fusidic acid and zinc. Acta Derm Venereol (Stockh). 1992;72:143–145. 401. Brozena SJ, Cohen LE, Fenske NA. Folliculitis decalvans – response to rifampin. Cutis. 1988;42:512–515.

Figure 11.47  Folliculitis decalvans. Irregular bald atrophic patches with follicular pustules. (Courtesy Dr A. Torrelo.)

Hair disorders

DISSECTING CELLULITIS OF THE SCALP Dissecting cellulitis of the scalp, also termed perifolliculitis capitis abscedens et suffodiens (PCAS), is an uncommon, chronic, inflammatory disease of the scalp characterized by painful fluctuant nodules and abscesses interconnected by tortuous ridges or deep sinus tracts with scarring alopecia. Pressure applied to one nodule often causes pus to emerge from interconnected nodules and sinuses several centimeters away. The process most commonly begins at the vertex or occiput and may progress to involve the entire scalp. It may be associated with acne conglobata and hidradenitis suppurativa to form the follicular occlusion triad or tetrad, if pilonidal cysts are included.408

402. Brooke RCC, Griffiths CEM. Folliculitis decalvans. Clin Exp Dermatol. 2001;26:120–122. 403. Paquet P, Pierard GE. Dapsone treatment of folliculitis decalvans. Ann Dermatol Venereol. 2004;131:195–197. 404. Goo B, Chung HJ, Chung WG, et al. Intramuscular immunoglobulin for recalcitrant suppurative diseases of the skin: a retrospective review of 63 cases. Br J Dermatol. 2007;157:563–568. 405. Walker SL, Smith HR, Lun K, et al. Improvement of folliculitis decalvans following shaving of the scalp. Br J Dermatol. 2000;142:1245–1246. 406. Parlette EC, Kroeger N, Ross EV. Nd: YAG laser treatment of recalcitrant folliculitis decalvans. Dermatol Surg. 2004;30:1152–1154. 407. Yip L, Ryan A, Sinclair R. Squamous cell carcinoma arising within folliculitis decalvans. Br J Dermatol. 2008;159:481–482. 408. Koca R, Altinyazar HC, Ozen OI, et al. Dissecting cellulitis in a white male: response to isotretinoin. Int J Dermatol. 2002;41:509–513. 409. Ramesh V. Dissecting cellulitis of the scalp in 2 girls. Dermatologica. 1990; 180:48–50. 410. Jolliffe DS, Sarkany I. Perifolliculitis capitis abscedens et suffodiens (dissecting cellulitis of the scalp). Clin Exp Dermatol. 1997;2:291–293. 411. Sperling LC. Inflammatory tinea capitis (kerion) mimicking dissecting cellulitis. Int J Dermatol. 1991;30:190–192. 412. Gilliam AC, Lessin SR, Wilson DM, et al. Folliculotropic mycosis fungoides with large-cell transformation presenting as dissecting cellulitis of the scalp. J Cutan Pathol. 1997;24:169–175. 413. Karpouzis A, Giatromanolaki A, Sivridis E, et al. Perifolliculitis capitis abscedens et suffodiens successfully controlled with topical isotretinoin. Eur J Dermatol. 2003;13:192–195.

Dissecting cellulitis is seen primarily in persons between 18 and 40 years of age, although it has been reported in children.409 The disease occurs in whites and blacks, with a greater frequency in the latter, and men are affected more frequently than women (4 : 1).410 Inflammatory tinea capitis (kerion)411 and folliculotropic mycosis fungoides412 may mimic dissecting cellulitis. The central pathogenic event is thought to be follicular hyperkeratosis leading to obstruction and retention of follicular products, secondary bacterial infection and follicular destruction.413 Tissue cultures are usually negative or grow a mixed flora. An immunologic reaction to Propionibacterium acnes may also play a role.414 In the acute suppurative phase, there is an acneiform dilation of the follicular infundibulum with intra- and perifollicular accumulation of neutrophils and subsequent follicular perforation. Later, keratogenous debris incites a granulomatous response with dermal fibrosis surrounding sinus tracts. The abscesses are composed of neutrophils and plasma cells and partially lined with squamous epithelium derived from the overlying epidermis or adjacent follicular epithelium. The disease follows a chronic relapsing course and is generally considered benign. However, metastasizing squamous cell carcinoma has developed in a long-standing lesion.415 There are reports of arthropathy associated with PCAS, such as SAPHO syndrome (synovitis, acne, palmoplantar pustulosis, hyperostosis, osteitis)416 and spondylarthopathy.417 Active skin disease usually precedes onset of the arthritis. Treatment options include numerous non-surgical and surgical modalities or a combination of both. Broad-spectrum systemic antibiotics, such as tetracycline or erythromycin, are effective in some cases.418 Trimethoprim (100 mg twice daily),417 clindamycin (600 mg every 8 h for 6 weeks) combined with topical isotretinoin,419 ciprofloxacin (250 mg twice daily),420 and rifampicin and oral isotretinoin421 have been reported to improve individual patients. Clindamycin gel combined with isotretinoin gel applied topically for 2 months, followed by isotretinoin gel alone for a further 8 months, resulted in a 1-year remission in one patient.413 Recently, adalimumab, a tumor necrosis factor blocker, was successfully used to treat a patient with longstanding disease.422 Topical antibiotics, antibacterial soaps, and

DISSECTING CELLULITIS OF THE SCALP

good results.393,402 In those unable to tolerate clindamycin, oral ciprofloxacin or clarithromycin may be substituted. Potent topical and intralesional corticosteroids can help curb the acute inflammation and should be used in combination with antibiotics.398,399 The addition of oral prednisone can improve efficacy, but should only be considered for highly active and rapidly progressing cases, and adverse effects with long-term use are prohibitive.396 Limited data on isotretinoin suggest variable results but some patients may respond at a dose of 1 mg/kg maintained for at least 6 months before tapering the dose.399 Dapsone can be considered a treatment option based on its anti-inflammatory action directed to the neutrophil metabolism. Dapsone at a dose of 75–100 mg daily has achieved disease remission but relapse occurs after treatment is stopped, and long-term treatment with 25 mg daily may stabilize the disease.403 Isolated reports of administration of intramuscular human immunoglobulin,404 shaving405 and laser epilation with Nd:YAG laser406 suggest some benefits for patients suffering from therapyresistant folliculitis decalvans. Squamous cell carcinoma arising within an area of folliculitis decalvans has been reported and the appearance of a nodule or ulcer requires assessment and biopsy if neoplasia is suspected.407

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414. Stites PC, Boyd AS. Dissecting cellulitis in a white male: A case report and review of the literature. Cutis. 2001;67:37–40. 415. Curry SS, Gaither DH, King LE Jr. Squamous cell carcinoma arising in dissecting perifolliculitis of the scalp: a case report and review of secondary squamous cell carcinomas. J Am Acad Dermatol. 1981;4: 673–678. 416. Libow LF, Friar DA. Arthropathy associated with cystic acne, hidradenitis suppurativa, and perifolliculitis capitis abscedens et suffodiens: treatment with isotretinoin. Cutis. 1999;64:87–90. 417. Salim A, David J, Holder J. Dissecting cellulitis of the scalp with associated spondyloarthropathy: case report and review. J Eur Acad Dermatol Venereol. 2003;17:689–691. 418. Moyer DG, Williams RM. Perifolliculitis capitis abscedens et suffodiens: a report of six cases. Arch Dermatol. 1962;85:378–384. 419. Brook I. Recovery of anaerobic bacteria from a case of dissecting cellulitis. Int J Dermatol. 2006;45:168–169. 420. Greenblatt DT, Sheth N, Teixeira F. Dissecting cellulitis of the scalp responding to oral quinolones. Clin Exp Dermatol. 2008;33:99–100. 421. Georgala S, Korfitis C, Ioannidou D, et al. Dissecting cellulitis of the scalp treated with rifampicin and isotretinoin: case reports. Cutis. 2008;82:195–198. 422. Sukhatme SV, Lenzy YM, Gottlieb AB. Refractory dissecting cellulitis of the scalp treated with adalimumab. J Drugs Dermatol. 2008;7:981–983.

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ACNE KELOIDALIS

topical and intralesional corticosteroids have also been used as adjuncts. Oral zinc sulfate has been reported to induce complete clearing of lesions by some423,424 but not all investigators.425 Surgical interventions include incision and drainage of painful nodules,409,426 complete scalp extirpation with skin grafting,427 and carbon dioxide laser ablation.428 Laser epilation using electron beam radiation,429 800-nm pulsed diode laser,430 and long-pulsed Nd:YAG laser431,432 have been reported as successful in patients with severe, treatment-refractory disease. Permanent hair loss may ensue; however, it is argued that this side-effect is preferable to active disease. Isotretinoin is the systemic drug of choice.408,414,425,426,433 Scerri et al. consider isotretinoin a first-line treatment, using an initial dose of 1 mg/kg per day and a maintenance dose of at least 0.75 mg/kg per day after clinical control is achieved. Treatment should be continued for at least 4 months after the disease appears clinically inactive to reduce recurrence.425

ACNE KELOIDALIS Acne keloidalis (folliculitis keloidalis nuchae) is a chronic scarring folliculitis that begins as small, smooth, firm papules with occasional pustules that occur on the occipital area of the scalp and nape of the neck (Fig. 11.48). With time, the papules coalesce into firm, hairless keloid-like plaques that can be painful and cosmetically disfiguring. Abscesses and sinuses exuding pus may be present in advanced cases.434 Patients often complain of burning and itching. It is seen most frequently in postpubertal males, especially blacks between the ages of 14 and 25, although it also occurs in white males and black women. Recent population studies report a prevalence of acne keloidalis nuchae of 0.67% in African school boys (6–21 years), being more common in older boys who have frequent haircuts.295 Among African men, an incidence of 9.4% was reported from a dermatologic department of a teaching hospital.435 The cause of acne keloidalis remains unclear. Constant irritation by shirt collars, football helmets, low-grade bacterial 423. Berne B, Venge P, Ohman S. Perifolliculitis capitis abscedens et suffodiens (Hoffman): complete healing associated with oral zinc therapy. Arch Dermatol. 1985;121:1028–1030. 424. Kobayashi H, Aiba S, Tagami H. Successful treatment of dissecting cellulitis and acne conglobata with oral zinc. Br J Dermatol. 1999;141:1136–1138. 425. Scerri L, Williams HC, Allen BR. Dissecting cellulitis of the scalp: response to isotretinoin. Br J Dermatol. 1996;134:1105–1108. 426. Khaled A, Zeglaoui F, Zoghlami A, et al. Dissecting cellulitis of the scalp: response to isotretinoin. J Eur Acad Dermatol Venereol. 2007;21:1430–1431. 427. Bellew SG, Nemerofsky R, Schwartz RA, et al. Successful treatment of recalcitrant dissecting cellulitis of the scalp with complete scalp excision and split-thickness skin graft. Dermatol Surg. 2003;29:1068–1070. 428. Glass LF, Berman B, Laub D. Treatment of perifolliculitis capitis abscedens et suffodiens with the carbon dioxide laser. J Dermatol Surg Oncol. 1989;15:673–676. 429. Chinnaiyan P, Tena LB, Brenner MJ, et al. Modern external beam radiation therapy for refractory dissecting cellulitis of the scalp. Br J Dermatol. 2005;152:777–779. 430. Boyd AS, Binhlam JQ. Use of an 800-nm pulsed-diode laser in the treatment of recalcitrant dissecting cellulitis of the scalp. Arch Dermatol. 2002;138:1291–1293. 431. Parlette EC, Kroeger N, Ross EV. Nd:YAG laser treatment of recalcitrant folliculitis decalvans. Dermatol Surg. 2004;30:1152–1154. 432. Krasner BD, Hamzavi FH, Murakawa GJ, et al. Dissecting cellulitis treated with the long-pulsed Nd:YAG laser. Dermatol Surg. 2006;32:1039–1044.

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Figure 11.48  Acne keloidalis. A chronic scarring folliculitis at the nape of the neck.

infection, curved ingrown hairs after a close haircut, chronic scratching, and an autoimmune process have all been suggested as pathogenic mechanisms.434–437 Ciclosporin-induced hypertrichosis has been reported to cause acne keloidalis nuchae following organ transplantation.438,439 The size of the lesions is thought to depend on the existence or repetition of irritant factors.440 It has been proposed that acne keloidalis is a primary form of scarring alopecia with its histology resembling that seen in other forms of cicatricial alopecia, such as the follicular degeneration syndrome.441 The histology of early lesions consists of dilatation of the follicular infundibulum similar to that seen in folliculitis decalvans. Intrafollicular neutrophilic inflammation fills the infundibulum and isthmus in inflammatory lesions. Later, there is a chronic, perifollicular lymphocytic and plasmacytic inflammation, most intense at the level of the isthmus and lower infundibulum, with granulomatous inflammation and scarring. Other findings are lamellar fibroplasia, complete disappearance of sebaceous glands, thinning of the follicular epithelium, and total epithelial destruction, with residual ‘naked’ hair fragments.441,442 Herzberg 433. Bjellerup M, Wallengren J. Familial perifolliculitis capitis abscedens et suffodiens in two brothers successfully treated with isotretinoin. J Am Acad Dermatol. 1990;23:752–753. 434. Dinehart SM, Herzberg AJ, Kerns BJ, et al. Acne keloidalis: a review. J Dermatol Surg Oncol. 1989;15:642–647. 435. Salami T, Omeife H, Samuel S. Prevalence of acne keloidalis nuchae in Nigerians. Int J Dermatol. 2007;46:482–484. 436. Knable AL, Hanke CW, Gonin R. Prevalence of acne keloidalis nuchae in football players. J Am Acad Dermatol. 1997;37:570–574. 437. Burkhart CG, Burkhart CN. Acne keloidalis is lichen simplex chronicus with fibrotic keloidal scarring. J Am Acad Dermatol. 1998;39:661. 438. Azurdia RM, Graham RM, Weismann K, et al. Acne keloidalis in caucasian patients on ciclosporin following organ transplantation. Br J Dermatol. 2000;143:465–467. 439. Carnero L, Silvestre JF, Guijarro J, et al. Nuchal acne keloidalis associated with ciclosporin. Br J Dermatol. 2001;144:429–430. 440. Adegbidi H, Atadokpede F, do Ango-Padonou F, et al. Keloid acne of the neck: epidemiological studies over 10 years. Int J Dermatol. 2005;44(Suppl 1):49. 441. Sperling LC, Homoky C, Pratt L, et al. Acne keloidalis is a form of primary scarring alopecia. Arch Dermatol. 2000;136:479–484. 442. Herzberg AJ, Dinehart SM, Kerns BJ, et al. Acne keloidalis. Transverse microscopy, immunohistochemistry and electron microscopy. Am J Dermatopathol. 1990;12:109–121.

Hair disorders

PSEUDOPELADE OF BROCQ The term pseudopelade of Brocq refers to a slowly progressive cicatricial alopecia, with no clinically evident folliculitis and no marked inflammation. It may be the end result of several different forms of scarring alopecia such as discoid lupus erythematosus or lichen planopilaris,450,451 although a specific, distinct clinically uninflamed type unrelated to other known forms of scarring alopecia has been recognized.452,453 It is generally seen in adults, with an onset between 25 and 45 years of age, although childhood cases have been reported.454,455 There is a female predominance (3 : 1).452 The condition is usually sporadic, although

443. Callender VD, Young CM, Haverstock CL, et al. An open label study of clobetasol propionate 0.05% and betamethasone valerate 0.12% foams in the treatment of mild to moderate acne keloidalis. Cutis. 2005;75:317–321. 444. Quarles FN, Brody H, Badreshia S, et al. Acne keloidalis nuchae. Dermatol Ther. 2007;20:128–132. 445. Kantor GR, Ratz JL, Wheeland RG. Treatment of acne keloidalis nuchae with carbon dioxide laser. J Am Acad Dermatol. 1986;14:263–267. 446. Glenn MJ, Bennett RG, Kelly AP. Acne keloidalis nuchae: Treatment with excision and second-intention healing. J Am Acad Dermatol. 1995;33: 243–246. 447. Bajaj V, Langtry JAA. Surgical excision of acne keloidalis nuchae with secondary intention healing. Clin Exp Dermatol. 2008;33:53–55. 448. Gloster HM Jr. The surgical management of extensive cases of acne keloidalis nuchae. Arch Dermatol. 2000;136:1376–1379. 449. Shah GK. Efficacy of diode laser for treating acne keloidalis nuchae. Indian J Dermatol Venereol Leprol. 2005;71:31–34. 450. Silvers DN, Katz BE, Young AW. Pseudopelade of Brocq is lichen planopilaris: Report of four cases that support this nosology. Cutis. 1993;51:99–105. 451. Amato L, Mei S, Massi D, et al. Cicatricial alopecia; a dermatopathologic and immunopathologic study of 33 patients (pseudopelade of Brocq is not a specific clinico-pathologic entity). Int J Dermatol. 2002;41:8–15.

familial cases with an autosomal-dominant pattern have been reported.456 Pseudopelade accounted for 24% of cases of cicatricial alopecia seen during a 5-year period from one center.399 Clinically, the alopecia consists of round to irregularly shaped patches of alopecia most commonly located on the parietal area and vertex of the scalp.396 Mild perifollicular erythema may be present, but pseudopelade usually lacks prominent inflammation or follicular hyperkeratosis. Indeed, asymptomatic scarring alopecia without inflammation or scales is the initial clue for the diagnosis of pseudopelade.457 Affected areas are shiny, ivorywhite with a slightly depressed, atrophic surface giving rise to the classic description of ‘footprints in the snow.’458 Interspersed between the patches may be a few hair-containing dilated hair follicles. Beard involvement459 and eyebrow loss460 with pseudopelade have been reported. On histology, early lesions are characterized by perifollicular and perivascular lymphocytic infiltrates without interface changes. As the alopecia develops, the infundibular epithelium becomes atrophic, and in advanced lesions, the follicular epithelium is destroyed and only naked hair shafts surrounded by histiocytic and foreign-body giant cell inflammation remain. Characteristic concentric lamellar fibroplasia surrounds inflamed follicles. Sebaceous glands are destroyed and deposits of elastic tissue may occur around these follicular scars.183 In advanced disease, elastin stains are important in differentiating idiopathic pseudopelade of Brocq in which there is preservation of elastic fibers from other scarring alopecias like lichen planopilaris and discoid lupus erythematosus in which the scar tissue consists of collagen devoid of elastin.461 The expression of interleukin (IL)-4, IL-6, basic fibroblast growth factor (bFGF) and transforming growth factor (TGF-β) suggests that these fibrogenic, T-helper 2 (IL-4, IL-6) and T-helper 3 (TGF-β) cytokines are essential for the fibrotic evolution of pseudopelade.453 Direct immunofluorescence studies are negative or show only IgM deposition along the follicular infundibular basement membrane.452 The condition often worsens in spurts, with periods of activity followed by dormant periods. Pseudopelade is usually slowly progressive, eventually burning itself out after several years, resulting in permanent hair loss but spontaneous regression has been reported.451 There is no consistently effective treatment for this disorder. The activity of the disease is determined by a positive pull test.

PSEUDOPELADE OF BROCQ

et al. proposed the following sequence of inflammatory events.442 Acute inflammation begins in the sebaceous gland, deep infundibulum, or isthmus. This weakens the follicular wall, which ruptures, releasing hair shafts into the surrounding dermis. The naked hairs stimulate a foreign body reaction with acute and chronic granulomatous inflammation. The granulomatous inflammation manifests itself clinically as papular lesions. Fibroblasts lay down collagen and scars form in the region of the inflammation. Subsequent fibrosis occurs within the dermis, which may distort and occlude the follicular lumen and consequently lead to hair retention within the deeper follicle and further smoldering granulomatous inflammation and scarring. Demodex may play a role in the pathogenesis. Medical treatment for early papular lesions includes potent topical corticosteroids, e.g. clobetasol propionate,443 intralesional injections of triamcinolone acetonide, topical e.g. clindamycin solution and oral antibiotics such as tetracycline, doxycycline, minocycline or erythromycin.434,441,444 Adjunctive use of antibacterial soaps, e.g., chlorhexidine or benzoyl peroxide wash has been advocated.444 Once large keloid-like plaques have developed, the condition is resistant to medical treatment, often requiring surgical removal, e.g., carbon dioxide laser ablation445 or excision.446–448 Two patients treated with the 810 nm diode laser epilation achieved 90–95% clearance after four treatments.449 Prophylaxis depends upon avoidance of close ‘clipper’ hair cuts436 and instructing patients not to scratch affected areas and substituting tight, high-collared shirts with soft or no-collared shirts whenever possible.444

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452. Braun-Falco O, Imai S, Schmoeckel C, et al. Pseudopelade of Brocq. Dermatologica. 1986;172:18–23. 453. Moretti S, Amato L, Massi D, et al. Evaluation of inflammatory infiltrate and fibrogenic cytokines in pseudopelade of Brocq suggests the involvement of T-helper 2 and 3 cytokines. Br J Dermatol. 2004;151:84–90. 454. Bulengo-Ransby SM, Headington JT. Pseudopelade of Brocq in a child. J Am Acad Dermatol. 1990;23:944–945. 455. Collier PM, James MP. Pseudopelade of Brocq occurring in two brothers in childhood. Clin Exp Dermatol. 1994;19:61–64. 456. Sahl WJ. Pseudopelade: An inherited alopecia. Int J Dermatol. 1996;35:715–719. 457. Alzolibani AA, Kang H, Otberg N, et al. Pseudopelade of Brocq. Dermatol Ther. 2008;21:257–263. 458. Ronchese F. Pseudopelade. Arch Dermatol. 1960;82:336–343. 459. Madani S, Trotter MJ, Shapiro J. Pseudopelade of Brocq in beard area. J Am Acad Dermatol. 2000;42:895–896. 460. Draelos ZK, Yeatts RP. Eyebrow loss, eyelash loss, and dermatochalasis. Dermatol Clin. 1992;10:793–798. 461. Elston DM, McCollough ML, Warschaw KE, et al. Elastic tissue in scars and alopecia. J Cutan Pathol. 2000;27:147–152.

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Diseases of Mucous Membranes and Appendageal Structures

ALOPECIA MUCINOSA

For active localized lesions, a combination of twice daily application of a potent topical corticosteroid and intralesional triamcinolone acetonide injections in a 10 mg/mL concentration at monthly intervals may be beneficial.457 In cases of failure of local therapy after a 12-week trial or more extensive lesions, hydroxychloroquine (200 mg twice daily) alone or in combination with prednisone (0.5 mg/kg) is indicated. A tapering course of prednisone over 2 months is used as a bridge therapy to induce remission while the antimalarial takes effect.457 If there is a good response to hydroxychloroquine, the same dose can be continued for 9–12 months, and thereafter the dose of hydroxychloroquine may be tapered to 200 mg once daily, then every other day. Most patients require 1–2 years of hydroxychloroquine.457 If the disfigurement is considerable and no active inflammatory changes are present for at least 2 years, autografting of hair from unaffected to scarred scalp and/or scalp reduction may be considered.457

Figure 11.49  Alopecia mucinosa. Boggy, erythematous plaque with scaling and loss of hair.

ALOPECIA MUCINOSA

788

Alopecia mucinosa or follicular mucinosis is an inflammatory disorder characterized clinically by grouped follicular papules and boggy, erythematous, nodular plaques with scaling and loss of hair (Fig. 11.49) and histologically by the accumulation of mucin (acid mucopolysaccharide) in the sebaceous glands and the outer root sheaths of affected hair follicles.462 Although the term follicular mucinosis is used interchangeably with alopecia mucinosa, follicular mucinosis should be regarded as a histological reaction pattern seen in a number of conditions, and not as a specific disease entity per se.463 Primary alopecia mucinosa affects all age groups, even from birth,464 is benign and consists of two forms.465 The acute form is localized to the head, neck, and shoulders with a few erythematous papules and plaques, prominent follicles, some scaling and shedding of hairs. Spontaneous recovery is usually observed within 2 years. In the other benign, but more chronic form, the inflammatory plaques with alopecia are more numerous and widespread, involving the trunk and limbs, and may persist for many years without evidence of an associated disorder. Unusual morphologies have been described including urticaria-like follicular mucinosis,466 acneiform follicular mucinosis467 and follicular mucinosis mimicking lichen spinulosus.468 Secondary alopecia mucinosa may be associated with cutaneous lymphoma in 9–60% of the

cases,396 or rarely with other cutaneous diseases, such as spongiotic dermatitis,469 angiolymphoid hyperplasia,470,471 and Ofuji’s disease.472 Most are T-cell lymphomas of the mycosis fungoides type.465,469,473,474 Less commonly, cutaneous B-cell lymphoma,475 myeloblastic leukemia,476 Hodgkin’s disease, or chronic lymphocytic leukemia are associated with follicular mucinosis.465,474 The cases associated with lymphoma tend to occur more in older patients (>30 years) than the benign ones, although follicular mucinosis with underlying lymphomas has been reported in children.474 Unfortunately, there is considerable overlap in the clinical and histopathological features between the benign and the malignancy-associated forms of alopecia mucinosa, making differentiation on clinicopathological criteria impossible.474,477,478 Notably, lesional T-cell clonality in primary alopecia mucinosa is common and does not connote malignancy or predict progression to lymphoma.477,478 The temporal relationship between the lymphoma and the follicular mucinosis is variable. Mycosis fungoides may precede follicular mucinosis, present with follicular mucinosis, or arise several years after the diagnosis of follicular mucinosis.478 The clinical diagnosis is suggested by the presence of papules and plaques that have a soft, gelatinous consistency, the presence of mucin, which can sometimes be squeezed out of affected

462. Pinkus H, Macaulay WL, Lund HZ, et al. Alopecia mucinosa. Arch Dermatol. 1957;76:491–524. 463. Boer A, Ackerman AB. Alopecia mucinosa or follicular mucinosis – the problem is terminology! J Cutan Pathol. 2004;31:210–211. 464. Dalle S, Marrou K, Balme B, et al. Neonatal follicular mucinosis. Br J Dermatol. 2007;157:609–610. 465. Emmerson RW. Follicular mucinosis: a study of 47 patients. Br J Dermatol. 1969;81:395–413. 466. Harthi FA, Kudwah A, Ajlan A, et al. Urticaria-like follicular mucinosis responding to dapsone. Acta Derm Venereol (Stockh). 2003;83:389–390. 467. Passaro EMC, Silveira MT, Valente NYS. Acneiform follicular mucinosis. Clin Exp Dermatol. 2004;29:396–398. 468. Comert A, Akin O, Demirkesen C. Follicular mucinosis mimicking lichen spinulosus in an 11-year-old boy. Eur J Dermatol. 2007;17:544–545. 469. Clark-Loeser L, Latkowski JA. Follicular mucinosis associated with mycosis fungoides. Dermatol Online J. 2004;10:22. 470. Wolff HH, Kinney J, Ackerman AB. Angiolymphoid hyperplasia with follicular mucinosis. Arch Dermatol. 1978;114:229–232. 471. Joshi R. Angiolymphoid hyperplasia with follicular mucinosis. Indian J Dermatol Venereol Leprol. 2007;73:346–347.

472. Lee JYY, Tsai YM, Sheu HM. Ofuji’s disease with follicular mucinosis and its differential diagnosis from alopecia mucinosa. J Cutan Pathol. 2003;30:307–313. 473. Binnick AN, Wax FD, Clendenning WE. Alopecia mucinosa of the face associated with mycosis fungoides. Arch Dermatol. 1978;114:791–792. 474. Gibson LE, Muller SA, Leiferman KM, et al. Follicular mucinosis: clinical and histopathologic study. J Am Acad Dermatol. 1989;20:441–446. 475. Benchikhi H, Wechsler J, Rethers L, et al. Cutaneous B-cell lymphoma associated with follicular mucinosis. J Am Acad Dermatol. 1995;33:673–675. 476. Sumner WT, Grichnik JM, Shea CR, et al. Follicular mucinosis as a presenting sign of acute myeloblastic leukemia. J Am Acad Dermatol. 1998; 38:803–805. 477. Cerroni L, Fink-Puches R, Back B, et al. Follicular mucinosis: a critical reappraisal of clinicopathologic features and association with mycosis fungoides and Sezary syndrome. Arch Dermatol. 2002;138:182–189. 478. Brown HA, Gibson LE, Pujol RM, et al. Primary follicular mucinosis: long-term follow-up of patients younger than 40 years with and without clonal T-cell receptor gene rearrangement. J Am Acad Dermatol. 2002;47: 856–862.

follicles, and the loss of hair in plaques with prominent follicles that may result in permanent alopecia. Symptoms may include dysesthesia and pruritus.396 Seborrheic dermatitis, pityriasis rosea, tinea capitis, and leprosy may be closely simulated. Biopsy should confirm the diagnosis. The histopathologic picture is characterized by mucin deposition in the outer root sheath and sebaceous glands. The keratinocytes of the outer root sheath may appear stellate-shaped and are splayed apart by the mucin. In more advanced lesions, the entire follicular epithelium may be altered with large mucin-filled intrafollicular cystic spaces.474 Mucin can be demonstrated by the use of colloidal iron and Alcian Blue stains. Variably dense perivascular and perifollicular lymphocytic infiltrates with occasional eosinophils are present in most cases. The presence of large numbers of eosinophils in the inflammatory infiltrate and marked mucinous changes in the follicular epithelium favor a benign form, whereas the presence of a band-like, atypical lymphocytic infiltrate near the dermal– epidermal junction, with significant epidermotropism, favors a lymphoma-associated follicular mucinosis.479 Some patients spontaneously improve.480 Treatment with topical464,468 and intralesional steroids,465,469 systemic steroids,467 superficial radiotherapy,481 dapsone,466,482,483 minocycline,484 indomethacin,485 isotretinoin,486,487 interferons,488 photochemotherapy (PUVA),489 and photodynamic therapy490 have been reported to be beneficial. Close follow-up of all patients is essential, including lymph node palpation with serial biopsies, especially in those with disease progression.396

LICHEN PLANOPILARIS Lichen planopilaris, also known as follicular lichen planus, represents lichen planus localized to the follicles. Three forms of lichen planopilaris are recognized: classic lichen planopilaris, Graham–Little syndrome and frontal fibrosing alopecia.396 Graham–Little syndrome is characterized by a triad of patchy, progressive scarring scalp alopecia, non-scarring loss of pubic and axillary hair and widespread keratosis pilaris-like horny follicular papules on the trunk and limbs.491 Frontal fibrosing alopecia is characterized by progressive symmetrical recession of the frontal hairline revealing a pale band of skin, lacking follicular ostia. Perifollicular inflammation and hyperkeratosis are confined to the immediate hairline, eyebrow loss is common and

479. Logan RA, Headington JT. Follicular mucinosis: a histologic review of 80 cases (abstr). J Cutan Pathol. 1988;15:324. 480. Lockshin BN, Khachemoune A, Cohen C. Follicular mucinosis in a 4-year-old boy. Int J Dermatol. 2004;43:950–952. 481. Coskey RJ, Mehregan AH. Alopecia mucinosa: a follow-up study. Arch Dermatol. 1970;102:193–194. 482. Kubba RK, Stewart TW. Follicular mucinosis responding to dapsone. Br J Dermatol. 1974;91:217–220. 483. Rustin MH, Bunker CB, Levene GM. Follicular mucinosis presenting as acute dermatitis and response to dapsone. Clin Exp Dermatol. 1989;14:382–384. 484. Yotsumoto S, Uchimiya H, Kanzaki T. A case of follicular mucinosis treated successfully with minocycline. Br J Dermatol. 2000;142:841–842. 485. Kodama H, Umemura S, Nohara N. Follicular mucinosis: response to indomethacin. J Dermatol. 1988;15:72–75. 486. Guerriero C, De Simone C, Guidi B, et al. Follicular mucinosis successfully treated with isotretinoin. Eur J Dermatol. 1999;9:22–24. 487. Arca E, Kose O, Tastan HB, et al. Follicular mucinosis responding to isotretinoin treatment. J Dermatol Treat. 2004;15:391–395. 488. Meissner K, Weyer U, Kowalzick L, et al. Successful treatment of primary progressive follicular mucinosis with interferons. J Am Acad Dermatol. 1991;24:848–850.

11

LICHEN PLANOPILARIS

Hair disorders

Figure 11.50  Lichen planopilaris. Irregular patches of scarring alopecia.

the histopathology is identical to classic lichen planopilaris.492 Classic lichen planopilaris includes the triad of typical lichen planus, spinous or acuminate follicular papules, and scarring alopecia of the scalp. It is slightly more common in women (1.8 : 1) with onset in middle age,399 although childhood cases have been reported.493 Lichen planopilaris is rare with an annual incidence rate of 1.15–7.6% in the USA.494 The alopecia of lichen planopilaris is insidious with progressive involvement over several months to years. Rapid onset is more common in those with co-existing extracranial lichen planopilaris or bullous lichen planus.396 Extracranial lichen planus may be present in 17–28% of patients at presentation399 and occurs at some time during the course of the disease in 50%.495 Patients may be asymptomatic, but itching, pain, tenderness, burning, and scaling are often present.396 Early lesions consist of spinous, hyperkeratotic follicular papules with erythema and scaling of the affected scalp. Active disease is usually confined to the hair-bearing rim and a positive pull test of anagen hairs indicates disease activity.496 The hair follicles are subsequently destroyed yielding atrophic, irregular, angularshaped patches of alopecia with follicular papules at the periphery (Fig. 11.50). The pattern of scalp hair loss is variable. Most

489. Kenicer KJA, Lakshmipathi T. Follicular mucinosis treated with PUVA. Br J Dermatol. 1982;107:48–49. 490. Fernandez-Guarino M, Castano AH, Carrillo R, et al. Primary follicular mucinosis: excellent response to treatment with photodynamic therapy. J Eur Acad Dermatol Venereol. 2008;22:393–394. 491. Bianchi L, Paro Vidolin A, Piemonte P, et al. Graham Little-PiccardiLassueur syndrome: effective treatment with ciclosporin A. Clin Exp Dermatol. 2001;26:518–520. 492. Kossard S, Lee MS, Wilkinson B. Postmenopausal frontal fibrosing alopecia: a frontal variant of lichen planopilaris. J Am Acad Dermatol. 1997;36:59–66. 493. Sehgal VN, Bajaj P, Srivastva G. Lichen planopilaris (cicatricial scarring alopecia) in a child. Int J Dermatol. 2001;40:461–463. 494. Ochoa BE, King LE Jr, Price VH. Lichen planopilaris: Annual incidence in four hair referral centers in the United States. J Am Acad Dermatol. 2008;58:352–353. 495. Mehregan DA, Van Hale HM, Muller SA. Lichen planopilaris: Clinical and pathologic study of forty-five patients. J Am Acad Dermatol. 1992;27:935–942. 496. Kang H, Alzolibani AA, Otberg N, et al. Lichen planopilaris. Dermatol Ther. 2008;21:249–256.

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DISCOID LUPUS ERYTHEMATOSUS (DLE)

commonly, there are asymmetrical, scattered foci of partial hair loss that may coalesce into larger areas. Occasionally, diffuse hair loss involving the entire scalp may be seen.497 The end stage may resemble pseudopelade. In lichen planopilaris, the inflammatory lymphocytic infiltrate mainly involves the bulge region, where the stem cells reside.498 Once this area is damaged, the hair loses its potential for regrowth with resulting scarring alopecia. Recent work on integrin expression emphasizes the importance of adhesion molecular expression patterns.499 Altered expression of integrins in lichen planopilaris provokes the loss of adhesion of follicular keratinocytes to the stroma and may explain the phenomenon of easy plucking of the hair. Lichenoid interface alteration of the epidermis and follicular epithelium is characteristic of lichen planopilaris. There is disruption of the epithelial–adventitial dermal junction with prominent dyskeratosis and necrotic, basal keratinocytes. A linear lymphocytic infiltrate abuts the follicular infundibular epithelium. Later lesions are characterized by a band-like fibrotic thickening of the papillary dermis, accompanied by fibrotic tracts at sites of destroyed follicles.497 Mucinous perifollicular fibroplasia within the upper dermis with absence of interfollicular mucin and superficial perifollicular wedge-shaped scarring may be seen.500 End-stage changes are identical to end-stage pseudopelade and end-stage discoid lupus erythematosus. Direct immuno­ fluorescence shows globular IgM and IgA deposits on cytoid bodies at the dermal–epidermal junction, papillary dermis, along the infundibulum, and isthmus.495 In addition, patchy deposits of fibrinogen are commonly seen around the hair follicles. It is important to biopsy an early lesion in order to obtain the diagnostic changes. Treatment consists of high-potency topical steroids,501 monthly intralesional triamcinolone acetonide (10 mg/mL)496 or combined use of these agents. Oral corticosteroids are reserved for rapidly progressing disease and severe symptoms. Prednisone is added at 1 mg/kg daily and can be tapered over 2–4 months.496 In patients with more than 10% scalp involvement and poor response to topical or intralesional corticosteroids, hydroxychloroquine (200 mg twice daily) may be considered.399 The first noticeable effects of treatment may be found within 3 months and maximal clinical efficacy may take up to 12 months. Tetracycline at 1 g/day showed statistically significant improvement in one study of lichen planopilaris.502 Isotretinoin, at a dose of 1 mg/kg, has been used in lichen planopilaris with resolution of inflammation after 4–8 months of therapy.399 Ciclosporin (3–5 mg/kg per day for 3–5 months)503 and mycophenolate

497. Annessi G, Lombardo G, Gobello T, et al. A clinicopathologic study of scarring alopecia due to lichen planus. Am J Dermatopathol. 1999;21:324–331. 498. Mobini N, Tam S, Kamino H. Possible rate of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype. J Cutan Pathol. 2005;32:675–679. 499. d’Ovidio R, Sgarra C, Conserva A, et al. Alterated integrin expression in lichen planopilaris. Head Face Med. 2007;3:11. 500. Tandon YK, Somani N, Cevasco NC, et al. A histologic review of 27 patients with lichen planopilaris. J Am Acad Dermatol. 2008;59:91–98. 501. Chieregato C, Zini A, Barba A, et al. Lichen planopilaris: report of 30 cases and review of the literature. Int J Dermatol. 2003;42:342–345. 502. Cevasco NC, Bergfeld WF, Remzi BK, et al. A case-series of 29 patients with lichen planopilaris: The Cleveland Clinic Foundation experience on evaluation, diagnosis, and treatment. J Am Acad Dermatol. 2007;57:47–53. 503. Mirmirani P, Willey A, Price VH. Short course of oral cyclosporine in lichen planopilaris. J Am Acad Dermatol. 2003;49:667–671.

790

mofetil (500 mg twice daily for 6 months)504 have been advocated for treatment refractory scalp disease. If active inflammation has not been present for more than 2 years, hair transplantation and/or scalp reduction can be attempted.496

DISCOID LUPUS ERYTHEMATOSUS (DLE) DLE is a common form of chronic cutaneous lupus erythematosus and is typically found in young to middle-aged adults (mean age 38 years) with a 2 : 1 female predominance.505 Onset of disease is between 17 and 57 years of age (mean age, 35 years),399 with > Cosmetics, sunscreens and moisturizers, particularly those

containing oils, may worsen acne. Advise the adolescent to take care to select cosmetics that are labeled noncomedogenic or nonacnegenic

836

>> A variant of cosmetic acne, known as pomade acne, may occur when greases used to style hair are inadvertently applied to the skin. Pomade acne is seen almost exclusively in AfricanAmericans and is characterized by the presence of comedones located on the forehead and temporal areas (see Fig. 13.21).   To prevent such lesions, patients can be advised to avoid placing hair care products on the skin

>> Young women often experience premenstrual flare-ups of acne

that may be caused by the androgenic effects of progesterone that is dominant during the second half of the menstrual cycle12

>> Environmental factors may exacerbate acne among young

people who come into contact with grease at work (e.g., those employed in auto-repair shops or fast-food restaurants). Patients may be unwilling or unable, however, to alter their employment status to accommodate concerns about acne

>> Psychological stress, such as that associated with anticipated academic examinations, may worsen acne74,75

treatment of acne. One also should attempt to address and dispel commonly held myths and provide information about those factors and behaviors that may worsen acne. The information contained in Table 13.1 and Box 13.1 may be of assistance in guiding this portion of the discussion. Patients should leave the clinician’s office knowing exactly how to use the medications prescribed and any adverse effects

to be anticipated. They should be advised that acne treatment is a long-term process, often taking 6–8 weeks before any therapeutic benefit is seen, and that when therapy is abandoned prematurely, the acne usually returns. Additionally, once lesions resolve, treatment needs to be continued, even to apparently normal skin, until it is clear that there no longer is a tendency for new lesions to form.

74. Chiu A, Chon SY, Kimball AB. The response of skin disease to stress. Arch Dermatol. 2003;139:897–900.

75. Yosipovitch G, Tang M, Dawn AG, et al. Study of psychological stress, sebum production and acne vulgaris in adolescents. Acta Derm Venereol. 2007;87:135–137.

Acne

Medications to treat acne may be separated into topical and systemic preparations.

Topical therapies Commonly employed topical preparations include benzoyl peroxide, antibiotics, retinoids, salicylic acid and a combination of these agents.

Benzoyl peroxide Benzoyl peroxide (BP) primarily has an antibacterial effect and is useful in controlling inflammatory acne.31,76 BP may also decrease formation of FFA, thereby improving obstructive (comedonal) disease.31,76 These two actions make it a useful firstline drug in the management of patients with mild inflammatory or mixed (i.e., inflammatory and comedonal) acne. BP is available with or without a prescription in concentrations ranging from 2.5% to 10%. Over-the-counter products include creams, lotions, washes, or gels. Prescription forms generally employ a gel vehicle, a factor that enhances efficacy. A single daily application of a product containing a 5% concentration is adequate for most patients. Increasing the concentration to 10% does not greatly enhance the therapeutic effect but does increase the likelihood of drying, erythema, and burning.77 BP usually is applied once daily, although twice-daily use may be beneficial for some patients. As with all topical medications, BP is applied as a thin coat to all acne-prone areas, not to individual lesions. When the entire face is to be treated, the patient may be instructed to dispense an amount the size of a pea on to a finger-tip. To distribute the medication, the finger is touched to each side of the forehead, each cheek and the chin. The medication is then spread to cover the entire face, avoiding sensitive areas such as the corners of the eyes, the alar folds, and the angles of the mouth. A BP wash that is used during a bath or shower may be used to treat larger areas such as the chest and back, although greater efficacy may be achieved by applying the gel formulation and allowing it to remain in place for several hours. Adverse reactions resulting from the use of BP include stinging after application and drying, redness, and peeling of the skin. These reactions often can be limited by selecting an emollient or water-based gel, by reducing the concentration of BP, or by reducing the frequency of application.12 Contact dermatitis is an unusual complication characterized by erythema, small papules,

76. Cotterill JA. Benzoyl peroxide. Acta Derm Venereol Suppl (Stockh). 1980;60(Suppl 89):57–63. 77. Mills OH Jr, Kligman AM, Pochi P, et al. Comparing 2.5%, 5% and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol. 1986;25: 664–667. 78. CHIPS. Drug Facts and Comparisons 2009. St Louis, MO: Wolters Kluwer Health; 2009. 79. Gollnick H, Schramm M. Topical drug treatment in acne. Dermatology. 1998;196:119–125. 80. Eady EA, Cove JH, Joanes DN, et al. Topical antibiotics for the treatment of acne vulgaris: a critical evaluation of the literature on their clinical benefit and comparative efficacy. J Dermatol Treat. 1990;1:215–226. 81. Chu A, Huber FJ, Plott RT. The comparative efficacy of benzoyl peroxide 5%/erythromycin 3% gel and erythromycin 4%/zinc 1.2% solution in the treatment of acne vulgaris. Br J Dermatol. 1997;136:235–238. 82. Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination of clindamycin/benzoyl peroxide gel compared with

and pruritus. Those who develop contact dermatitis should avoid BP and use an alternate product. Patients should be advised that BP may bleach hair, towels, clothing, and bedding. BP is considered pregnancy category C by the Food and Drug Administration (FDA) (i.e., risk to the fetus cannot be ruled out).78

Topical antibiotics Topical antibiotics reduce concentrations of P. acnes, inflammatory mediators and, possibly, FFA.31,79 As a result, these agents have been most useful in the management of mild to moderate inflammatory acne. The practical difficulties and cost associated with applying topical antibiotics to large areas limit their use to the treatment of facial acne. In the USA, products containing clindamycin or erythromycin alone are available and have comparable efficacy.80 Sodium sulfacetamide, with or without sulfur, also is available. Topical antibiotics are available in a variety of vehicles. As with other topical agents, lotions and creams are less drying than solutions or gels. Products that combine agents enhance the therapeutic effect.81– 84 For example, BP 5% and erythromycin 3% is more effective than either drug alone,83 and a formulation of erythromycin and zinc is of greater benefit than erythromycin alone.84 Similarly, a combination of clindamycin and benzoyl peroxide is more effective than individual components.82 Interestingly, the BP and zinc components of these combination products inhibit erythromycin-resistant propionibacteria in vitro.85–87 The disadvantages of combination preparations are cost and the need for refrigeration of some products in order to maintain drug stability. An area of concern related to the use of topical or systemic antibiotics is the emergence of resistant forms of P. acnes. In the UK, for example, between 1991 and 1996, the percentage of patients attending a dermatology clinic carrying antibiotic-resistant organisms rose from 34.5% to 60%.86 In 1996, 47%, 41%, and 26% of these patients harbored strains of P. acnes that were resistant to erythromycin, clindamycin or tetracycline, respectively.86 The majority of strains resistant to erythromycin exhi­ bited cross resistance to clindamycin and other macrolide, lincosamide, and streptogramin antibiotics.86 Multiple drug resistance was observed in 18% of isolates.86 Among propionibacteria resistant to tetracyclines, the degree of resistance to tetracycline is greater than that to doxycycline which, in turn, exceeds that to minocycline.86 Eady and colleagues have demonstrated an association between carriage of erythromycin-resistant

83.

84. 85. 86. 87.

PATHOPHYSIOLOGY AND HISTOGENESIS

Medications

13

clindamycin gel, benzoyl peroxide gel and vehicle gel: Combined results of two double-blind investigations. J Am Acad Dermatol. 1997;37:590–595. Packman AM, Brown RH, Dunlap FE, et al. Treatment of acne vulgaris: Combination of 3% erythromycin and 5% benzoyl peroxide in a gel compared to clindamycin phosphate lotion. Int J Dermatol. 1996;35: 209–211. Schachner L, Pestana A, Kittles C. A clinical trial comparing the safety and efficacy of a topical erythromycin-zinc formulation with a topical clindamycin formulation. J Am Acad Dermatol. 1990;22:489–495. Bojar RA, Eady EA, Jones CE, et al. Inhibition of erythromycin-resistant propionibacteria on the skin of acne patients by topical erythromycin with and without zinc. Br J Dermatol. 1994;130:329–336. Eady EA. Bacterial resistance in acne. Dermatology. 1998;196:59–66. Eady EA, Bojar RA, Jones CE, et al. The effects of acne treatment with a combination of benzoyl peroxide and erythromycin on skin carriage of erythromycin-resistant propionibacteria. Br J Dermatol. 1996;134: 107–113.

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BOX 13.2 RECOMMENDATIONS FOR ANTIBIOTIC USE TO REDUCE THE SELECTION OF RESISTANT ORGANISMS

>> Only prescribe antibiotics when necessary and do not use as monotherapy

>> Treat for as brief a period as possible, recognizing that 3–6

months may be required to achieve a therapeutic effect (resistant strains begin to emerge 12–24 weeks after beginning therapy)

>> If antibiotic re-treatment is required, employ the same agent unless there was a previous therapeutic failure

>> Use BP adjunctively to prevent the emergence of resistant

organisms or for a minimum of 5–7 days between antibiotic courses to eliminate resistant organisms

PATHOPHYSIOLOGY AND HISTOGENESIS

>> Avoid the use of concomitant oral and topical therapy with dissimilar antibiotics

(Adapted from Eady EA, Cove JH, Joanes DN, et al. Topical antibiotics for the treatment of acne vulgaris: a critical evaluation of the literature on their clinical benefit and comparative efficacy. J Dermatol Treat. 1990;1:215–226.)

propionibacteria and poor clinical response to oral treatment with this agent.88 Because multiple factors influence antibiotic efficacy, the exact clinical significance of these data is not known. For example, topical concentrations of an antibiotic surpass those achievable by the oral route and, therefore, may exceed the minimal inhibitory concentration for strains considered resistant by laboratory testing.86 Nevertheless, these data have led some clinicians to prescribe topical or oral erythromycin only for previously untreated acne patients who are unlikely to harbor resistant organisms,86,88 and to limit the use of topical antibiotics to prevent the development of drug resistance. Recommendations for antibiotic use to reduce the selection of resistant organisms are presented in Box 13.2.

Topical retinoids For patients with moderate to severe acne, whether inflammatory or mixed, or those with significant numbers of comedones, topical retinoids are indicated.12,31,73 These drugs normalize the keratinization process within follicles, reducing obstruction and the risk for follicular rupture.12,89–93 Retinoids exert their effect by activating nuclear receptors (dimers composed of retinoic acid

88. Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria in antibiotic treated acne patients: Association with therapeutic failure. Br J Dermatol. 1989;121:51–57. 89. Velcier CM, Heckbert SR, Lampe JW, et al. Antibiotic use in relation to the risk of breast cancer. JAMA. 2004;291:827–835. 90. Friedman GD, Oestreicher N, Chan J, et al. Antibiotics and risk of breast cancer: up to 9 years of follow-up of 2.1 million women. Cancer Epidemiol Biomarkers Prev. 2006;15:2102–2106. 91. Moysich KB, Beehler GP, Zirpoli G, et al. Use of common medications and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2008;17: 1564–1595. 92. Bernerd F, Démarchez M, Ortonne J-P, et al. Sequence of morphological events during topical application of retinoic acid on the rhino mouse skin. Br J Dermatol. 1991;125:419–425. 93. Kligman LH, Kligman AM. The effect on rhino mouse skin of agents which influence keratinization and exfoliation. J Invest Dermatol. 1979;73: 354–358.

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receptors and retinoid X receptors). These dimers bind specific DNA sequences (retinoic acid response elements) in the promoter region thereby regulating transcriptional activity.94,95 Tretinoin (Retin-A and others) is the best known topical retinoid and is available in creams (0.025%, 0.05%, 0.1%), gels (0.01%, 0.025%), micro gels (0.04%, 0.1%), and a liquid (0.05%). The vehicle has an impact on efficacy; creams are less potent than gels which, in turn, are less potent than the liquid. Newer formulations appear to be as effective but less irritating than traditional varieties.93,96,97 Tretinoin is also available in generic forms and in a 0.025% concentration combined with clindamycin 1.2%. Many adolescents who use topical retinoids such as tretinoin experience irritation, redness, or dryness. For persons with skin of color, this inflammation may result in hypo- or hyperpigmentation that can last several months. To prevent or limit adverse effects, therapy is often begun with a lower strength preparation (e.g., tretinoin cream 0.025%). Patients are advised to use the medication every third night, progressing as tolerated over 2–3 weeks, to a nightly application. Alternatively, the retinoid can be applied for increasing lengths of time each night until overnight use is tolerated. Other adverse effects should be reviewed with the patient. About one-half of individuals experience an apparent temporary worsening of acne 2–3 weeks after starting tretinoin. Skin irritation may increase sensitivity to sunlight; as a result, a nonacnegenic, noncomedogenic sunscreen should be used. Applying too much tretinoin will worsen the irritant effect. Because tretinoin is nearly identical in chemical structure to isotretinoin, some concerns have been raised about potential teratogenicity. However, there have been no reports of malformations occurring in infants born to women who used tretinoin during pregnancy.12,31,98 Nevertheless, tretinoin is classified as pregnancy category C (i.e., risk to the fetus cannot be ruled out) and, for this reason, its use is avoided during pregnancy.78 Since BP inactivates tretinoin, the two drugs should not be applied simultaneously. Rather, one should be applied in the morning and the other at night. Other retinoids and retinoid-like agents are available. Adapalene (Differin), while not a retinoid, possesses retinoid-like activity and in a 0.1% gel has been shown to be as effective as tretinoin gel 0.025%, but less irritating.99,100 Unlike tretinoin, it is not inactivated by BP and is not inactivated by ultraviolet light.73 It is available as 0.1% and 0.3% alcohol-free gels and as a 0.1% cream. However, recently, a stable combination of 2.5% benzoyl peroxide and 0.1% adapalene gel has been approved in the USA. The principles of use and potential adverse effects are

94. Lavker RM, Leyden JJ, Thorne EG. An ultrastructural study of the effects of topical tretinoin on microcomedones. Clin Ther. 1992;14:773–780. 95. Leyden JJ. Topical treatment of acne vulgaris: Retinoids and cutaneous irritation. J Am Acad Dermatol. 1998;38(Suppl):S1–S4. 96. Webster GF. Topical tretinoin in acne therapy. J Am Acad Dermatol. 1998;39(Suppl):S38–S44. 97. Chandraratna RAS. Rational design of receptor-selective retinoids. J Am Acad Dermatol. 1998;39(Suppl):S124–S128. 98. Jick SS, Terris BZ, Jick H. First trimester topical tretinoin and congenital disorders. Lancet. 1993;341:1181–1182. 99. Lucky AW, Cullen SI, Funicella T, et al. Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad Dermatol. 1998;38(Suppl):S24–S30. 100. Lucky AW, Cullen SI, Jarratt MT, et al. Comparative efficacy and safety of two 0.025% tretinoin gels: Results from a multicenter, double-blind, parallel study. J Am Acad Dermatol. 1998;38(Suppl):S17–S23.

Acne

Other topical agents Azelaic acid 20% (Azelex) is both antibacterial and anticomedonal.103,104 It is applied twice daily and appears to be well tolerated, although some patients experience pruritus, burning, stinging, tingling, or erythema.103 No systemic toxicity has been reported. Azelaic acid has been shown to be comparable in efficacy to BP 5%, tretinoin 0.05%, or erythromycin 2%.103,105 It may be an alternative for patients with mild to moderate inflammatory and comedonal acne, particularly those who are unable to tolerate a topical retinoid. Dapsone gel 5% has received approval from the FDA for the treatment of acne. In vehicle-controlled trials, dapsone therapy was associated with significant reductions in lesion number and in overall improvement in acne severity.106,107

Systemic therapies Oral antibiotics Oral antibiotics appear to possess greater efficacy and are easier to use than topical preparations and, for this reason, are prescribed for patients with more severe or extensive inflammatory acne.12,31,72,73,108 In addition to decreasing bacterial colonization, antibiotics such as tetracycline reduce neutrophil chemotaxis and have an inhibitory effect on proinflammatory cytokines and MMP-9.12,109–111 Antibiotics also decrease the concentration of FFA in sebum.112–115 Tetracycline and erythromycin are most often prescribed; both drugs are effective and inexpensive.31 However, the emergence of drug-resistant strains of P. acnes may limit their use. Depend-

101. Cunliffe WJ, Caputo R, Dreno B, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials. J Am Acad Dermatol. 1997;36(Suppl):S126–S134. 102. Shalita A, Weiss JS, Chalker DK, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: A multicenter trial. J Am Acad Dermatol. 1996;34:482–485. 103. Kakita L. Tazarotene versus tretinoin or adapalene in the treatment of acne vulgaris. J Am Acad Dermatol. 2000;43(Suppl):S51–S54. 104. Hughes BR, Norris JFB, Cunliffe WJ. A double-blind evaluation of isotretinoin 0.05%, benzoyl peroxide 5% gel and placebo in patients with acne. Clin Exp Dermatol. 1992;17:165–168. 105. Elbaum KJ. Comparison of the stability of topical isotretinoin and topical tretinoin and their efficacy in acne. J Am Acad Dermatol. 1988;19: 486–491. 106. Medical Letter, Inc. Azelaic acid – A new topical drug for acne. Med Lett Drugs Ther. 1996;38:52–53. 107. Weiss JS. Current options for the topical treatment of acne vulgaris. Pediatr Dermatol. 1997;14:480–488. 108. Nguyen QH, Bui TP. Azelaic acid: Pharmacokinetic and pharmacodynamic properties and its therapeutic role in hyperpigmentation disorders and acne. Int J Dermatol. 1995;34:75–84. 109. Lucky AW, Maloney JM, Roberts J, et al. Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long term (1 year) treatment. J Drugs Dermatol. 2007;6:981–987.

ing on disease severity and the patient’s weight, each is initiated at a dose of 250– 500 mg twice daily, although the higher dose is usually favored.12,31,108 Both are available in liquid form for patients who cannot swallow pills or capsules. The primary adverse effect of erythromycin is gastrointestinal upset that may be avoided by taking the medication with food. Tetracycline, like erythromycin, may cause gastrointestinal disturbances. To assure absorption, it should not be taken with milk and should be taken on an empty stomach (i.e., 30 min before or 2 h after a meal). Tetracycline should not be used during pregnancy or for patients > Personal and/or family history of atopic diseases and the predisposition to overproduction of IgE antibodies

Historical, actual, or expected (in very young children)

Must have three clinical criteria:

In peripheral blood (RAST, ELISA) or in skin (intracutaneous challenge)

1. Pruritus

2. Principal criteria (2 of 3 present)

ATOPIC DERMATITIS



Typical distribution and morphology of eczema lesions: infant, childhood or adult type



If distribution is not typical, exclude other entity (dyshidrotic eczema, contact dermatitis, contact urticaria)

– –

Pruritus Chronic or chronically relapsing course

the basis of true AD. In the same vein, the Japanese have created their own criteria which better fit their particular group of patients with AD (Box 14.5).132 There are many varied criteria used in different countries meeting the needs of that particular ethnic group. The criteria of Hanifin (once again modified in 2001)133 and the UK group have gained most acceptance for epidemiological and drug trials, but most physicians use simple criteria for the diagnosis of AD including xerosis, and a typical eruption in a typical age-related distribution. Measurements of severity were not utilized prior to 1989 and there was no standardized method of defining improvement or exacerbation for use in drug trials. A plethora of scoring systems has been developed in an attempt to create a useful and practical method to assess changes in clinical features Numerous different systems have been proposed, some of which used grid patterns, others severity and extent, and yet others subjective

132. Japanese Dermatological Association. Criteria for the diagnosis of atopic dermatitis. J Dermatol. 1997;24:561. 133. Hanifin J. Defining AD and assessing its impact: Seeking simplified, inclusive and internationally applicable criteria. Paper presented at the International symposium on Atopic Dermatitis, National Eczema Association for Science and Education. Portland, Oregon; September 6–9, 2001. 134. Costa C, Rilliet A, Nicolet M, et al. Scoring atopic dermatitis: the simpler the better? Acta Derm Venereol (Stockh). 1989;69:41–45. 135. Queille-Roussel C, Raynaud F, Saurat J-H. A prospective computerized study of 500 cases of atopic dermatitis in childhood. Acta Derm Venerol (Stockh). 1985;114:87–92. 136. Rajka G, Langeland T. Grading of the severity of atopic dermatitis. Acta Derm Venereol (Stockh). 1989;144(Suppl):13–14. 137. Hanifin JM. Standardized grading of subjects for clinical research studies in atopic dermatitis: workshop report. Acta Derm Venereol Suppl (Stockh). 1989;144:28–30. 138. Bahmer FA, Schafer J, Schubert H-J. Quantification of the extent and the severity of atopic dermatitis: the ADASI score. Arch Dermatol. 1991;127:1239. 139. European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD Index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186:23–31. 140. Berth-Jones J. Six area, six sign atopic dermatitis (SASSAD) severity score: a simple system for monitoring disease activity in atopic dermatitis. Br J Dermatol. 1996;135(Suppl 48):25–30. 141. Emerson RM, Charman CR, Williams HC, et al. Modified Rajka and Langeland severity assessment (MRSA) for atopic dermatitis: a useful tool for epidemiological studies (abstract). Br J Dermatol. 1998;139(Suppl 51):65.

860

BOX 14.5 JAPANESE DERMATOLOGICAL ASSOCIATION CRITERIA (1997)132

2. Typical morphology and distribution 3. Chronic and chronically relapsing course

and objective features (Table 14.1).134–148 The large number of scoring systems available reflects the requirements of different clinical situations, including natural history and drug investigation.149,150 Lack of comparative data precludes having a single recognized standard. Some of the scoring methods may obtain a low and positive score while the AD is severe,151 and with most of the assessments there is a marked intra- and inter-observer variability. The earliest score of SSS proposed by Costa et al.134 was based on its simplicity. Attributed to Queille–Roussel et al.,135 it relies on physician observation plus information from the patient, but severity is assessed at one site only. Rajka and Langeland136 developed a scoring system, designed for use at ‘baseline’, for broadly categorizing patients into ‘mild’, ‘moderate’, and ‘severe’ AD groups. It relies on extent, course and intensity of disease. Scoring systems ADSI and ADASI138 (Atopic Dermatitis [Area] Severity Index) evolved from more complex attempts to translate PASI, an established and widely accepted system developed for grading psoriasis severity, to suit AD severity scoring. ADASI involves using body charts, color coding for severity, and a grid system.

142. Cherill R, Graeber M, Hanifin J, et al. Eczema area and severity index (EASI): a new tool to evaluate atopic dermatitis (abstract). J Eur Acad Dermatol Venereol. 1998;11(Suppl 2):48. 143. Charman D, Varigos G, Horne DJ, et al. The development of a practical and reliable assessment measure for atopic dermatitis (ADAM). J Outcome Meas. 1999;3:21–33. 144. Wolkerstorfer A, de Waard van der Spek FB, Glazenburg EJ, et al. Scoring the severity of atopic dermatitis: three item severity score as a rough system for daily practice and as a pre-screening tool for studies. Acta Derm Venereol. 1999;79:356–359. 145. Hanifin JM, Thurston M, Omoto M, et al. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol. 2001;10:11–18. 146. Eun HC, Finlay AY. Measurement of atopic dermatitis disability. Ann Dermatol. 1990;2:9–12. 147. Lewis-Jones MS, Finlay AY. The Children’s Dermatology Life Quality Index (CSLQI): initial validation and practical use. Br J Dermatol. 1995;132: 942–949. 148. Chamlin SL, Frieden LJ, Williams ML, et al. Quality of life in young American children with atopic dermatitis: instrument development. (Abstract). National Eczema Association International Symposium on Atopic Dermatitis, Portland, Oregon; 2001. 149. Charman C, Williams H. Outcome measure of disease severity in atopic eczema. Arch Dermatol. 2000;136:763–769. 150. Finlay AY. Measurement of disease activity and outcome in atopic dermatitis. Br J Dermatol. 1996;135:509–515. 151. Wurtrich B. Minimal forms of atopic eczema. In: Ruzicka T, Ring J, Przybilla B, eds. Handbook of atopic eczema. Berlin: Springer-Verlag; 1991:46–53.

Eczematous dermatitis

14

YEAR

SEVERITY SCORING SYSTEM

SSS134

1989

Simple Scoring System Signs and symptoms, disease extent attributed to Queille-Roussel et al.135

The Rajka and Langeland scoring system136

1989

Based on extent, course and intensity of the disease

Hanifin JM137

1989

Standardized grading of subjects for clinical research studies in atopic dermatitis; workshop report

ADASI138

1991 1998

= Atopic Dermatitis Severity Index [Based on PASI – Frederiksson and Pettersson 1978 an index for psoriasis]

SCORAD139

1993

Uses extent, area of involvement and intensity of six signs

SASSAD140

1996

= Six area, six sign AD Refinement of SCORAD grading 0–3 (absent, mild, moderate, severe) of six signs – erythema, exudation, excoriation, dryness, cracking and lichenification at six sites – arms, hands, legs, feet, head and neck, and trunk

MRSA141

1998

= Modified Rajka and Langeland Severity Assessment (Nottingham Severity Score)

EASI142

1998

= Eczema Area and Severity Index

ADAM143

1999

= Assessment Measure for Atopic Dermatitis

TIS144

1999

= Three Item Severity score Evaluation of erythema, edema/papulation and excoriation on a scale of 0–3

EASI revision145

2001

= Eczema Area and Severity Index modification of PASI

EDI146

1990

= Eczema Disability Index developed from the Psoriasis Disability Index

CDLQI147

1995

= Children’s Dermatology Life Quality Index used to demonstrate the high level of handicap experienced by children with AD

CADI148

2001

= Children’s Atopic Dermatitis Index

ATOPIC DERMATITIS

Table 14.1  Assessment methods for atopic dermatitis. Severity scoring systems for atopic dermatitis – landmark attempts to produce standardized assessment methods for AD

Quality of life measures

The European Task Force on AD developed the SCORAD system,139 which represents an evaluation encompassing the extent of the disease and patient symptomatology. It uses body diagrams to record extent and area of involvement, and records the intensity of six signs (erythema, edema/ papulation, oozing/ crusts, excoriation, lichenification, and dryness). Subjective assessment includes pruritus, sleep loss, and ‘overall skin condition.’ This system was developed with children in mind and has become the most utilized system in Europe. The SASSAD (Six Area, Six Sign Atopic Dermatitis) severity score140 is a refinement of SCORAD and allows for quick and easy assessment. The Nottingham Eczema Severity Score,141 the Eczema Area and Severity Index (EASI),142,145 and the Assessment Measure for Atopic Dermatitis (ADAM)143 are all refinements of early systems. A multicenter study has shown the ease of administration and validity of the EASI score.152 In a recent review of the various

scoring systems only three had good validity: the EASI system, the SCORAD score, and POEM (Patient-oriented Eczema Measure),153,154 There is still a good deal of confusion about which severity score is the superior one, and all the scoring systems await further evaluation. For children, their families, and caregivers, AD can profoundly affect their quality of life and indices designed to measure such variables as disturbed sleep, degree of pruritus, and self-esteem have been developed. The EDI (Eczema Disability Index)146 was based on the Psoriasis Disability Index; the Children’s Dermatology Life Quality Index (CDLQI),147 designed specifically with children in mind, has been used to demonstrate the high level of handicap experienced by children with AD. The CADI (the Children’s Atopic Dermatitis Index)148 – a 62-question survey instrument was developed to assess the quality of life of American children 6 years and younger with AD. Some people find Jellinek’s Pediatric Symptom Checklist useful.155

152. Barbier N, Paul C, Luger T, et al. Validation of the eczema area and severity index for atopic dermatitis in a cohort of 1550 patients from the pimecrolimus cream 1% randomized controlled clinical trials programme. Br J Dermatol. 2004;150:96–102. 153. Schmitt J, Langan S, Williams HC. What are the best outcome measurements for atopic eczema? A systematic review. European Dermato-Epidemiology Network. Allergy Clin Immunol. 2007;120: 1389–1398.

154. Ricci G, Dondi A, Patrizi A. Useful tools for the management of atopic dermatitis. Am J Clin Dermatol. 2009;10:287–300. 155. Jellinek MS, Murphy JM, Little M, et al. Use of the Pediatric Symptom Checklist to screen for psychosocial problems in pediatric primary care: a national feasibility study. Arch Pediatr Adolesc Med. 1999;153: 254–260.

861

iv

Reaction Patterns

ATOPIC DERMATITIS

Figure 14.13  Keratosis pilaris on the cheek of a child with AD (Courtesy Dr A Lucky).

Figure 14.12  Keratosis pilaris on the arm of a child with AD (Courtesy Dr A Lucky).

DISEASES THAT MAY BE MORE SEVERE IN ATOPIC DERMATITIS BUT CAN OCCUR IN UNAFFECTED SUBJECTS

862

A number of other diseases such as keratosis pilaris atrophicans, erythromelanosis follicularis faciei et colli and ulerythema oophorogenes may mimic KP. Atrophoderma vermiculatum (AV) is a rare follicular disorder primarily affecting children with reticular or honeycomb atrophy of the cheeks and forehead. Along with keratosis pilaris atrophicans faciei (KPAF) and keratosis follicularis spinulosa decalvans (KFSD), AV falls within the broader spectrum of keratosis pilaris atrophicans (KPA).157 Treatment is aimed at hydrating the affected area with oil baths and emollients, including lactic and alpha glycolic acid preparations. In some cases, treatment with topical retinoids may be helpful but should not be used continuously.

Keratosis pilaris

Pityriasis alba

Keratosis pilaris (KP) is a condition that is seen mainly on the extensor aspects of the upper arms (Fig. 14.12) and anterior aspects of the thighs. It begins early in life and tends to improve with age. In young children, the lateral aspects of the cheeks near the hairline are often involved and may be mistaken for childhood acne (Fig. 14.13). The lesions consist of asymptomatic hyperkeratotic follicular papules, which may have an underlying erythematous telangiectatic background. Keratosis pilaris is a common disorder and is found in many young children; it may be accentuated by the xerosis in AD patients. It is worse in the winter and clears somewhat in the summer. Although the lesions on the cheeks disappear around puberty, KP elsewhere may persist in a milder form for life, particularly the erythematous background. It presents no more than a mild cosmetic problem.156

Pityriasis alba (PA) is identified by hypopigmented patches on the cheeks, upper arms, and upper trunk of children mainly 6–14 years, particularly toward the end of summer when the rest of the skin is tanned.158,159 The lesions are ill-defined, white, and at times scaly patches that are often misdiagnosed as tinea corporis or tinea versicolor. PA is thought to represent a subclinical dermatitis, resulting in post-inflammatory hypopigmentation. It is seen very commonly in patients with AD. Lesions often recur yearly until puberty, after which time it is unusual to see facial lesions. Histologically, there is acanthosis and mild spongiosis with moderate hyperkeratosis and some parakeratosis. Melanocyte counts are normal.160 The lesions may be treated with lowpotency topical corticosteroid preparations (hydrocortisone 1% ointment twice to three times a day for 2–3 weeks) followed by

156. Hwang S, Schwartz RA. Pilaris: a common follicular hyperkeratosis. Cutis. 2008;82:177–180. 157. Luria RB, Conologue T. Atrophoderma vermiculatum: a case report and review of the literature on keratosis pilaris atrophicans. Cutis. 2009;83: 83–86.

158. Vinod S, Singh G, Dash K, et al. Clinico epidemiological study of pityriasis alba. Indian J Dermatol Venereol Leprol. 2002;68:338–340. 159. Lin RL, Janniger CK. Pityriasis alba. Cutis. 2005;76:21–24. 160. In SI, Yi SW, Kang HY, et al. Clinical and histopathological characteristics of pityriasis alba. Clin Exp Dermatol. 2009;34:591–597.

Figure 14.14  The ‘sago grain vesicles’ in dyshidrotic eczema (Courtesy

14

ATOPIC DERMATITIS

Eczematous dermatitis

Figure 14.15  Severe dyshidrotic eczema (Courtesy Dr A. Torrelo).

Dr A. Lucky).

sun exposure, but they may take several months to repigment and parents should be reassured that complete repigmentation will eventually occur. Topical calcineurin inhibitors may also be useful (Schachner, pers comm).

Lichen spinulosus Lichen spinulosus is identified by round, occasionally pruritic, follicular papules that coalesce to form round plaques on the trunk and extremities. It is common in black skin and in children with AD. At times, the lesions are hypopigmented, but their diagnostic feature is the presence of grouped hyperkeratotic follicular spines. Some patients respond well to mild corticosteroid preparations.161 Figure 14.16  Typical nummular plaques with crusting, oozing and pustules.

Dyshidrotic eczema Dyshidrotic eczema (dyshidrosis), pompholyx162 is a condition that affects the palms, the soles, and the sides of the fingers and toes; it is commonly associated with hyperhidrosis and in patients with AD. The lesions consist of small, pruritic, multiloculated vesicles (Figs 14.14, 14.15), resembling ‘sago grains’ with erythema, scaling, and crusting being common findings. Occasionally there may be large bullae. It is difficult to distinguish from an Id reaction or a fungal infection. Biopsy shows spongiotic vesicles but no occlusion of sweat ducts, as previously believed. The pathogenesis of this condition is not understood. Therapy is often unsatisfactory. Burow’s or saline compresses followed by a medium-strength topical corticosteroid preparation three times a day is helpful. This is both anti-inflammatory and anti-pruritic. Initially, while the lesions are vesicular, a cream is preferable and later when they become crusted and dry, an ointment should be applied. Topical tacrolimus has been used with good effect in adults.163 161. Tilly JJ, Drolet BA, Esterly NB. Lichenoid eruptions in children. J Am Acad Dermatol. 2004;51:606–624. 162. Veien NK. Acute and recurrent vesicular hand dermatitis. Dermatol Clin. 2009;27:337–353,.

Nummular dermatitis The term nummular meaning ‘coin-shaped’ describes the morphology of the eczematous lesions seen in this condition. In children, the lesions differ from those seen in adults; the latter are associated with dry skin, involve the lower legs primarily, and present with scaly well-demarcated plaques. In children, the etiology is unknown; lesions begin as exudative, and very pruritic, follicular papules that coalesce to form plaques anywhere on the body (Fig. 14.16). The disease in adults and children is probably the result of two different pathogeneses. A refined tar preparation liquor carbonic detergens (LCD) 5–10% in a potent corticosteroid ointment used three times a day, with an antibiotic (Cefalexin (Cephalexin) 125 mg qid) and antihistamines (hydroxyzine 10–20 mg tid) produces a good therapeutic result although the condition is difficult to treat. The lesions heal with recurrences until puberty. They may be present in the setting of AD but often occur independently. 163. Schnopp C, Remling R, Möhrenschlager M, et al. Topical tacrolimus (FK506) and mometasone furoate in treatment of dyshidrotic palmar eczema: a randomized, observer-blinded trial. J Am Acad Dermatol. 2002;46:73–77.

863

iv

Reaction Patterns

Eczema cracquele

ATOPIC DERMATITIS

Eczema cracquele (asteatotic eczema) is not often seen in children, but it may occur in association with AD. It is worse in the dry winter months and is also seen in those who shower frequently with subsequent dehydration of the skin. The lesions consist of scaling, mainly on the lower legs. The pattern of the scale is that of a fine cracking or pavement-stone appearance. If the condition worsens, an acute pruritic dermatitis may supervene. Another similar condition that children may develop is a dry erythema on the dorsa of their hands from washing their hands too frequently in dry winter months. Patients should be advised to humidify the environment, bathe with an emulsifying oil in lukewarm water, use a mild soap, and follow bathing by leaving a moist film of oil and water on the body and then applying an emollient of petrolatum, or any commercial product preferred by the patient. Chapped hands should be treated with mild cleansers, avoidance of alcohol-containing hand sanitizers, and applications of emollients after hand washing in the winter months. If a dermatitis occurs, a low- or medium-potency topical corticosteroid (cream or ointment) should be used three times a day until the eruption disappears.

Juvenile plantar dermatitis Juvenile plantar dermatitis (JPD) presents in childhood with symmetric scaling, cracking, and painful fissuring on both feet. The toes (particularly the big toes), anterior third of the soles, and heels are often involved (Fig. 14.17). The problem is much worse when wearing occlusive footwear such as sneakers, plastic boots, and shoes with rubber soles, and is thus often worse in the winter. Since fashion now dictates that sneakers are worn both in summer and winter, the condition often persists in the summer months. It is frequently worse in atopics.164 There is a marked improvement at puberty. Like dyshidrotic eczema, JPD appears to be associated with excessive sweating, which is common in younger children, resulting in xerosis as the foot dries. With cotton socks, leather shoes, including the soles, and greasy emollients the condition improves. Medium-strength topical corticosteroid ointment three times a day is indicated in more severe cases where fissuring is prominent and pain severe. A colloidal solution of hydrocortisone painted in the fissures three times a day may also be helpful. Tacrolimus 0.1% ointment is useful when used twice a day.165

COMPLICATIONS OF ATOPIC DERMATITIS Children with AD may develop more severe viral and bacterial skin infections compared with the general population. This is possibly because of their reduced immune status; yet it is only certain infections that are handled poorly. Eczema vaccinatum

164. Moorthy TT, Rajan VS. Juvenile plantar dermatosis in Singapore. Int J Dermatol. 1984;23:476–479. 165. Shipley DR, Kennedy CT. Juvenile plantar dermatosis responding to topical tacrolimus ointment. Clin Exp Dermatol. 2006;31:453–454. 166. Andreas Wollenberg, Stefanie Wetzel, et al. Viral infection in atopic dermatitis. Pathogenic aspects and clinical management. J Allergy Clin Immunol. 2003;12:667–674. 167. Goodyear HM, McLeish P, Randall S, et al. Immunological studies of herpes simplex virus infection in children with atopic eczema. Br J Dermatol. 1996;134:85–93.

864

Figure 14.17  Juvenile plantar dermatosis with fissure on the lateral aspect of the foot of an 11-year-old.

(EV) occurred when children or their families were inoculated with the vaccinia virus for the prevention of smallpox; it is no longer seen since vaccination has been discontinued. Nevertheless, there is concern that with the risk of bioterrorism or in military personnel and their children who have AD, this disease may resurface if vaccination is introduced once again. EV was associated with a high mortality rate.166 Herpes simplex virus (HSV) infection is now the main cause of extensive viral infection in AD patients. The eponym Kaposi’s varicelliform eruption is used for any herpetic or vaccinial infection that occurs in a number of widespread skin diseases. These include Darier’s disease, pemphigus foliaceous, burns, mycosis fungoides and Sézary syndrome, ichthyosis vulgaris and Hailey– Hailey disease.166 Herpetic infection in AD patients is known as eczema herpeticum (EH) (Figs 14.18, 14.19). Experimentally, there have been no demonstrable herpes simplex immune defects found in AD patients: it is thought that the reduced number of natural killer cells and IL-2 receptors may contribute to the susceptibility of children with AD to cutaneous HSV infections.167 Research has shown that specific cathelicidins are low in AD patients who are susceptible to EH.168 Patients with EH have a significantly earlier onset of AD, have severe manifestations of AD and a significantly higher total serum IgE level than control patients.169 The majority of EH occurs in patients with

168. Howell MD, Wollenberg A, Gallo RL, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117:836–841. 169. Beck LA, Boguniewicz M, Hata T, et al. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol. 2009;124:260–269, e1–e7.

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B A

Figure 14.19  Superficial secondary staphylococcal infection in a boy with atopic dermatitis (Courtesy Dr A. Torrelo).

untreated AD, arguing against a role for topical corticosteroids in the development of EH. More than 75% of the patients with EH had not received corticosteroid treatment in the 4 weeks prior to the onset of the vesicles.170 Lesions begin after a patient with AD has been in close contact with a person who has herpes simplex, most often on the lips; a history of contact with an infected person is not always

170. Wollenberg A, Zoch C, Wetzel S, et al. Predisposing factors and clinical features of eczema herpeticum: A retrospective analysis of 100 cases. J Am Acad Dermatol. 2003;49:198–205. 171. Currie JM, Wright RC, Miller OG. The frequency of warts in atopic patients. Cutis. 1971;8:243, 175. 172. Williams H, Pottier A, Strachan D. Are viral warts seen more commonly in children with eczema? Arch Dermatol. 1993;129:717–720. 173. Solomon LM, Telner P. Eruptive molluscum contagiosum in atopic dermatitis. Can Med Assoc J. 1966;95:978–979.

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Figure 14.18  (A) Typical vesicular lesions on the hand in eczema herpeticum; (B) Eczema herpeticum on the shoulder of a child with AD (Courtesy Dr A. Torrelo).

forthcoming. The eruption is usually associated with a primary infection, although recurrences of EH are quite common. A monomorphic eruption of dome-shaped vesicles on an erythematous base and subsequent pustules in the eczematous lesions along with fever and lymphopenia help make the clinical diagnosis. The eruption subsequently spreads to normal skin and within 24–48 h, small erosions with crusting occur. Prior to the availability of systemic acyclovir and antibiotics, the mortality for EH was high owing to systemic spread of the virus or superinfection with bacteria. Acyclovir should be administered either intravenously 15–30 mg/kg divided into three doses, or orally in a dose of 30 mg/kg per day for 7–10 days, depending on the severity of the condition. In addition to acyclovir, saline or Burow’s solution compresses may be useful and systemic antibiotics may be warranted. Verrucae171 are thought to be more common and severe in AD patients, but this was not corroborated in a report of verrucae and AD in the UK.172 and there are no other studies of this association. Mollusca contagiosa173 and the associated dermatitis are also thought to be more severe and widespread in children with AD.174 They may be more difficult to eliminate. Nevertheless mollusca do not persist indefinitely. Chickenpox (Varicella zoster virus) and other viral infections rarely cause problems in children with AD. Although the incidence of tinea corporis infections is supposedly increased,175 this has not been corroborated in any studies in children. Patients with AD have significant Staphylococcus aureus (S. aureus) colonization on their skin, and in the nares.176 The barrier defect in AD with inflammation from staphylococcal coloniza-

174. Wollenberg A, Wetzel S, Burgdorf WH, et al. Viral infections in atopic dermatitis: Pathogenic aspects and clinical management. J Allergy Clin Immunol. 2003;112:667–674. 175. Hanifin JM, Ray LF, Lobitz WC Jr. Immunological reactivity in dermatophytosis. Br J Dermatol. 1974;90:1–8. 176. Lebon A, Labout JA, Verbrugh HA, et al. Role of Staphylococcus aureus nasal colonization in atopic dermatitis in infants: the Generation R Study. Arch Pediatr Adolesc Med. 2009;163:745–749.

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tion and other stressors act to incite inflammation by stimulating a Th1 → Th2 shift in immunophenotype.177 Two studies suggest that clinical infection occurs frequently in AD patients with bad disease.173,178 However, despite large areas of excoriated skin and large numbers of staphylococcal organisms, patients seldom develop severe systemic infection. Two studies have found a reduction of S. aureus after the use of topical corticosteroids.179,180

Histologic findings

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The histologic picture in AD is non-specific and non-diagnostic. Acute dermatitis is characterized by epidermal intercellular edema (spongiosis). Intra-epidermal vesicles may be permeated by T lymphocytes and neutrophils may be present in the stratum corneum. The stratum corneum is often parakeratotic and contains aggregates of coagulated plasma, forming crusts clinically. The upper dermis shows vascular dilatation, edema, and a perivenular mononuclear cell infiltrate. Eosinophils, basophils, and neutrophils are present in normal numbers in the dermis. Chronic dermatitis shows epidermal acanthosis with regular elongation of rete ridges, hyperkeratosis, and little spongiosis. There is an increased number of IgE-bearing Langerhans cells (LC) in the epidermis181,182 and macrophages dominate the dermal mononuclear cell infiltrate.183 There are increased numbers of mast cells but they are generally fully granulated. Eosinophils may be increased and major basic protein (MBP) is often deposited in large amounts in the superficial dermis.184 MBP is a cytolytic protein produced by activated eosinophils which, together with other eosinophil-derived cytokines and mediators, contributes to inflammation and tissue injury. Demyelination and fibrosis of cutaneous nerves are seen at all levels of the dermis. The number of capillaries may be increased and their walls thickened.

177. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Opin Allergy Clin Immunol. 2009;9:437–446. 178. David TJ. Infection and prevention: current controversies in childhood atopic eczema: a review. J R Soc Med. 1989;82:420–422. 179. Stalder JF, Fleury M, Sourisse M, et al. Local steroid therapy and bacterial skin flora in atopic dermatitis. Br J Dermatol. 1994;131;536–540. 180. Nilsson EJ, Henning CG, Magnusson J. Topical corticosteroids and Staphylococcus aureus in atopic dermatitis. J Am Acad Dermatol. 1992;27:29–34. 181. Bruynzeel-Koomen C, van Wichen DF, Toonstra L, et al. The presence of IgE molecules on epidermal Langerhans cells in patients with atopic dermatitis. Arch Dermatol Res. 1986;278(3):199–205. 182. Barker JNWM, Alegre VA, MacDonald DM. Surface-bound immunoglobulin E on antigen presenting cells in cutaneous tissue of atopic dermatitis. J Invest Dermatol. 1988;90:117. 183. Leung DYM, Bhan AK, Schneeberger EE, et al. Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies. J Allergy Clin Immunol. 1983;71:47–56. 184. Cheng JF, Ott NL, Peterson EA, et al. Dermal eosinophils in atopic dermatitis undergo cytolytic degeneration. J Allergy Clin Immunol. 1997;99:683–692. 185. Elias PM. Epidermal lipids, barrier function, and desquamation. J Invest Dermatol. 1983;80(Suppl):44s–49s. 186. Fartasch M, Diepgen TL. The barrier function in atopic dry skin. Disturbance of membrane-coating granule exocytosis and formation of epidermal lipids? Acta Derm Venereol Suppl (Stockh). 1992;176: 26–31.

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PATHOPHYSIOLOGY OF ATOPIC DERMATITIS Thomas Bieber Barrier function A functional epidermal compartment is a prerequisite for competent physical and chemical barrier function of the skin, mainly provided by the brick and mortar-like structure of the stratum corneum.185 Clinically, epidermal barrier dysfunction is characterized by dry and scaly skin (xerosis) affecting lesional and non-lesional areas and results in a typical increased transepidermal water loss (TEWL) from the inside to the outside of the skin. Disturbed epidermal barrier function is an explanation for the facilitated penetration (outside-inside) of allergens, bacteria, and viruses. An alteration of skin ceramides with disturbed maturation of lamellar bodies, serving as the major water-retaining molecules in the extracellular space of the so-called cornified envelope has been implicated as causing this modification of the skin barrier.185–187 Furthermore, it has been shown that variations of the stratum corneum pH may impair lipid metabolism in the skin. Alterations in the expression of enzymes involved in the subtle balance of epidermal adhesion structures such as the chymotryptic enzyme (SCCE) and their anti-proteasic counterparts such as SPINK5 or KLK7 are also likely to contribute to the breakdown of the epidermal barrier in AD.188,189 Immunohistochemical190 and genetic studies have highlighted the importance of mutations in the filaggrin (FLG) gene as a crucial feature in the pathogenesis of AD. FLG aggregates the keratin cytoskeleton to provide the template for the subsequent step in the assembly of the cornified envelope, and its breakdown products play a role in the water-binding capacity of the stratum corneum191,192 instead of thereby perhaps allowing an increased penetration of environmental allergens into the skin is allowed193,194 and supported by intense pruritus, favoring immunological sensitization and inflammation.194,195

187. Imokawa G, Abe A, Jin K, et al. Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol. 1991;96:523–526. 188. Hansson L, Backman A, Ny A, et al. Epidermal overexpression of stratum corneum chymotryptic enzyme in mice: a model for chronic itchy dermatitis. J Invest Dermatol. 2002;118(3):444–449. 189. Vasilopoulos Y, Cork MJ, Murphy R, et al. Genetic association between an AACC insertion in the 3’UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis. J Invest Dermatol. 2004;123:62–66. 190. Seguchi T, Cui CY, Kusuda S, et al. Decreased expression of filaggrin in atopic skin. Arch Dermatol Res. 1996;288:442–446. 191. Scott IR, Harding CR. Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment. Dev Biol. 1986;115:84–92. 192. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-offunction variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38:441–446. 193. Proksch E, Folster-Holst R, Jensen JM. Skin barrier function, epidermal proliferation and differentiation in eczema. J Dermatol Sci. 2006;43: 159–169. 194. Hudson TJ. Skin barrier function and allergic risk. Nat Genet. 2006;38: 399–400. 195. Cork MJ, Robinson DA, Vasilopoulos Y, et al. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol. 2006;118:3–21; quiz 2–3.

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Dendritic cells in atopic dermatitis Once IgE-related sensitization has been developed, it is assumed that specific IgE represents the major recognition structure for allergens on effector cells or allergy, i.e. mast cells and basophils. Since the demonstration of IgE205,206 and the expression of its

196. Schroder JM, Harder J. Antimicrobial skin peptides and proteins. Cell Mol Life Sci. 2006;63:469–486. 197. Braff MH, Gallo RL. Antimicrobial peptides: an essential component of the skin defensive barrier. Curr Top Microbiol Immunol. 2006;306:91–110. 198. Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol. 2007;7:179–190. 199. McGirt LY, Beck LA. Innate immune defects in atopic dermatitis. J Allergy Clin Immunol. 2006;118:202–208. 200. Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–1160. 201. Rieg S, Steffen H, Seeber S, et al. Deficiency of dermicidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo. J Immunol. 2005;174:8003–8010. 202. Howell MD, Gallo RL, Boguniewicz M, et al. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity. 2006;24:341–348. 203. Peng WM, Jenneck C, Bussmann C, et al. Risk factors of atopic dermatitis patients for eczema herpeticum. J Invest Dermatol. 2007;127:1261–1263. 204. Howell MD, Wollenberg A, Gallo RL, et al. Cathelicidin deficiency predisposes to eczema herpeticum. J Allergy Clin Immunol. 2006;117:836–841. 205. Bruynzeel-Koomen C, van Wichen DF, Toonstra J, et al. The presence of IgE molecules on epidermal Langerhans cells in patients with atopic dermatitis. Arch Dermatol Res. 1986;278:199–205. 206. Bieber T, Dannenberg B, Prinz JC, et al. Occurrence of IgE-bearing epidermal Langerhans cells in atopic eczema: a study of the time course of the lesions and with regard to the IgE serum level. J Invest Dermatol. 1989;93:215–219.

high affinity receptor on epidermal Langerhans cells in patients with AD,207,208 the role of dendritic cells has been extensively studied in the context of AD.209 In lesional skin of AD, while plasmacytoid dendritic cells are almost absent,210 two distinct populations of myeloid dendritic cells have been reported: Langerhans cells (LC) and inflammatory dendritic epidermal cells (IDEC).211 Both express high density of the high affinity receptor for IgE (FcεRI) in lesional skin of AD but not in other conditions. While LC are present in normal skin, IDEC are detected only in inflamed skin. LC and IDEC play a central role in the uptake and presentation of allergens to Th1/Th2 cells and possibly also to regulatory T cells. Upon FcεRI ligation, LC produce IL-16 which specifically recruits CD4 T cells.212 However, they produce a limited range of chemokines such as MCP-1 and almost no proinflammatory cytokines.213 Upon allergen capture via FcεRI, Langerhans cells contribute Th2 polarization while IDEC lead to a Th1 polarization and to the release of proinflammatory cytokines. Using the atopy patch test as a model, it has been shown that 72 h after allergen challenge, high numbers of IDEC invade the epidermis while alterations of the phenotype of LC and IDEC occur including the upregulation of FcεRI.214

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Epithelial cells of the skin are equipped with highly conserved recognition structures, the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs),196–198 C-type lectins, nucleotide-binding oligomerization domain (NOD) and peptidoglycan recognition proteins.199 TLRs can bind a variety of microbial structures due to highly conserved surface molecules, the pathogen associated molecular pattern (PAMP). At least 10 different TLRs have been described so far in humans and are more or less specialized in binding bacterial, fungal (both cell walls) or viral (DNA or RNA with so-called CpG motifs) structures. The binding of microbial products to cell surface of epithelial cells leads to cell activation, ultimately resulting in the production of anti-microbial peptides (AMPs).196,197 These proteins belong to the family of defensins and cathelicidins. In human skin, at least one cathelicidin (LL37), three defensins, i.e. the beta defensin 1, 2 and 3 (HBD1, HBD2 and HDB3) and dermicidin have been described. Recently, it has been shown that AMPs are downregulated in the skin of human atopic individuals,200,201 most probably due to the particular inflammatory micromilieu exerted (created?) by the cytokines IL-4, IL-13 and IL-10.199,202 These findings provide the rationale for the altered competence in managing microbial attacks observed in AD patients. Lesional but also normal looking skin is highly colonized by bacteria such as Staphylococcus aureus or fungi such as Malassezia. They are also predisposed to extensive herpes infections such as eczema herpeticum or to eczema vaccinatum most probably due to a reduced production of LL-37.203,204

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T cells in atopic dermatitis Besides antigen presenting dendritic cells, a marked perivascular CD45RO/CLA+ T-cell infiltrate is found in lesional skin of AD. Allergen specific CD4 and CD8 T-cells can be isolated from lesional skin. However, although the Th2 mediated cytokines IL-4, IL-5 and IL-13 seem to be predominant in the acute phase of the disease, in chronic lesions an increase of IFN-γ and IL-12, as well as IL-5 and GM-CSF could be detected,215 being characteristic for a Th1/Th0 dominance. The maintenance of chronic AD involves the production of the Th1 cytokines IL-12 and IL-18, as well as several remodeling-associated cytokines such

207. Bieber T, de la Salle H, Wollenberg A, et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J Exp Med. 1992;175:1285–1290. 208. Wang B, Rieger A, Kilgus O, et al. Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI. J Exp Med. 1992;175:1353–1365. 209. Novak N, Bieber T. The role of dendritic cell subtypes in the pathophysiology of atopic dermatitis. J Am Acad Dermatol. 2005;53(Suppl 2):S171–S176. 210. Wollenberg A, Wagner M, Gunther S, et al. Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol. 2002;119:1096–1102. 211. Wollenberg A, Kraft S, Hanau D, et al. Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol. 1996;106:446–453. 212. Reich K, Heine A, Hugo S, et al. Engagement of the Fc epsilon RI stimulates the production of IL-16 in Langerhans cell-like dendritic cells. J Immunol. 2001;167:6321–6329. 213. Novak N, Valenta R, Bohle B, et al. FcepsilonRI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J Allergy Clin Immunol. 2004;113:949–957. 214. Kerschenlohr K, Decard S, Przybilla B, et al. Atopy patch test reactions show a rapid influx of inflammatory dendritic epidermal cells in patients with extrinsic atopic dermatitis and patients with intrinsic atopic dermatitis. J Allergy Clin Immunol. 2003;111:869–874. 215. Taha RA, Leung DY, Ghaffar O, et al. In vivo expression of cytokine receptor mRNA in atopic dermatitis. J Allergy Clin Immunol. 1998;102: 245–250.

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as IL-11 and transforming growth factor (TGF)β-1, expressed preferentially in chronic forms of the disease.216 IFN-γ produced by Th1 cells has been implicated in the Fas-induced apoptosis of keratinocytes in AD.217 Clearly, a generalized Th2-deviated immune response is closely linked to the condition of AD, but the skin disease itself is a biphasic inflammation with an initial Th2 phase, followed by chronic lesions harboring Th0/Th1 cells. This biphasic pattern of T-cell activation has also been demonstrated in studies on allergen patch-test skin reaction sites.218 Twenty-four hours after allergen application to the skin, increased expression of IL-4 mRNA and protein is observed, after which IL-4 expression declines to baseline levels. In contrast, IFN-γ mRNA expression is not detected in 24-h patch-test lesions, but is strongly overexpressed at the 48–72 h time points. Interestingly, the increased expression of IFN-γ mRNA in atopic patch-test lesions is preceded by a peak of IL-12 expression coinciding with the appearance of eosinophils and IDEC. These cells may therefore be instrumental in this Th2 to Th1/Th0 switch. The recruitment of T cells into the skin is orchestrated by a complex network of cytokines and chemokines which may contribute to the chronicity of the inflammatory reaction. Homeostatic and inflammatory chemokines produced by keratinocytes and/or endothelial cells have been shown to be involved in this process,219 as supported by microarray analyses.220 The IL-7-like cytokine TSLP221 induces dendritic cells to produce CCL17 and CCL22, two major atopy-associated chemokines. These chemo­ kines preferentially attract CCR4+ Th2 cells. Furthermore, TSLPtreated dendritic cells contribute to expand T cells producing IFN-γ and IL-5 and IL-13. Thus, TSLP may amplify and sustain proallergic response as well as the generation of IFN-γ producing cytotoxic T cells in the skin.222 Interestingly, TSLP overexpression in mice leads to an atopic dermatitis-like phenotype and an increased IgG and IgE .The chemokines CCL1, CCL27 (CTACK) and CCL18 represent the most strongly expressed chemokines in AD.223–225 However, whether these chemokines behave differently in the acute versus chronic phase of the disease remains to be explored. Most of the chemokines can be upregulated upon skin challenge with allergens or Staphylococcus aureus-derived products.

216. Toda M, Leung DY, Molet S, et al. Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions. J Allergy Clin Immunol. 2003;111:875–881. 217. Trautmann A, Akdis M, Kleemann D, et al. T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest. 2000;106:25–35. 218. Grewe M, Walther S, Gyufko K, et al. Analysis of the cytokine pattern expressed in situ in inhalant allergen patch test reactions of atopic dermatitis patients. J Invest Dermatol. 1995;105:407–410. 219. Homey B, Steinhoff M, Ruzicka T, et al. Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol. 2006;118:178–189. 220. Nomura I, Gao B, Boguniewicz M, et al. Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J Allergy Clin Immunol. 2003;112:1195–1202. 221. Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–680. 222. Gilliet M, Soumelis V, Watanabe N, et al. Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells. J Exp Med. 2003;197:1059–1063. 223. Morales J, Homey B, Vicari AP, et al. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci U S A. 1999;96:14470–14475.

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Finally, considering the chronicity of AD, the putative role of T cells with regulatory activities (Tregs)226 has been addressed more recently. High expression of the alpha-chain of the IL-2 receptor (CD25) as well as the nuclear factor Foxp3 have been suggested to be characteristic for these cells. Interestingly, while there is an increased pool of circulating CLA+, CCR6+ Tregs in the periphery of AD patients,227 lesional skin is devoid of functional Tregs.228 Clearly, the complexity of the Treg compartment is not yet fully solved and the role of these cells in the regulation of chronic inflammatory skin disease is yet to be understood.

Staphylococcus aureus The particular inflammatory micromilieu in AD alters the skin’s innate immune response and explains the strong colonization, in over 90% of AD patients, of Staphylococcus aureus (S. aureus).229 Binding of S. aureus to the skin is significantly enhanced in AD, probably due an altered composition of fibrin and fibrinogen. An increased activity of S. aureus-derived ceramidase may be responsible for aggravating the skin barrier and scratching enhances S. aureus binding by disturbing the skin barrier. Superinfections often provoke exacerbation of lesional skin. S. aureus derived toxins have been shown to play an important role in the pathogenesis of AD230 by amplifying the inflammatory reaction via multiple pathways. S. aureus-derived toxins A (SEA), B (SEB), C (SEC), and D (SED) are frequently detected in patients and provoke an IgE-mediated sensitization, which correlates with the disease severity.231 These toxins act as superantigens by interacting directly with the MHC–T-cell-complex on antigen presenting cells and induce an antigen-independent proliferation of T-cells. Toxins also upregulate the expression of the skin homing receptor CLA on T-cells and the production of keratinocyte-derived chemokines involved in the recruitment of T-cells. By inducing the competing β-isoform of the glucocorticoid receptor, superantigens induce a state of steroid resistance. Finally, S. aureusderived toxins subvert the function of regulatory T cells and may thereby augment skin inflammation.230 Taken together, S. aureusderived toxins largely contribute to the amplification of the skin inflammation and may lead to typical eczematoid skin reactions in AD patients.

224. Homey B, Alenius H, Muller A, et al. CCL27-CCR10 interactions regulate T cell-mediated skin inflammation. Nat Med. 2002;8:157–165. 225. Gombert M, Dieu-Nosjean MC, Winterberg F, et al. CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and Langerhanstype dendritic cells to sites of atopic skin inflammation. J Immunol. 2005;174:5082–5091. 226. Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol. 2006;24:209–226. 227. Ou LS, Goleva E, Hall C, et al. T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol. 2004;113:756–763. 228. Verhagen J, Akdis M, Traidl-Hoffmann C, et al. Absence of T-regulatory cell expression and function in atopic dermatitis skin. J Allergy Clin Immunol. 2006;117:176–183. 229. Leung DY. Infection in atopic dermatitis. Curr Opin Pediatr. 2003;15:399–404. 230. Cardona ID, Cho SH, Leung DY. Role of bacterial superantigens in atopic dermatitis: implications for future therapeutic strategies. Am J Clin Dermatol. 2006;7:273–279. 231. Bunikowski R, Mielke M, Skarabis H, et al. Prevalence and role of serum IgE antibodies to the Staphylococcus aureus-derived superantigens SEA and SEB in children with atopic dermatitis. J Allergy Clin Immunol. 1999;103:119–124.

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Besides sensitization to food and aeroallergens, it has been reported that the majority of sera from patients with severe AD contain IgE antibodies directed against a variety of human (self-) proteins.232,233 The serum levels of these IgE autoantibodies correlate to the disease severity. Several distinct proteins, coined as autoallergens, have been characterized including structures expressed in keratinocytes and endothelial cells.234–236 They are possibly generated by molecular mimicry due to homology between environmental allergens such as microbial structures and self-proteins. Since the autoallergens characterized so far are mainly intracellular proteins, release of these structures from damaged keratinocytes and recognition by IgE must be due to cellular damage secondary to scratching. A recent study has shown that 25% of adult patients display IgE autoantibodies. Early onset disease, strong pruritus, recurrent bacterial skin infections and high total IgE levels are the hallmarks of these individuals. Furthermore, the emergence of IgE against autoallergens can be detected as early as at the age of 1 year. Based on these data, it has been speculated that IgE immune responses are initiated by environmental allergens in combination with skin inflammation. However, allergic inflammation can be maintained by human endogenous antigens in patients with severe AD. If the postulated pathophysiological role of these antibodies is confirmed, AD should be considered as a disease at the frontier between allergy and autoimmunity.

DIFFERENTIAL DIAGNOSIS OF ATOPIC DERMATITIS The differential diagnosis of AD includes other eczematous disorders: scabies, seborrheic dermatitis, contact dermatitis, psoriasis, immunodeficiency and other rare causes should also be considered (Box 14.6). It is difficult at times to distinguish scabies from AD, particularly in infants. Both diseases are extremely pruritic. Xerosis and facial involvement are findings in AD, although in infancy it is not unusual for scabies to affect the face. Recent onset of itching in family members is helpful in the diagnosis of scabies. There are typical burrows and hyperpigmented nodules, which are not features of AD. The eruption of scabies is polymorphous, with papules, nodules, vesicles, eczematous, and urticarial lesions all occurring in the same individual. Palms and soles in infants often have small typical pustules and burrows are most easily visualized in these areas. If a child presents for the first time with a pruritic eruption at the age of 5, scabies would be more likely than AD. Seborrheic dermatitis (SD) is no longer seen with the same frequency in the Western world as it was 10–15 years ago. It presents in infants around 6 weeks of age and is usually asymp-

232. Valenta R, Maurer D, Steiner R, et al. Immunoglobulin E response to human proteins in atopic patients. J Invest Dermatol. 1996;107: 203–208. 233. Mittermann I, Aichberger KJ, Bunder R, et al. Autoimmunity and atopic dermatitis. Curr Opin Allergy Clin Immunol. 2004;4:367–371. 234. Valenta R, Natter S, Seiberler S, et al. Molecular characterization of an autoallergen, Hom s 1, identified by serum IgE from atopic dermatitis patients. J Invest Dermatol. 1998;111:1178–1183. 235. Aichberger KJ, Mittermann I, Reininger R, et al. Hom s 4, an IgE-reactive autoantigen belonging to a new subfamily of calcium-binding proteins,

BOX 14.6 RARE CAUSES OF DERMATITIC ERUPTIONS 1. Acrodermatitis enteropathica 2. Agammaglobulinemia 3. Ataxia telangiectasia 4. Gluten-sensitive enteropathy 6. Langerhans cell histiocytosis 7. Hurler syndrome 8. Leiner’s disease 9. Omenn syndrome 10. Phenylketonuria 11. Prolidase deficiency 12. Wiskott–Aldrich syndrome

ATOPIC DERMATITIS

Role of autoallergens

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tomatic. It may be difficult to distinguish between the ‘cradle cap’ and diffuse scaling on the scalp seen in both AD and SD. Whereas in AD the scale is dry and excoriations are frequent, in SD the scale is yellow and greasy. The popliteal fossae may be affected with erythematous patches in both conditions. In AD the lesions are exudative and in SD they have more scale. Yates et al. have shown that the differentiation between AD and SD is not always obvious in early infancy, as pruritus may rarely be prominent in SD.237 Allergy or irritation may result in a contact dermatitis which mimics AD. In infants and young children, an allergic contact dermatitis is not common; nickel allergy is the most frequent. Nickel dermatitis presents as an eczematous eruption following the pattern of an undershirt or sleepwear with nickel snaps. There are often other eczematous areas (an Id reaction) far from the area of contact, particularly in the antecubital fossae, making it difficult to distinguish from AD as pruritus may occur in SD. Psoriasis is not uncommon in infancy and childhood. In infants, it is mostly seen in the diaper area and scalp but may be seen anywhere. In children it is most common on the scalp, elbows, and knees, but may occur anywhere. The lesions are usually asymptomatic, while AD is intensely pruritic, and consist of scaly erythematous, well-demarcated small plaques. The typical silver scale seen in adults is not common particularly in the diaper area. The main reason for confusion with AD is the lack of recognition of psoriasis in this age group. Immunodeficiency disorders, including agammaglobu­ linemia, Wiskott–Aldrich disease, Netherton syndrome, and Omenn syndrome present early in life and look just like AD. Pruritus is a feature of all these diseases. The lack of localization, failure to thrive, and recurrent infections point to an immunodeficiency. There is generally hepatosplenomegaly in Omenn

can induce Th cell type 1-mediated autoreactivity. J Immunol. 2005; 175:1286–1294. 236. Schmid-Grendelmeier P, Fluckiger S, Disch R, et al. IgE-mediated and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis. J Allergy Clin Immunol. 2005;115:1068–1075. 237. Yates VM, Kerr RE, MacKie RM. Early diagnosis of infantile seborrhoeic dermatitis and atopic dermatitis – clinical features. Br J Dermatol. 1983;108:633–638.

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syndrome, which is not a feature of AD. Bleeding with hemorrhagic crusts and dermatitis is typical of Wiskott–Aldrich syndrome. Other causes of dermatitis may be confused with AD (Box 14.6). Atopic dermatitis may be so severe that whole-body erythema results. This must be differentiated from other causes of erythroderma in infants and children. These include various ichthyoses, Netherton syndrome, psoriasis, pityriasis rubra pilaris, nutritional deficiencies, and drug eruptions.

THERAPEUTICS Eric Simpson ATOPIC DERMATITIS

Effective management of atopic dermatitis AD hinges upon establishing good rapport with the child and parents. During the first office visit, parents need to be educated about the nature of the disease, potential aggravating factors to be avoided, and treatment strategies they can implement. A printed handout with instructions may be helpful to the family. Due to the chronic relapsing course of AD, parents have often become disillusioned and skeptical. They are usually subjected to a barrage of information from well-meaning friends, relatives, and healthcare professionals, much of which may be misleading and conflicting. Having a child with moderate to severe AD has a profound impact on the social, emotional, and financial perspectives of families.238 Effective treatment not only improves the quality of the child’s life but also helps the entire family unit.

The role of education Education develops rapport, empowers parents and improves compliance. Several studies have shown that supplementary education, such as with a nurse educator, can greatly improve disease control.239,240 Some key areas to be specifically addressed during the child’s first visit are steroid phobia, the role of allergy in AD, and proper skin care. Worry regarding the risk of topical steroid use is common, with 24% of families in one study reporting non-compliance with topical steroids due to safety concerns.241 The true degree of the underuse of topical steroids is likely much higher. One small study revealed proper compliance with topical steroid use occurred in only one-third of patients.242 Potential risks and benefits of steroidal medications should be thoroughly explained, emphasizing the vital role they play in flare control. Explaining that the risks of undertreatment, such as chronically inflamed skin and diminished sleep quality with the associated detrimental effects on growth and development,

238. Su JC, Kemp AS, Varigos GA, et al. Atopic eczema: its impact on the family and financial cost. Arch Dis Child. 1997;76:159–162. 239. Cork MJ, Britton J, Butler L, et al. Comparison of parent knowledge, therapy utilization and severity of atopic eczema before and after explanation and demonstration of topical therapies by a specialist dermatology nurse. Br J Dermatol. 2003;149:582–589. 240. Ricci G, Bendandi B, Aiazzi R, et al. Three years of Italian experience of an educational program for parents of young children affected by atopic dermatitis: improving knowledge produces lower anxiety levels in parents of children with atopic dermatitis. Pediatr Dermatol. 2009;26:1–5. 241. Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol. 2000;142:931–936. 242. Krejci-Manwaring J, Tusa MG, Carroll C, et al. Stealth monitoring of adherence to topical medication: adherence is very poor in children with atopic dermatitis. J Am Acad Dermatol. 2007;56:211–216.

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can aid in this discussion. Education regarding the etiology of the disease will also help allay fears regarding allergy. It is important to clarify that allergic sensitizations (positive skin prick tests or elevated serum IgE (RAST) tests) are primarily useful in determining which exposures may lead to immediate food reactions or asthma exacerbations, not eczematous flares. Redirecting parental energy away from allergic concerns and towards proper skin care leads to improved results. One study revealed that good topical skin care and disease control allay food allergy concerns.243 Written instructions with detailed information regarding bathing, cleansing, moisturizer use, and topical steroids are essential. Written action plans have improved compliance in asthma management but have yet to be formally studied in AD.244

Basic skin care Atopic dry skin is characterized by a decrease in skin lipids, an altered water-binding capacity of the stratum corneum, and increased transepidermal water loss.245 This impaired barrier function leads to increased skin irritability. Bubble baths and excessive exposure to soap, shampoo, and detergents aggravate dryness and should be discouraged; however, bathing is not considered to be harmful for atopic dry skin. Indeed, bathing in lukewarm water for 5–15 minutes rehydrates the stratum corneum,246 although benefits are only seen if an emollient is applied within 2–3 min of leaving the water to prevent evaporation.247 Bathing once or twice daily is soothing during an acute flare, helps reduce bacterial counts, and aids penetration of topical steroids applied after the bath. Showering is not as beneficial, but a short shower is not harmful, as long as an emollient is applied immediately afterwards. A mild, unscented, emollient or moisturizing soap or soap substitute can be used if necessary. There are many emollients available that are suitable for use on atopic dry skin. In general, creams and ointments are more beneficial than lotions. Urea and lactic acid-based creams are effective for dry skin but can cause stinging on areas of inflammation. Some children appear to be very prone to the sensation of stinging and, in this situation, a bland emollient such as petroleum jelly (white petrolatum) or petrolatum-based ointment is preferable. Compliance deteriorates if treatments produce discomfort. The moisturizer should be applied two or more times a day, with an application always after bathing. The moisturizer should not be applied over any medicated therapy to avoid dilution effects. Although frequent moisturizing reduces the irritability of atopic skin, patients with AD have a lower itch threshold than those with normal skin. Irritants to be avoided

243. Thompson MM, Hanifin JM. Effective therapy of childhood atopic dermatitis allays food allergy concerns. J Am Acad Dermatol. 2005;53 (Suppl 2):S214-S219. 244. Chisolm SS, Taylor SL, Balkrishnan R, et al. Written action plans: potential for improving outcomes in children with atopic dermatitis. J Am Acad Dermatol. 2008;59:677–683. 245. Aoki T, Fukuzumi T, Adachi J, et al. Re-evaluation of skin lesion distribution in atopic dermatitis. Analysis of cases 0 to 9 years of age. Acta Derm Venereol Suppl (Stockh). 1992;176:19–23. 246. Stender IM, Blichmann C, Serup J. Effects of oil and water baths on the hydration state of the epidermis. Clin Exp Dermatol. 1990;15: 206–209. 247. Hanifin JM, Tofte SJ. Update on therapy for atopic dermatitis. J Allergy Clin Immunol. 1999;104:S123–S125.

Eczematous dermatitis

Overall therapeutic strategy Considering the chronic and relapsing nature of AD, optimal management can be divided into three phases: (1) the shortterm clearance phase for treatment of flares, (2) a long-term maintenance phase that prolongs the period until the next AD flare, and (3) a disease relapse strategy. This step-wise approach to therapy will improve the management of most patients with AD; however, it is labor-intensive for the patient and timeconsuming for the physician to explain. The goal of the clearance phase is to gain acute control of the inflammation with the use of topical steroid ointments for 3–10 days for mild to moderate disease. The use of topical therapies on damp skin after bathing enhances penetration. An emollient should be applied to non-inflamed areas and a short course (5 days) of antibiotics appropriate to the sensitivities of the infecting organism should be prescribed if crusting or pustules are present. Severe disease may require the use of wet-wraps or a short course (1–6 months) of oral cyclosporine to obtain adequate control. Factors contributing to the disease flare should be identified and addressed such as improper skin care or a concurrent Sta-

phylococcus infection. Scheduling a follow-up visit 1 week after the initial visit gives an opportunity to provide moral support to the patient or family during the intensive clearance phase, and an opportunity to reinforce the maintenance strategies. There is also some evidence that frequent follow-up visits improve compliance.248 The maintenance phase then begins with utilizing good skin care and moisturization for mild to moderate disease. If the disease flares within 1 month despite the routine application of emollient, begin a topical calcineurin inhibitor (TCI) twice daily to early disease to reduce the need for topical steroid re-introduction. In severely affected patients that may not be adequately maintained on this regimen, topical steroids twice weekly, or once daily TCIs two or three times per week, applied to normal skin at frequent flare sites, can prolong the time between flares.249–253 More severe disease may require UVB phototherapy or chronic oral immunosuppressive therapy to maintain control. Disease relapse should be controlled using a shorter version (3–5 days) of the disease clearance strategy. The strength, length of use, and type of topical therapy will vary depending on the disease severity, the degree of lichenification, and response to previous treatment courses. Very mild disease may resolve with emollients alone. Suggested detailed treatment courses for AD not responding to emollients alone are shown in Table 14.2.

ATOPIC DERMATITIS

include woolen clothing, abrasive or occlusive synthetic fabrics, sand, grass, and direct skin contact with irritating foods such as citrus fruits.

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Table 14.2  Suggested detailed treatment courses for AD not responding to emollients alone PHASE OF TREATMENT

MILD DISEASE

MODERATE DISEASE

SEVERE DISEASE

Clearance phase

Low potency topical steroid twice daily ×4–7 days, after bathing

Medium to high potency topical steroid twice daily ×4–7 days after bathing

High potency steroid after bathing or with wet wraps ×5–10 days or start cyclosporine 5 mg/kg

Maintenance phase

Petrolatum-based emollients twice daily to uninvolved skin and twice weekly topical steroids to new areas of inflammation

Petrolatum-based emollients twice daily to uninvolved skin and TCI twice daily to residual or recurrent disease or twice weekly topical steroid to active areas

Petrolatum-based emollients twice daily to uninvolved skin and topical steroid 2×/week to healed areas that frequently flare or TCI three times weekly to healed sites that frequently flare and early recurrent disease and/or phototherapy or systemic therapy such as methotrexate or cyclosporine

TCI, topical calcineurin inhibitor.

248. Feldman SR, Camacho FT, Krejci-Manwaring J, et al. Adherence to topical therapy increases around the time of office visits. J Am Acad Dermatol. 2007;57:81–83. 249. Peserico A, Stadtler G, Sebastian M, et al. Reduction of relapses of atopic dermatitis with methylprednisolone aceponate cream twice weekly in addition to maintenance treatment with emollient: a multicentre, randomized, double-blind, controlled study. Br J Dermatol. 2008;158: 801–807. 250. Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patients. Br J Dermatol. 2002;147:528–537.

251. Berth-Jones J, Damsstra RJ, Golsch S, et al. Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double-blind, parallel group study. BMJ. 2003;326:1367. 252. Paller AS, Eichenfield LF, Kirsner RS. Three times weekly tacrolimus ointment reduces relapse in stabilized atopic dermatitis: A new paradigm for use. Pediatrics. 2008;122:e1210–e1218. 253. Thaçi D, Reitamo S, Gonzalez Ensenat MA, et al; European Tacrolimus Ointment Study Group. Proactive disease management with 0.03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study. Br J Dermatol. 2008;159: 1348–1356.

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Glucocorticoids

ATOPIC DERMATITIS

Topical glucocorticoids remain the mainstay for the treatment of AD flares. Inflammation should be treated aggressively initially, with the aim of complete or near complete clearance. Once areas of inflammation have completely cleared, the steroid should be stopped and the skin moisturized regularly. In more moderate to severe disease that flares shortly after an intensive 1–2 week course of mid- to high-potency topical steroids, twice weekly mid-potency steroid applied to either normal skin that frequently flares or to early disease has been shown to be safe for up to 20 weeks.254,255 The choice of strength and vehicle of topical steroid depends on several factors including disease severity, disease distribution, presence of lichenification, and compliance. In general, topical steroid ointment preparations are preferable to creams as they are more potent due to their occlusive effects, provide a better temporary skin barrier, and produce less stinging. New drug delivery vehicles have been recently developed including emollient foams, hydrogels, lotions and creams that are well tolerated even in inflamed skin. Newer formulations of mild and midpotency steroids (desonide and fluticasone) have safety data available in children as young as 3 months.256–259 These new products are significantly more expensive than their generic ointment counterparts, although they may be useful in improving compliance in older children, especially in hot, humid climates where ointments can feel overly occlusive. Lotions and solutions may be used for scalp therapy, although their alcohol content frequently produces burning discomfort. Parents should be warned to avoid use of any potency of topical steroid for longer than 1 week in areas that are prone to skin atrophy such as the face, neck, axillae, and groin. Low potency topical steroids (1–2.5% hydrocortisone acetate, desonide) are adequate for mild cases of AD. For moderate to severe disease, a medium-potency preparation such as triamcinolone acetonide 0.1% may be used. If a medium potency topical steroid is used, a weaker preparation can be used on sensitive areas such as the face, or alternatively, the mediumpotency topical steroid can be applied to the face, but for only 2–3 days. Using only one steroid preparation for face and body can reduce the confusion of having multiple steroids for different body parts. In general, highly potent steroids are not usually required, except for localized areas in longstanding dermatitis where significant lichenification has developed. Topical steroids are the treatment of choice for disease flares but they may also play a role in reducing flares in controlled disease. Three studies, all including pediatric patients, have shown a greatly reduced time to flare after initial disease control

254. Hanifin JM, Paller AS, Eichenfield L, et al. Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol. 2005;53(Suppl 2):S186–S194. 255. Berth-Jones J, Takwale A, Tan E, et al. Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br J Dermatol. 2002;147:324–330. 256. Hebert AA, Cook-Bolden FE, Basu S, et al. Desonide Hydrogel Study Group. Safety and efficacy of desonide hydrogel 0.05% in pediatric subjects with atopic dermatitis. J Drugs Dermatol. 2007;6:175–181. 257. Branco N, Branco BC, Maibach HI. Cutaneous corticosteroid therapy and cataract in man. Cutan Ocul Toxicol. 2002;21:161–168. 258. Hebert AA, Desonide Foam Phase III Clinical Study Group. Desonide foam 0.05%: safety in children as young as 3 months. J Am Acad Dermatol. 2008;59:334–340.

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when a topical steroid is used twice weekly to normal skin sites that frequently flare.249–251 All studies showed a reduced time to first flare and a fewer number of flares. There were no reports of atrophy in 16–20 weeks of maintenance therapy. Wet dressings are a useful adjunct to topical steroids. The evaporation of water from the skin surface results in vasoconstriction, relief of pruritus, and debridement of crusts from the skin surface.260 Percutaneous penetration of topical steroids is increased, generally reducing the total quantity of steroid required to settle an acute flare. Some clinicians use total-body wet dressings, which can be done with clothing such as pajamas, cotton tubular dressings or wet towels. After a bath, a low- to medium-potency topical steroid is applied to inflamed areas. A warm, damp layer of clothing or dressing is then applied, followed by a dry layer. These dressings can be left on for as long as 8 h, but are often better tolerated for short periods of 20– 30 min. The dressings are done two or three times a day for 3–7 days, until the flare settles. Localized wet dressings, such as damp socks for ankles, are useful when there is marked lichenification and slow response to topical steroids alone. Failure to respond to topical steroids is usually due to inadequate quantities being applied (poor compliance, fear of adverse effects), inadequate quantities prescribed or use of an inappropriately weak preparation. Superinfection or the development of contact allergy to the topical steroid or other topical preparations being applied may also need to be considered. Tachyphylaxis can develop, so periodically changing the topical steroid prescribed or rotating with calcineurin inhibitors may be necessary. When topical steroids are used appropriately, they have a good safety profile and an excellent risk to benefit ratio.261 It is important to emphasize this to parents, as ‘corticophobia’ is widespread. Local adverse effects are potency-dependent and include perioral dermatitis (steroid-induced rosacea) on the face, telangiectasias, folliculitis, secondary infections, atrophy, striae, local hypertrichosis, and allergic contact dermatitis.261 Atrophy and striae are the most significant and feared local adverse effects, but are rarely seen with low- to medium-strength preparations, particularly in children under 10 years of age. These local adverse effects may complicate the use of potent and superpotent preparations, particularly when inappropriately used on the face, neck, closed flexures, breasts, and inner thighs in teenagers. Rare cases of glaucoma and cataracts have been reported, primarily with inappropriate prolonged treatment to the periocular area.257,262 There is no evidence to date in human or animal studies that prolonged topical steroids are carcinogenic to the skin, although few long-term studies have been performed. The Food and Drug Administration requires long-term carcinogen-

259. Eichenfield LF, Miller BH, Cutivate Lotion Study Group. Two randomized, double-blind, placebo-controlled studies of fluticasone propionate lotion 0.05% for the treatment of atopic dermatitis in subjects from 3 months of age. J Am Acad Dermatol. 2006;54:715–717. 260. Weston WL, Lane AT, Morelli JG. Color textbook of pediatric dermatology. St Louis: Mosby; 1996. 261. Callen J, Chamlin S, Eichenfield LF, et al. A systematic review of the safety of topical therapies for atopic dermatitis. Br J Dermatol. 2007;156:203–221. 262. Sahni D, Darley CR, Hawk JL. Glaucoma induced by periorbital topical steroid use – a rare complication. Clin Exp Dermatol. 2004;29: 617–619.

Eczematous dermatitis

263. Goodyear HM, Spowart K, Harper JI. ‘Wet wrap’ dressings for the treatment of atopic dermatitis (Letter). Br J Dermatol. 1991;125:604. 264. Wolkerstorfer A, Visser RL, De Waard van der Spek FB, et al. Efficacy and safety of wet wrap dressings in children with severe atopic dermatitis: influence of corticosteroid dilution. Br J Dermatol. 2000;143:999–1004. 265. Ellison JA, Patel L, Ray DW, et al. Hypothalamic-pituitary-adrenal function and glucocorticoid sensitivity in atopic dermatitis. Pediatr. 2000;105: 794–799. 266. Heuck C, Ternowitz T, Herlin T, et al. Knemometry in children with atopic dermatitis treated with topical glucocorticoids. Pediatr Dermatol. 1998;15: 7–11. 267. Patel L, Clayton PE, Addison GM, et al. Linear growth in prepubertal children with atopic dermatitis. Arch Dis Child. 1998;79:169–172. 268. Grassberger M, Baumruker T, Enz A, et al. A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases; in vitro pharmacology. Br J Dermatol. 1999;141:264–273. 269. Kelly PA, Burckart GL, Venkataramana R. Tacrolimus: a new immunosuppressive agent. Am J Health Syst Pharm. 1995;52:1521–1535. 270. Fleischer AB. Treatment of atopic dermatitis: Role of tacrolimus ointment as a topical noncorticosteroid therapy. J Allergy Clin Immunol. 1999;104:S126–S130. 271. De Paulis A, Stellato C, Cirillo R, et al. Anti-inflammatory effect of FK-506 on human skin mast cells. J Invest Dermatol. 1992;98:800–804. 272. Lawrence ID. Tacrolimus (FK-506): experience in dermatology. Dermatol Ther. 1998;5:74–84. 273. Reitamo S, Rissanen J, Remitz A, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single centre randomized trial. J Invest Dermatol. 1998;111:396–398.

Title calcineurin inhibitors (TCIs) Tacrolimus and pimecrolimus are non-steroidal immunosuppressants that act directly on T lymphocytes, particularly CD4 cells. They bind to cytoplasmic proteins of the immunophilin family, forming a complex.268,269 This complex then binds to, and competitively inhibits, calcineurin, a phosphatase that is active only when bound to calcium and calmodulin. The binding phenomenon inhibits the ability of calcineurin to activate the promotor region of the gene for IL-2, -3, -4, -5, GM-CSF, TNF-α and IFN-γ.270 It also inhibits the release of mast cell and basophil preformed mediators271 and downregulates FcεRI on LC.272 This broad range of inflammatory inhibition mechanisms may downregulate the entire inflammatory cascade leading to clinical disease. TCIs have no effect on collagen synthesis, therefore do not produce skin atrophy.273 A systematic review from 2005 of 25 randomized controlled studies involving over 4000 participants revealed both pimecrolimus and tacrolimus to be more effective than placebo.274 There have been few studies comparing TCI efficacy to that of topical steroids, so the relative anti-inflammatory potency of these agents is difficult to determine. Tacrolimus 0.03% and 0.1% have been shown to be superior to hydrocortisone acetate 1%275 and equivalent to the Class 5 topical steroid, hydrocortisone butyrate 0.1%.276 Tacrolimus 0.1% was superior to pimecrolimus cream in two head-to-head studies.277,278 Tacrolimus and pimecrolimus are currently approved as second-line therapy for the treatment of AD when the continued use of topical corticosteroids is unsafe or ineffective. In practice, they are usually used in conjunction with topical steroids. A common way they are utilized is as steroid-sparing agents. For example, after a flare has been controlled with corticosteroids, a TCI may be applied to early recurrent disease to reduce the need for further steroid rescues. This ‘real-world’ approach has been formally studied and a reduction in steroid use along with improved disease control has been verified.279,280 TCIs are also helpful as monotherapy to thin skin areas such as the face, thighs, or intertriginous areas. Most recently, a new paradigm

ATOPIC DERMATITIS

esis animal studies as part of the approval process for new formulations of topical steroids, and no signals for carcinogenicity have been seen.261 Topical steroids can be absorbed into the systemic circulation. Hypothalamic-pituitary axis (HPA) suppression can be induced by potent topical steroids used over large areas in children and may transiently develop when diluted steroids are used under wet dressings.263,264 Ellison and colleagues265 showed that HPA suppression was rarely found in children or adolescents with moderate to severe AD who used mild- or moderate-potency topical steroids over many years. Several studies of low- to-mid potency topical steroids have not shown evidence of HPA-axis suppression. The clinical relevance of HPA-axis suppression by topical steroids is unknown. Growth retardation has been the biggest concern and the most difficult to study. Children with AD may have retarded growth due to severe dermatitis, nutritional factors, sleep disturbances, and concomitant asthma treated with inhaled or oral steroids. The kinemometer, a lower leg lengthmeasuring device, has been used to assess systemic activity of exogenous glucocorticoids in children. Heuck and colleagues266 showed twice-daily application of a potent topical steroid under occlusion did not significantly reduce growth rate, but growth significantly increased after it was discontinued. They hypothesized that, by controlling disease activity, growth potential improves. Patel and colleagues267 followed 80 pre-pubertal children with AD and reported they were not short compared with controls. As they approached teenage years, their height velocity decreased and a delay in bone age was noted, features consistent with constitutional growth delay. They did not find that prolonged treatment with moderate-potency topical steroids had any adverse influence on growth. A systematic review of topical steroid safety published in 2007 identified six studies examining growth and topical steroid use with varying results.261 Systemic steroids are rarely appropriate in the management of chronic atopic dermatitis. Although a short course (such as 5 days) will rapidly settle an acute flare, there is often a rebound flare after discontinuation. Long-term systemic steroids are contraindicated due to the myriad of associated systemic complications.

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274. Ashcroft DM, Dimmock P, Garside R, et al. Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials. BMJ. 2005;330:516. 275. Reitamo S, Van Leent EJ, Ho V, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol. 2002;109:539–546. 276. Reitamo S, Rustin M, Ruzicka T, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol. 2002;109: 547–555. 277. Fleischer AB Jr, Abramovits W, Breneman D, et al; US/Canada tacrolimus ointment study group. Tacrolimus ointment is more effective than pimecrolimus cream in adult patients with moderate to very severe atopic dermatitis. J Dermatol Treat. 2007;18:151–157. 278. Paller AS, Lebwohl M, Fleischer AB Jr, et al. US/Canada Tacrolimus Ointment Study Group. Tacrolimus ointment is more effective than pimecrolimus cream with a similar safety profile in the treatment of atopic dermatitis: results from 3 randomized, comparative studies. J Am Acad Dermatol. 2005;52:810–822. 279. Sigurgeirsson B, Ho V, Ferrandiz C, et al. Effectiveness and safety of a prevention-of-flare-progression strategy with pimecrolimus cream 1% in the management of paediatric atopic dermatitis. J Eur Acad Dermatol Venereol. 2008;22:1290–1301. 280. Gollnick H, Kaufmann R, Stough D, et al. Pimecrolimus cream 1% in the long-term management of adult atopic dermatitis: prevention of flare progression. A randomized controlled trial. Br J Dermatol. 2008;158: 1083–1093.

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has emerged where intermittent TCI application to healed areas is used to improve long-term control of moderate-severe disease. Studies have shown that tacrolimus applied two or three times a week to frequent flare sites greatly improves long-term control.252,253 The safety of pimecrolimus and tacrolimus has been demonstrated in several short- and long-term studies in the pediatric population including global trials involving more than 7600 children using tacrolimus alone.254,255,281–283 However, in 2005, the US Food and Drug Administration (FDA) initiated a review of the TCIs. This was based on rare reports of cancer in patients using TCIs, and a theoretical risk of malignancy based on the mechanism of action of TCIs, as well as data from animal studies with sustained high exposure to TCIs and data from transplant recipients receiving systemic calcineurin inhibitors.284,285 The FDA review was followed by product label revisions for tacrolimus ointment and pimecrolimus cream in January 2006 that included the addition of a black-box warning and a medication guide. Some systemic absorption is detectable early in treatment, decreasing as skin barrier function improves.286 In the largest pediatric study to date involving 351 atopic children, 84% had no detectable blood levels.287 Kawashima and colleagues288 also reported significant blood levels in patients with severe AD who were initially treated with large quantities (10–20 g/day) of tacrolimus; however, laboratory results (including serum creatinine) show no changes and no systemic adverse events have been reported. Harper and colleagues289 noted consistently low blood levels in children aged 1–4 years, even in those with up to 69% of body surface area treated; recent safety reviews have concluded that systemic exposure to TCIs is minimal and transient, with maximum blood concentration in most patients below the limit of quantification. No data have been found to associate TCIs with an increased risk of lymphoproliferative disease282 and some recent data suggest that there may be a reduced risk of lymphoma in AD patients290,291; however, the long-term safety, especially with respect to future skin malignancy, is not known. Ongoing long-term observational trials will provide further information on the safety profile of TCIs.292,293

Although the TCIs are only approved for use in children over the age of 2 years, studies of pimecrolimus in infants 3–23 months of age have also shown good efficacy with no untoward adverse events294 and minimal systemic absorption.295 The most common side-effects encountered with the use of TCIs are stinging and burning at the application site. These are usually mild and resolve within the first few days of use.283,296 The probability of experiencing burning and stinging can be greatly reduced by initiating a few days of topical corticosteroid prior to initiating TCIs, especially in moderate–severe flares.

281. Beck LA. The efficacy and safety of tacrolimus ointment: a clinical review. J Am Acad Dermatol. 2005;53(Suppl 2):S165-S170. 282. Munzenberger PJ, Montejo JM. Safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Pharmacotherapy. 2007;27: 1020–1028. 283. Wahn U, Bos JD, Goodfield M, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics. 2002;110:e2. 284. Krueger GG, Eichenfield L, Goodman JJ, et al. Pharmacokinetics of tacrolimus following topical application of tacrolimus ointment in adult and pediatric patients with moderate to severe atopic dermatitis. J Drugs Dermatol. 2007;6:185–193. 285. US Food and Drug Administration. Alert for healthcare professionals – Pimecrolimus (marketed as Elidel) 2008. Available at: www.fda.gov/ cder/drug/infosheets/hcp/elidelHCP.htm (accessed April 18, 2008). 286. Alaiti S, Kang S, Fiedler VC, et al. Tacrolimus (FK-506) ointment for atopic dermatitis: A phase I study in adults and children. J Am Acad Dermatol. 1998;38:69–76. 287. Paller A, Eichenfield LF, Leung DY, et al. A 12-week study of tacrolimus ointment for the treatment of dermatitis in pediatric patients. J Am Acad Dermatol. 2001;44(Suppl 1):S47–S57. 288. Kawashima M, Nakagawa H, Ohtsuki M, et al. Tacrolimus concentrations in blood during topical treatment of atopic dermatitis. Lancet. 1996;348: 1240–1241. 289. Harper J, Green A, Scott G, et al. First experience of topical SDZ ASM 981 in children with atopic dermatitis. Br J Dermatol. 2001;144:781–787.

290. Arellano FM, Wentworth CE, Arana A, et al. Risk of lymphoma following exposure to calcineurin inhibitors and topical steroids in patients with atopic dermatitis. J Invest Dermatol. 2007;127:808–816. 291. Arellano FM, Arana A, Wentworth CE, et al. Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom. J Allergy Clin Immunol. 2009;123:1111–1116, e1–e13. 292. Rico M, Paller A. APPLES: A prospective pediatric longitudinal evaluation to assess the long-term safety of tacrolimus ointment for the treatment of atopic dermatitis. Buenos Aires, Argentina: World Congress of Dermatology; Oct 2007. 293. The Pediatric Eczema Elective Registry (PEER) Program. Available at: www.ThePeerProgram.org 294. Lakhanpaul M, Allen BR, Wahn U, et al. Pimecrolimus (Elidel SDZ ASM 981) cream 1%: minimal systemic absorption in infants with extensive atopic eczema. Poster, 2001. 295. Papp K, Ho V, Halbert A, et al. Pimecrolimus (Elidel SDZ ASM 981) cream 1% is effective and safe in infants aged 3–23 months with atopic eczema. Poster presented at American Academy of Dermatology, 60th Annual Meeting, New Orleans, 2001. 296. Soter NA, Fleischer AB Jr, Webster GF, et al. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part II, safety. J Am Acad Dermatol. 2001;44(1 Suppl):S39–S46. 297. Boguniewicz M, Zeichner JA, Eichenfield LF, et al. MAS063DP is effective monotherapy for mild to moderate atopic dermatitis in infants and children: a multicenter, randomized, vehicle-controlled study. J Pediatr. 2008;152:854–859.

Skin barrier repair devices The skin barrier is compromised in the lesional skin of AD as evidenced by increased transepidermal water loss, reduced water-holding capacity and an increased susceptibility to irritants. Three new prescription creams, MimyX (Steifel Labora­ tories), Epiceram (Ceragenix), and Atopiclair297 (Graceway Pharmaceuticals), have arrived on the market that make claims of improving AD and restoring the skin barrier. These therapies were approved under the Food and Drug Administration’s 510(k) registration, which classifies these therapies as medical devices which, by definition, do not contain an active ingredient and serve purely as a barrier. Little clinical data regarding diseasespecific efficacy is needed in 510(k) approval. Limited data suggest that these products may have modest efficacy in AD, but currently their role in AD management is unclear.

Treatment of infection With the increasing recognition of the role of Staphylococcus aureus as a trigger factor for AD, antibacterial therapy should be considered during acute flares. It is important to distinguish clinically between colonization and infection: almost all patients with AD are colonized with Staphylococcus, and thus cultures alone are not an indication for treatment. Widespread golden crusting, follicular pustules, and furuncles suggest sta-

Eczematous dermatitis

Allergen avoidance Many parents have the notion that finding the cause of their child’s AD through allergy assessment will reduce the need for topical treatment. Often, these notions are reinforced by the findings of positive allergy tests (ordered by allergists or alternative practitioners) and equating these with true allergy. Allergy is defined as ‘an adverse health event that results from stimulation of a specific immune response’.307 Positive tests without clinical correlations should not be interpreted as allergy. Parents should be informed that, even if food or environmental allergies are truly present, effective treatment for AD still revolves around good skin care and topical therapy. Allergy testing does not need to be routinely ordered but may be considered for children with a history of acute food reactions or those with intractable AD who are not progressing well despite good topical therapy. Any elimination diets instituted should be strictly supervised by pediatricians or nutritionists to ensure they are nutritionally adequate. Reducing exposure to environmental allergens, particularly house dust mites and animal dander, has not been shown to prevent or improve established AD.303 Given the large number of negative prospective studies,308,309 these measures cannot be recommended for routine use in AD management or prevention.

Antihistamines and leukotriene inhibitors

Phototherapy

Antihistamines have long been used in AD, although few randomized, double-blind, placebo-controlled clinical studies have evaluated efficacy. Klein and Clark,302 in an evidence-based review of the efficacy of antihistamines in relieving the pruritus of AD, concluded that the majority of trials (16 studies published between 1966 and 1999) have been flawed in terms of sample size or study design. A systematic review published in 2004 found little evidence to support the use of sedating or nonsedating antihistamines in AD treatment.303 Anecdotally, sedating antihistamines can be useful in promoting sleep during a flare, but there is little evidence to support the effectiveness of non-sedating agents. There appears to be no role for leukotriene antagonists in the treatment of AD. Three controlled studies in adults failed to find any benefit from montelukast therapy in AD.304–306

Phototherapy can reduce both pruritus and inflammation in AD. All forms of phototherapy are best introduced after the stabilization of an acute flare and should be considered an adjunct to topical therapy. Children need to be at least old enough to cooperate with phototherapy and one should be aware of future effects if using ultraviolet light for long periods. Ultraviolet radiation has potent inhibitory effects on antigen presentation by Langerhans cells, and on T lymphocyte activation, and can modify cytokine production by keratinocytes.310 Both UVB (280–320) and UVA (320–400) alone have been shown to be effective, but the response rate improves with the combination of UVB and UVA.311,312 The emerging phototherapy of choice has become narrowband UVB. Three uncontrolled studies in children have shown narrowband UVB to be both safe and effective for the short-term treatment of AD in children.313–315

298. Nilsson EJ, Henning CG, Magnusson J. Topical corticosteroids and Staphylococcus aureus in atopic dermatitis. J Am Acad Dermatol. 1992;27:29–34. 299. Metry D. Poster from Society for Pediatric Dermatology Annual Meeting. Chicago; July 2007. 300. Paller J. ISAD poster. 2008. 301. Krakowski AC, Eichenfield LF, Dohil MA. Management of atopic dermatitis in the pediatric population. Pediatrics. 2008;122:812–824. 302. Klein PA, Clark RAF. Evidence based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol. 1999;135:1522–1525. 303. Hanifin JM, Cooper KD, Ho VC, et al. Administrative regulations for evidence-based clinical practice guidelines. Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association. J Am Acad Dermatol. 2004;50:391–404. 304. Veien NK, Busch-Sorensen M, Stausbol-Gron B. Montelukast treatment of moderate to severe atopic dermatitis in adults: a randomized, doubleblind, placebo-controlled trial. J Am Acad Dermatol. 2005;53:147–149. 305. Friedmann PS, Palmer R, Tan E, et al. A double-blind, placebo-controlled trial of monetlukast in adult atopic eczema. Clin Exp Allergy. 2007;37: 1536–1540.

306. Capella GL, Grigerio E, Altomare G. A randomized trial of leukotriene receptor antagonist montelukast in moderate-to-severe atopic dermatitis of adults. Eur J Dermatol. 2001;11:209–213. 307. Kimber I, Dearman RJ. What makes a chemical a respiratory sensitizer? Curr Opin Allergy Clin Immunol. 2005;5:119–124. 308. Simpson EL. Atopic dermatitis prevention. Dermatol Ther. 2006;19: 108–117. 309. Harris JM, Williams HC, White C, et al. Early allergen exposure and atopic eczema. Br J Dermatol. 2007;156:698–704. 310. Cooper KD. New therapeutic approaches in atopic dermatitis. Clin Rev Allergy. 1993;11:543–557. 311. Jekler J, Larko O. Combined UVA-UVB versus UVB phototherapy for atopic dermatitis: A paired comparison study. J Am Acad Dermatol. 1990;22:49–53. 312. Sidbury R, Hanifin JM. Old, new and emerging therapies for atopic dermatitis. Dermatol Clin. 2000;18:1–11. 313. Jury CS, McHenry P, Burden AD, et al. Narrowband ultraviolet B (UVB) phototherapy in children. Clin Exp Dermatol. 2006;31:196–199. 314. Clayton TH, Clark SM, Turner D, et al. The treatment of severe atopic dermatitis in childhood with narrowband ultraviolet B phototherapy. Clin Exp Dermatol. 2007;32:28–33. 315. Ahmad K, Rogers S, McNicholas PD, et al. Narrowband UVB and PUVA in the treatment of mycosis fungoides: a retrospective study. Acta Derm Venereol. 2007;87:413–417.

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phylococcal infection and this can be readily confirmed with a swab (using a moistened cotton swab) for Gram stain and bacterial culture. Treatment with topical steroids alone reduces the density of staphylococcal organisms on the skin,298 but clinical outcome is improved if combined with oral anti­biotics such as dicloxacillin or cefalexin (cephalexin) (both 40  mg/kg per day in four divided doses). Erythromycin (30–50  mg/kg daily) is suitable for penicillin-allergic patients unless there is resistance. Increasing staphylococcal resistance (MRSA) should be considered; antibiotics such as clindamycin or trimethoprim/ sulfa may be needed depending on antibiotic sensitivities. For isolated episodes of infection, treatment duration of 5 days is usually adequate. For children with severe dermatitis and recurrent infections, more prolonged courses of oral antibiotics may be indicated, but the risk of antibiotic resistance increases. In these children, antibiotic sensitivities should be periodically rechecked as resistant strains of Staphylococcus aureus may emerge. Diluted sodium hypochlorite baths (‘bleach baths’) at a final concentration of 0.005% may reduce the staphylococcal burden in chronically infected patients and may improve disease control.299,300 This concentration can be achieved with 1 4 − 1 2 cup of common bleach in a full 40 gallon bathtub.301

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Narrowband UVB has been shown to be more effective than broadband UVB,316 broadband UVA, UVA,317 and medium dose UVA1.318 No head-to-head studies have compared narrowband UVB with UVA/UVB combination. UVA1 is more effective than conventional UVA/UVB combination319 but has not yet been studied in children. It is likely to be poorly tolerated as the treatment duration is long (30–60 min) and, unless the machine is modified,320 it causes marked overheating and discomfort. The adverse effects of UVA1 are not well delineated. PUVA therapy (8-methoxypsoralen and UVA) is effective for chronic recalcitrant AD, although potential adverse effects of premature aging and malignancy need to be discussed in detail. Sheehan and colleagues321 evaluated 53 children (mean age 11.2 years) with severe AD, unresponsive to other therapy. Twice-weekly treatment resulted in clearance or near clearance of disease in 39 (74%) after a mean of 9 weeks, with a cumulative UVA dose of 1118 J/cm.245 Of particular note, 82% of these 39 children were able to maintain remission of disease following gradual withdrawal of treatment.

Systemic immunosuppressive therapy Cyclosporin Cyclosporin is the best studied and most effective systemic therapy for pediatric AD, although renal toxicity precludes its long-term use. Cyclosporin (CyA) is a macrolide immunosuppressive that alters cytokine gene transcription, inhibiting T cell activation, and modulating the cell-mediated immune response.322 It may work in AD by altering IL-4 transcription and monocyte interleukin-10 production, promoting a Th1 cytokine profile.323 Since 1984, several randomized controlled studies have confirmed the efficacy and safety of oral CyA in the treatment of AD in children as reviewed by Schmitt et al. in 2008.32 The use of CyA in childhood AD should be limited to patients with severe disease, poorly controlled with more conservative therapy. It is most effective if started at 5 mg/kg and then tapered to doses ranging between 2.5 and 5 mg/kg. Because of potential adverse effects, the duration of treatment should be kept short (3–6 months). A maintenance strategy must be in place as CyA

316. George SA, Bilsland DJ, Johnson BE, et al. Narrowband (TL-O1) UVB air-conditioned phototherapy for chronic severe adult atopic dermatitis. Br J Dermatol. 1993;128:49–56. 317. Reynolds NJ, Franklin V, Gray JC, et al. Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial. Lancet. 2001;357:2012–2016. 318. Legat FJ, Hofer A, Brabek E, et al. Narrowband UV-B vs medium-dose UV-A1 phototherapy in chronic atopic dermatitis. Arch Dermatol. 2003;139:223–224. 319. Krutmann J, Diepgen TL, Luger TA, et al. High-dose UVA1 therapy for atopic dermatitis: results of a multicenter trial. J Am Acad Dermatol. 1998;38:589–593. 320. Von Kobyletzki G, Pieck C, Hoffmann K, et al. Medium dose UVA-1 cold-light phototherapy in the treatment of severe atopic dermatitis. J Am Acad Dermatol. 1999;41:931–937. 321. Sheehan MP, Atherton DJ, Norris P, et al. Oral psoralen photochemotherapy in severe childhood atopic eczema: an update. Br J Dermatol. 1993;129:431–436. 322. Liu J. FK 506 and cyclosporin; molecular probes for studying intracellular signal transduction. Immunol Today. 1993;14:290–295. 323. Campbell DE, Kemp AS. Cyclosporin restores cytokine imbalance in childhood atopic dermatitis. J Allergy Clin Immunol. 1997;99:857–859. 324. Harper JI, Ahmed I, Barclay G, et al. Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol. 2000;142:52–58.

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is being tapered, such as narrowband UVB or intensive topical therapy. Harper and colleagues324 reported an alternative dosing strategy using multiple short courses (12 weeks) for 1 year that was comparable to continuous dosing. Parents must be thoroughly informed of the potential for renal damage, hypertension, cytochrome P450 drug interactions and possibly increased malignancy if used long term. Topical preparations of CyA are ineffective.325

Azathioprine Two RCTs have shown a 25–37% improvement in adults with AD.255,326 There have been no controlled studies of azathioprine in children. The largest retrospective study revealed that of the 48 children treated with azathioprine, 85% had a ‘good’ or ‘excellent’ response.327 Despite the paucity of studies, a survey of dermatologists in the UK reported that 75% used azathioprine to treat adult patients with severe AD and 3% in childhood AD; 89% found it effective.328 Dosing of azathioprine should be made according to the patient’s thiopurine methyltransferase levels and ranges between 0.5 mg and 2.5 mg/kg per day.329 More research is obviously required, but it may be an option for children or adolescents with severe AD unresponsive to other therapies. Side-effects of long-term use may include a risk of lymphoma and skin cancer as has been seen in solid-organ transplant patients, although no cases of lymphoma have been reported in dermatological patients.330

Mycophenolate mofetil Mycophenolate mofetil (MMF) is an immunosuppressant medication that inhibits inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis used by B and T lymphocytes. Data on the use of MMF for AD is limited to case reports and case series. In 2007, Heller et al. described the experiences of 14 pediatric patients treated with MMF for severe AD.331 Only one patient did not respond and eight patients had at least a 90% improvement. Responses were seen at doses of 30–50 mg/kg per day in this study. The benefit of MMF is that it does not cause nephrotoxicity like CyA and may not have the same risk of lymphoma that has been seen with azathioprine.332

325. De Prost Y, Bodemer C, Teillac D. Randomised double-blind placebocontrolled trial of local cyclosporin in atopic dermatitis. Acta Dermatol Venereol (Stockh). 1989;144:136–138. 326. Meggitt SJ, Gray JC, Reynolds NJ. Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial. Lancet. 2006;367: 839–846. 327. Murphy LA, Atherton D. A retrospective evaluation of azathioprine in severe childhood atopic eczema, using thiopurine methyltransferase levels to exclude patients at high risk of myelosuppression. Br J Dermatol. 2002;147:308–315. 328. Tan BB, Lear JT, Gawkrodger DJ, et al. Azathioprine in dermatology: A survey of current practice in the UK. Br J Dermatol. 1997;136:351–355. 329. Wolverton SE. Comprehensive dermatologic drug therapy. In: Wolverton SE, ed. Philadelphia: WB Saunders; 2001. 330. Gruber SA, Skjei KL, Sothern RB, et al. Cancer development in renal allograft recipients treated with conventional and cyclosporine immunosuppression. Transplant Proc. 1991;23:1104–1105. 331. Heller M, Shin HT, Orlow SJ, et al. Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patients. Br J Dermatol. 2007;157:127–132. 332. Robson R, Cecka JM, Opelz G, et al. Prospective registry-based observational cohort study of the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil. Am J Transplant. 2005;5:2954–2960.

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Methotrexate Methotrexate has been used effectively in the pediatric population to treat psoriasis,333 but there are no studies examining methotrexate for the treatment of pediatric AD. Uncontrolled studies suggest methotrexate has some efficacy in treating adult AD, so it is an option for the pediatric patient with severe disease.334 Doses tolerated in a previous study of pediatric psoriasis ranged between 0.2 and 0.4 mg/kg.335

Biologics To date, interferon gamma (IFN-γ) remains the best studied and only biologic proven effective for AD. Although the aim of recombinant IFN-γ therapy is to correct a Th2:Th1 imbalance, the exact mechanisms underlying the efficacy of IFN-γ in AD are unknown. Several studies have now shown IFN-γ to produce clinical benefit, with about 45% of patients achieving >50% improvement.336 Treatment is accompanied by a reduction in circulating eosinophil counts but no decline in serum IgE. It appears to be safe, even when used for as long as 24 months.337 Adverse effects include flu-like symptoms, leukopenia, and thrombocytopenia. Its cost and the need for subcutaneous administration preclude widespread use. Efalizumab (Raptiva, a monoclonal antibody that blocks T cell activation and migration) has shown some improvement in AD in an open-label study of adults.338 One patient developed prolonged thrombocytopenia. Only one pediatric patient has been reported to have received efalizumab for AD. Despite an initial

333. Kaur I, Dogra S, De D, et al. Systemic methotrexate treatment in childhood psoriasis: further experience in 24 children from India. Pediatr Dermatol. 2008;25:184–188. 334. Weatherhead SC, Wahie S, Reynolds NJ, et al. An open-label, dose-ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol. 2007;156:346–351. 335. Kumar B, Dhar S, Handa S, et al. Methotrexate in childhood psoriasis. Ped Dermatol. 1994;11: 271–273. 336. Hanifin JM, Schneider LC, Leung DY, et al. Recombinant interferon gamma therapy for atopic dermatitis. J Am Acad Dermatol. 1993;28:189–197. 337. Stevens SR, Hanifin JM, Hamilton T, et al. Long term effectiveness and safety of recombinant human interferon gamma therapy for atopic dermatitis despite unchanged serum IgE levels. Arch Dermatol. 1998;134:799–804. 338. Takiguchi R, Tofte S, Simpson B, et al. Efalizumab for severe atopic dermatitis: a pilot study in adults. J am Acad Dermatol. 2007;56:222–227. 339. Allen A, Siegfried E, Silverman R, et al. Significant absorption of topical tacrolimus in 3 patients with Netherton syndrome. Arch Dermatol. 2001;137:747–750. 340. Jacobi A, Antoni C, Manger B, et al. Infliximab in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol. 2005;52:522–526. 341. Buka RL, Resh B, Roberts B, et al. Etanercept is minimally effective in 2 children with atopic dermatitis. J Am Acad Dermatol. 2005;53:358–359.

positive clinical response, the child developed thrombocytopenia and it had to be discontinued.339 Most recently, three cases of fatal PML have been reported in patients with psoriasis treated with efalizumab leading to a boxed warning in 2009. Further safety data are needed before efalizumab can be recommended as a potential therapy for AD. Elevated levels of TNF-γ in lesions of AD and TNF-α inhibition may improve inflammation. Jacobi et al. described nine adult subjects who were given doses of infliximab, 5 mg/kg up to 38 weeks.340 Only two subjects showed a positive response after 10 weeks. Buka and colleagues described two pediatric patients with AD who did not respond favorably to etanercept, although the doses used (25 mg twice a week and 12.5 mg twice a week) were lower than typically used for the treatment of psoriasis.341 There are small uncontrolled studies reporting benefits from the use of alefacept and rituximab in adult AD; however, these agents have not been studied in the pediatric population.342,343

ATOPIC DERMATITIS

The pregnancy category for MMF is D because of reports of serious congenital malformations from maternal exposure to the drug. Appropriate contraceptive precautions should be in place for females of childbearing age. The Medication Guide for MMF was also updated in 2009 to reflect the cases of progressive multifocal leukoencephalopathy (PML) reported in some patients on this medication. Other side-effects may include headache, anemia, leukopenia, urinary symptoms, weakness and gastrointestinal disturbances.

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Other treatments for AD Thymopentin is a synthetic pentapeptide derived from the thymic hormone thymopoietin. It promotes the differentiation of mature T lymphocytes and has been proposed to do so preferentially for the Th1 subset.310 Clinical efficacy has been shown,344,345 but the need for daily subcutaneous injections is a disadvantage. Tar preparations such as 5–10% liquor carbonis detergens cream can be useful for thick, lichenified plaques of dermatitis. Topical sodium cromoglycate can also be used, with the aim of inhibiting mast cell degranulation. Kita and Hiratsuka346 used 1% topical sodium cromoglycate in a water solution and noted benefit; Moore and colleagues347 showed anti-inflammatory effect with cromolyn sodium inhalation solution mixed with a water-based emollient cream concentration of 0.21% concentration. These preliminary findings require further follow-up with larger series. Oral evening primrose oil contains the n6 series of essential fatty acids. Although a few small studies have shown benefit in AD,348–350 these have been criticized for methodological flaws.

342. Moul DK, Routhouska SB, Robinson MR, et al. Alefacept for moderate to severe atopic dermatitis: a pilot study in adults. J Am Acad Dermatol. 2008;58:984–989. 343. Simon D, Hosli S, Kostylina G, et al. Anti-CD20 (rituximab) treatment improves atopic eczema. J Allergy Clin Immunol. 2008;121:122–128. 344. Kang K, Cooper KD, Hanifin JM. Thymopentin pentapeptide (TP-5) improves clinical parameters and lymphocyte subpopulations in atopic dermatitis. J Am Acad Dermatol. 1983;8:372–377. 345. Leung DYM, Hirsch RL, Schneider L, et al. Thymopentin therapy reduces the clinical severity of atopic dermatitis. J Allergy Clin Immunol. 1990;85: 927–933. 346. Kita H, Hiratsuka S. Effect of topical cromoglycate solution on atopic dermatitis: combined treatment of sodium cromoglycate solution with the oral anti-allergic medication, oxatomide. Eur J Pediatr. 1994;153:66–71. 347. Moore C, Ehlayel MS, Junprasert J, et al. Topical sodium cromoglycate in the treatment of moderate to severe atopic dermatitis. Ann Allergy Asthma Immunol. 1998;81:452–458. 348. Lovell CR, Burton JL, Horrobin DF. Treatment of atopic eczema with evening primrose oil. Lancet. 1981;1:278. 349. Wright S, Burton JL. Oral evening primrose seed oil improves atopic eczema. Lancet. 1982;2:1120–1122. 350. Schalin-Karrila M, Mattila L, Jansen CT, et al. Evening primrose oil in the treatment of atopic eczema: effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. Br J Dermatol. 1987;117: 11–19.

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Three large double-blind placebo-controlled parallel group studies have failed to show any benefit.351–353 Phosphodiesterase (PDE) inhibitors target the cyclic nucleotide abnormalities characteristic of AD. Potent PDE inhibitors given orally have a high incidence of nausea and vomiting, but Hanifin and colleagues354 have identified a type 4 PDE inhibitor (CP-80633) that provided rapid and persistent anti-inflammatory activity when used topically. This is not available for clinical use. There are several anecdotal reports of high-dose intravenous immunoglobulin (IVIG) being of therapeutic value in adults and children with AD,355–357 although Wakim and colleagues failed to show benefit in one small open label study.358 Traditional Chinese herbal medicine has also been used to treat AD. Although benefit has been shown with some preparations,359,360 potentially life-threatening adverse events such as hepatotoxicity, cardiomyopathy, and renal failure have been reported.361 One analysis of Chinese herbal creams showed eight of 11 samples contained dexamethasone.362 Supportive psychotherapy and behavior therapy have also been advocated as adjuncts to other treatment for AD (systematic review). Schachner and colleagues363 showed benefits from parental massage for 20 min each day. The children’s dermatitis, affect and activity level improved and parental anxiety decreased.

Prognosis and course of the disease AD is a disease of exacerbations and remissions. Although the majority of patients with AD improve with age, there are a disturbing number of cases that persist into adult life and a small subsection that have their dermatitis for the first time in adult life. It is prudent that patients with severe AD be advised to refrain from occupations that involve irritants to the hands, as there may be an increased incidence of hand dermatitis in adults who have had AD. There are numerous factors that influence this persistence of AD: severity of the eruption, development in the first 6 months

351. Berth-Jones J, Graham-Brown RAC. Placebo-controlled trial of essential fatty acid supplementation in atopic dermatitis. Lancet. 1993;341:1557–1560. 352. Bamford JT, Gibson RW, Renier CM. Atopic eczema unresponsive to evening primrose oil. J Am Acad Dermatol. 1985;13:959–965. 353. Hederos CA, Berg A. Epogam evening primrose oil treatment in atopic dermatitis and asthma. Arch Dis Child. 1966;75:494–497. 354. Hanifin JM, Chan SC, Cheng JB, et al. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol. 1996;107:51–56. 355. Kita H. High dose gammaglobulin treatment for atopic dermatitis. Arch Dis Child. 1994;70:335–336. 356. Gelfand EW, Landwehr LP, Esterl B, et al. Intravenous immune globulin: an alternative therapy in steroid dependent allergic diseases. Clin Exp Immunol. 1996;104(Suppl 1):61–66. 357. Jolles S, Hughes J, Rustin M. The treatment of atopic dermatitis with adjunctive high dose intravenous immunoglobulin: a report of 3 patients and review of the literature. Br J Dermatol. 2000;142:551–554. 358. Wakim M, Alazard M, Yajima A, et al. High dose intravenous immunoglobulin in atopic dermatitis and hyper IgE syndrome. Ann Allergy Asthma Immunol. 1998;81:153–158. 359. Sheehan MP, Atherton DJ. One-year follow up of children treated with Chinese medicinal herbs for atopic eczema. Br J Dermatol. 1994;140:488–493. 360. Armstrong N, Ernst E. Treatment of eczema with Chinese herbs; a systematic review of randomized clinical trials. Br J Clin Pharmacol. 1999;48:262–264. 361. Ernst E. Adverse effects of herbal drugs in dermatology. Br J Dermatol. 2000;143:923–929.

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of life, AD association with other atopic diseases, high IgE, acute food allergies and disease persisting after 5 years of age.364,365 Wuthrich365 followed 121 patients who had suffered from AD since infancy, reviewing them at the mean ages of 15 and 23.5 years. In only 11% of patients did the dermatitis disappear in childhood; persistence into adult life occurred in 63%, with 32% having a chronic continuous course. During puberty, 25% cleared, but in 20% AD reappeared. Other studies have also shown persistence of disease into adult life. Depending on the extent of the disease and other risk factors, figures vary anywhere from 15–80%.366,367 Despite these conflicting results, the majority of patients with AD have periods of complete clearing in teenage and adult life. The patients with persistent disease are not as severely affected as they had been in infancy and have much longer periods of remission between exacerbations. Asthma develops in approximately 30% of patients with AD.368 A study in a tertiary care center found 76% of the AD group had wheezing, whereas only 12% of the control group had this symptom.369 AD develops earlier than asthma and hayfever, and because of the time sequence the conditions are now known as the atopic march.370 Allergic rhinitis develops in 25% of AD patients,371 and 15% of patients with AD have both allergic rhinitis and asthma. There have been rare reports of AD with Hodgkin’s disease,372 Sézary syndrome,373 and cutaneous T-cell lymphoma.374 It is impossible to know if this is a coincidence or not.

DIAPER DERMATITIS James G. H. Dinoulos INTRODUCTION The terms ‘diaper dermatitis’, ‘napkin dermatitis’, ‘nappy rash’, and ‘diaper rash’ have been employed to describe the array of

362. Keane FM, Munn SE, du Vivier AWP, et al. Analysis of Chinese herbal creams prescribed for dermatological conditions. BMJ. 1999;318:563–567. 363. Schachner L, Field T, Hernandez-Reif M, et al. Atopic dermatitis symptoms decreased in children following massage therapy. Pediatr Dermatol. 1998;15:390–395. 364. Katoh N, Hirano S, Kishimoto S. Prognostic factor of adult patients with atopic dermatitis. J Dermatol. 2008;35:477–483. 365. Wuthrich B. Clinical aspects, epidemiology and prognosis of atopic dermatitis. Ann Allergy Asthma Immunol. 1999;83:464–470. 366. Katoh N, Hirano S, Kishimoto S. Prognostic factor of adult patients with atopic dermatitis. J Dermatol. 2008;35:477–483. 367. Sandström MH, Faergemann J. Prognosis and prognostic factors in adult patients with atopic dermatitis: a long-term follow-up questionnaire study. Br J Dermatol. 2004;150:103–110. 368. Burgess JA, Lowe AJ, Matheson MC, et al. Does eczema lead to asthma? J Asthma. 2009;46:429–436. 369. Sampson HA. Atopic dermatitis. Ann Allergy. 1992;69:469–479. 370. Kuster W, Peterson M, Christophers E, et al. A family study of atopic dermatitis: clinical and genetic characteristics of 188 patients and 2,151 family members. Arch Dermatol Res. 1990;282:98–102. 371. Salob SP, Atherton DJ. Prevalence of respiratory symptoms in children with atopic dermatitis attending pediatric dermatology clinics. Pediatrics. 1993;91:8–12. 372. Winkelmann RK, Rajka G. Atopic dermatitis and Hodgkin’s disease. Acta Dermatol Venereol (Stockh). 1983;63:176. 373. Rajka MD, Winkelmann RK. Atopic dermatitis and Sézary syndrome. Arch Dermatol. 1984;120:83–84. 374. Lange-Vejlsgaard G, Ralfkiaer E, Larsen JK, et al. Fatal cutaneous T cell lymphoma in a child with atopic dermatitis. J Am Acad Dermatol. 1989;20: 954–958.

Eczematous dermatitis

Inflammatory

>> Irritant diaper dermatitis >> Allergic contact diaper dermatitis >> Jacquet’s diaper dermatitis >> Granuloma gluteale infantum >> Intertrigo >> Perianal pseudoveruccous papules and nodules (PPPN) >> Seborrheic dermatitis >> Atopic dermatitis >> Psoriasis Infectious

>> Candidiasis >> Folliculitis (Staph. aureus) >> Perianal streptococcal disease >> Bullous impetigo Nutritional

>> Acrodermatitis enteropathica (zinc deficiency) >> Essential fatty acid deficiency >> Biotin deficiency >> Kwashiorkor secondary to malabsorption >> Cystic fibrosis >> Langerhans cell histiocytosis

skin conditions occurring under the diaper. Diaper rashes are among the most common skin conditions seen in infancy. Most diaper rashes occur as a direct result of wearing diapers and are referred to as irritant diaper dermatitis. Rarely, there is true allergic contact dermatitis to diapers. Primary cutaneous disorders such as psoriasis and seborrheic dermatitis frequently occur under the diaper and tend to be worsened by the occlusive properties of the diaper. Systemic disorders, such as acrodermatitis enteropathica and Langerhans cell histiocytosis, occur independently of the wearing of the diaper and may mimic irritant diaper dermatitis. Disorders of the gastrointestinal tract such as cystic fibrosis, celiac disease and inflammatory bowel disease often produce perineal eruptions as well as other inflammatory, infectious, nutritional, and malignant conditions as listed in Box 14.7.

375. Koblenzer PJ. Diaper dermatitis: an overview. Clin Pediatr. 1973;12:386. 376. Levin S. History of medicine-diapers. S Afr Med J. 1970;44:256–263. 377. Jacquet L. Traité des maladies de l’enfance. In: Grancher J, Comby J, Marfan AB, eds. Paris: Masson & Co; 1905:714. 378. Boisits EK, McCormack JJ. Diaper dermatitis and the role of predisposition. In: Maibach HI, Boisitis EK, eds. Neonatal skin; structure and function. New York: Marcel Dekker; 1982:191. 379. Zahorsky J. The ammoniacal diaper in infants and young children. Am J Dis Child. 1915;10:436. 380. Verbov JL. Skin problems in children. Practitioner. 1976;217:403–415. 381. Berg RW. Etiology and pathophysiology of diaper dermatitis. Adv Dermatol. 1988;3:75–90.

HISTORY OF DIAPERING The term diaper dermatitis includes all eruptions that occur in the area covered by the diaper. These conditions are caused directly by the wearing of diapers (irritant contact dermatitis), those that are aggravated by diapers (e.g., psoriasis), and those that occur whether or not diapers are worn (e.g., acrodermatitis enteropathica).375 In many societies where diapers are not worn, infants escape a condition that is commonly seen in pediatric practice in more industrialized countries.376 The first true description of diaper dermatitis was made by Jacquet in 1905,377 although Parrott described a lesion in the diaper area in 1887.378 In 1915, Zahorsky described the frequency of diaper eruptions associated with an ‘ammoniacal’ smelling diaper.379 In Great Britain in the 1970s, diaper dermatitis accounted for 20% of all skin consultations in the 0- to 5-year age group,380 and in Japan, the prevalence varied between 6% and 50%, depending on definitions and inclusion criteria.381–383 Since the advent of newer diapering practices, mainly the introduction of disposable diapers with super-absorbent gel centers, the figure has dropped considerably.384 Nevertheless, mothers in the USA still frequently consult pediatricians for diaper eruptions.385 Diapers have only gained widespread acceptance in the Western world during the last 70 years, with the appearance of the modern diaper in the 1920s. These have evolved through using pieces of cloth and safety pins, to the 1930s, when diaper services became widely available, and more recently to disposable diapers that have been used extensively in the last 40 years.376 There are three methods of diapering utilized in most countries. Parents can buy ready-made cloth diapers and launder them at home. With this method, there is a residue of chemicals left in the diaper despite numbers of rinses. It is the most common cause of irritant diaper dermatitis (IDD) in infants. Major problems in the past have arisen from antiseptics used in laundering.386,387 Quaternary ammonium compounds are now the most common chemical used in the laundering of home diapers. A diaper service is another method of diapering. Diaper services usually provide their customers with their own new diapers, that are collected weekly or bi-weekly. They are cycled through as many as 11 hot rinses, the first seven being with detergents. Two or more diapers may be used simultaneously, increasing the absorbency. The diapers are usually covered with a plastic pant. Disposable diapers were first used in the 1960s and have become increasingly refined. They have changed from paper, to an absorbable cellulose center, to the most modern diapers, which have a super-absorbent gel center carrying wetness from

DIAPER DERMATITIS

BOX 14.7 DIFFERENTIAL DIAGNOSIS OF AN ERUPTION IN THE DIAPER REGION

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382. Jordan WE, Lawson KD, Berg RW, et al. Diaper dermatitis frequency and severity among a general infant population. Pediatr Dermatol. 1986;3: 198–201. 383. Longhi F, Carlucci G, Bellucci R, et al. Diaper dermatitis: a study of contributing factors. Contact Derm. 1992;26:248–252. 384. Wong DL, Brantly D, Clutter LB, et al. Diapering choices: a critical review of the issues. Pediatr Nurs. 1992;18:41–54. 385. Krowchuk DP. Characterization of diaper dermatitis in the United States. Arch Pediatr Adolesc Med. 2000;154:943–946. 386. Brown BW. Fatal phenol poisoning from improperly laundered diapers. Am J Public Health. 1970;60:901. 387. Jensen JPA. Transcutaneous absorption of boron from a baby ointment used prophylactically against diaper dermatitis. Nord Med. 1971;86: 1425–1429.

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the inside to the outside of the diaper and leaving the skin dry. This is achieved by an intricate wicking system preventing back flow and a gel that can hold 80 times its weight. These newer diapers cause the least problems with diaper dermatitis, markedly reducing IDD.388–392 Even newer changes have employed a slow release of petrolatum,393 and a breathable outer sheet.394 Both formulations purport to further reduce the incidence of diaper dermatitis. One study, using diapers with a breathable outer sheet, reports a reduction in candidal diaper dermatitis.394 An added benefit of disposable diapers has been the development of cuffs that better contain urine and feces, contributing to a reduction in gastroenteritis in day-care settings.395–397 Studies have compared the incidence of IDD in diapers from a diaper service and disposable diapers, and have reached inconclusive results.398–400 No studies have compared the newer formulation of disposable diapers with diaper services. The crucial factor in preventing IDD appears to be the number of diaper changes and in this respect, both diaper service and disposable diapers are better than home-laundered diapers. One to two percent of non-biodegradable waste in North America is composed of disposable diapers. On the other hand, the 11 or more rinses in boiling water used by diaper services is a drain on natural resources.

Figure 14.20  Typical irritant contact dermatitis. The flexures are spared.

INFLAMMATORY CONDITIONS Irritant diaper dermatitis (IDD) True primary diaper dermatitis or ‘irritant diaper dermatitis’ is the most common eruption seen in the diaper area. The incidence of IDD is equal between the sexes. Commonly, IDD develops between 3 weeks and 2 years of age, but rarely may be seen in the immediate newborn period.401 It most commonly peaks between 6 and 9 months. IDD varies in appearance, depending upon the severity of the rash. Chafing of the diaper area may occur on the convex surfaces and a ‘tide mark’ dermatitis occurs at the margin of the diaper, sparing the creases (Fig. 14.20). This is caused by friction from the diaper and wet skin. A typical contact irritation is seen in well-demarcated patches corresponding to the area of the absorbent pads on the buttocks in toddlers wearing ‘pull-up’-style diapers (Fig. 14.21). Erythema on the buttocks may also be seen

388. Campbell RL, Seymour JL, Stone LC, et al. Clinical studies with disposable diapers containing absorbent gelling materials: evaluation of effects on infant skin condition. J Am Acad Dermatol. 1987;17:978–987. 389. Lane AT, Rehder PA, Helm K. Evaluations of diapers containing absorbent gelling material with conventional disposable diapers in newborn infants. Am J Dis Child. 1990;144:315–318. 390. de Prost Y. Results of an efficacy clinical diaper study with superabsorbent panty diaper conducted in French day care centers. In: Tronnier H, Schmitt GJ, eds. Diaper dermatitis: later insight into pathogenesis, prophylaxis, and therapy. Munich: Verlag Medical Concepts; 1987:111–114. 391. Oranje AP, Bilo AC, de Waard S, et al. Dutch clinical diaper study. In: Tronnier H, Schmitt GJ, eds. Diaper dermatitis: later insight into pathogenesis, prophylaxis and therapy. Munich: Verlag Medical Concepts; 1987:115–122. 392. Tronnier H. Tolerance and efficacy, characteristics of panty diapers with highly absorbent pad. In: Tronnier H, Schmitt GJ, eds. Diaper dermatitis: later insight into pathogenesis, prophylaxis and therapy. Munich: Verlag Medical Concepts; 1987:123–126. 393. Odio MR, O’Connor RJ, Sarbaugh F, et al. Continuous topical administration of a petrolatum formulation by a novel disposable diaper? Effect on skin condition. Dermatology. 2000;200:238–243.

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Figure 14.21  Contact dermatitis to the absorbent material in toddler style diapers (Courtesy Dr A. Lucky). in infants with cystic fibrosis who are treated with the enzyme cotazyme. Skin surfaces coming into direct contact with the diaper are subject to friction, and are more commonly affected. Mild IDD is generally asymptomatic; infants develop redness and mild

394. Akin F, Spraker M, Aly R, et al. Effects of breathable disposable diapers: reduced prevalence of candida and common diaper dermatitis. Pediatr Dermatol. 2001;18:282–290. 395. Van R, Wun CC, Morrow AL, et al. The effect of diaper type and overclothing on fecal contamination in day care centers. JAMA. 1991;265:1840–1844. 396. Kubinl M, Kressner B, Raynor W, et al. Comparison of stool containment in cloth and single-use diapers using a simulated infant feces. Pediatrics. 1993;91:632–636. 397. Van R, Morrow AL, Reves RR, et al. Environmental contamination in child daycare centers. Am J Epidemiol. 1991;133:460–470. 398. Seymour JL, Keswick BH, Hanifin JM, et al. Clinical effects of diaper types on the skin of normal infants and infants with atopic dermatitis. J Am Acad Dermatol. 1987;17:988–997. 399. Jordan WE, Blaney TL. Factors influencing infant diaper dermatitis. In: Maibach HI, Boisits EK, eds. Neonatal skin; structure and function. New York: Marcel Dekker; 1982:205. 400. Stein H. Incidence of diaper rash when using cloth and disposable diapers. J Pediatr. 1982;101:721–723. 401. Scheinfeld N. Diaper dermatitis: A review and brief survey of eruptions of the diaper area. Am J Clin Dermatol. 2005;6:273.

Eczematous dermatitis

scaling on the convex surfaces of the buttocks, thighs, and lower abdomen with relative sparing of the skin folds. In moderate to severe IDD, the skin becomes more deeply erythematous with a typical glistening or glazed appearance, and infants develop shiny pink papules, plaques and nodules that may become eroded, ulcerated and secondarily infected with bacteria and yeast. Patients may develop itchy pink papules (autoeczematous or ID reaction) beyond the diaper area.402 Severe diaper dermatitis such as Jacquet’s, granuloma gluteale infantum and Candida infection have separate designations and are discussed below. The causes of IDD had been partially elucidated. In the early 20th century, the odor of ammonia in diapers led to a theory that ammonia caused IDD. In 1921, Cooke described an organism, Bacterium ammoniagenes, capable of splitting urea into ammonia. He recovered this organism from the feces of infants with IDD, and proposed the term ‘ammoniacal dermatitis’. For much of the 20th century, treatment of ammoniacal dermatitis was aimed at inhibiting the growth of B. ammoniagenes. Rinsing diapers in dilute vinegar was thought to neutralize ammonia, and was the standard daily routine for infants with a diaper rash.403 In 1977, Leyden et al. further investigated the role of ammonia in IDD and found diaper ammonia concentrations and the percentage of bacteria capable of liberating ammonia from urea to be the same in infants with and without IDD. Furthermore, direct placement of ammonia under occlusion did not induce IDD, and the number of B. ammoniagenes, now known to be a Proteus species, was the same in children with and without IDD.404 The etiology of IDD is multifactorial. Contributing factors in the formation of IDD include skin wetness, biochemical irritants, and an increased pH of the stratum corneum (SC) as a consequence of exposure of the skin to urine and feces. The pH of normal skin ranges from 4.5 to 6.0. Skin pH is determined largely by metabolic pathways involving free fatty acid production from phospholipids, as well as exogenous elements such as lactic acid, eccrine sweat, and free fatty acids derived from sebaceous gland lipids. Acidification of the stratum corneum (acid mantle) is a tightly regulated process that protects the skin from harmful microorganisms and promotes pH-dependent lipid processing and formation of functional lipid lamellae.402 The damp environment created by the diaper leads to over-hydrated skin, which is prone to mechanical damage and chafing, due to an increased coefficient of friction. Prolonged wetness leads to maceration (softening) of the stratum corneum, disruption of the intercellular lipid lamellae, and increased penetration of skin irritants.402,405 Prolonged skin contact with urine and feces induces IDD. Berg406 utilized a hairless mouse model to examine the role of urine and feces in skin breakdown. He showed that urine increases skin pH by breaking down urea, when in the presence of fecal urease. Higher pH leads to increased activity of fecal

The diaper area poses unique challenges to assure adequate skin care. Urine and stool must be wiped away from the skin and body folds to assure a normally functioning skin barrier.409 Normal skin pH and skin flora must be maintained by cleansing products. Soaps with an alkaline pH change the propionibacterial growth on skin, whereas syndets (synthetic detergents) with a pH of 5.5 do not cause changes in cutaneous microflora. The role of the type of diaper in preventing IDD has been discussed above. Once IDD is present, successful treatment regimens should emphasize frequent and gentle cleansing of all possible irritants. Excessive cleansing and scrubbing with harsh soaps and alcohol should be avoided because of the negative impact on the skin barrier. An effective cleanser should also restore and maintain a physiologic pH. Gentle cleansing of the groin skin should be done with lukewarm water in a basin (similar to a Sitz bath), or with ‘diaper wipes’, followed by a gentle, complete drying. Most diaper wipes available on the market today are made up of a mixture of wood pulp and polypropylene held together by a thermobonding; they are entirely synthetic. Both types are designed to limit abrasion without unnecessary fragrances and preservatives, and without alcohol. Wipes should not be used when the skin is broken down.410 Diapers should be checked for feces or urine at least every 3 h, and changed as often as possible. Warm water, mild soap and cotton balls are a mild, effective and sufficient alternative means for cleaning the diaper area.401 After gentle cleansing, emollients which have good barrier properties should be spread over the area to decrease friction, prevent over-hydration, and provide protection from stool, urine, other irritants and microorganisms. In general, thicker ointments and pastes are more effective than lotions, creams and oils, due to their superior ability to adhere to the skin surface. Residual emollient should be left on the skin and gently wiped off after defecating. Use of mineral oil instead of water can be useful to remove thick emollients such as zinc oxide. Emollients should be reapplied after each diaper change. Most barrier products contain a combination of zinc oxide and petrolatum. Powders also help to reduce friction and absorb moisture; however, because of the risk of aspiration they are not recommended as a treatment of choice. Products containing talcum powder, baking soda, or boric acid should especially be avoided

402. Adam R. Skin care of the diaper area. Pediatr Dermatol. 2008;25: 427–433. 403. Cooke JV, Keith HR. A Type of urea-splitting bacterium found in the human intestinal tract. J Bacteriol. 1927;13:315–319. 404. Leyden JJ, Katz S, Stewart R, et al. Urinary ammonia and ammoniaproducing microorganisms in infants with and without diaper dermatitis. Arch Dermatol. 1977. 405. Atherton DJ. A review of the pathophysiology, prevention and treatment of irritant diaper dermatitis. Current medical research and opinion. 2004;20:645–649.

406. Berg RW. Etiologic factors in diaper dermatitis: a model for development of improved diapers. Pediatrician. 1987. 407. Berg RW, Buckingham KW, Stewart RL. Etiologic factors in diaper dermatitis: the role of urine. Pediatr Dermatol. 1986;3:102–106. 408. Buckingham KW, Berg RW. Etiologic factors in diaper dermatitis: the role of feces. Pediatr Dermatol. 1986;3:107–112. 409. Atherton DJ. The aetiology and management of irritant diaper dermatitis. J Euro Acad Dermatol Venereol. 2001;15(Suppl)1–4. 410. Shin HT. Diaper dermatitis that does not quit. Dermatol Therapy. 2005;18:124–135.

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proteases and lipases, which damage the skin barrier, leading to increased skin permeability. The role of feces in IDD is complex. Studies by Buckingham and Berg have shown that no single component of feces is entirely responsible for the irritation. The proteolytic and lipolytic enzymes in feces can directly irritate skin and can also increase the susceptibility of skin to other irritants in the diaper environment.407,408

DIAPER DERMATITIS

Treatment of IDD

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Figure 14.23  An example of Jacquet’s diaper dermatitis with eroded nodules on the labia.

Figure 14.22  Candida diaper dermatitis with beefy red erythema and peripheral satellite pustules (Courtesy Dr A. Lucky).

because of toxicity, and all powders should be kept away from the infant’s face to prevent aspiration.410 A non-fluorinated, lowpotency topical corticosteroid, covered by an emollient, may be added to the regimen if conservative treatment fails. Potent and/ or fluorinated corticosteroids should be avoided in the diaper area.

Candida infection in IDD Candida diaper dermatitis classically presents with diffuse erythema and peripheral scale which extends over the genitalia (Fig. 14.22) and often has peripheral satellite red pustules and scaly papules. Sometimes there are only small, pink, discrete or coalescing papules surmounted by scale. The anterior perineum, the perianal areas and the groin creases are affected, which helps differentiate candida dermatitis from IDD (i.e., the ‘valleys’ rather than the ‘hills’ are involved). The more classical picture of a beefy red diaper area with satellite pustules is rarely seen, possibly because of earlier treatment with antifungal and antiinflammatory agents. Skin barrier breakdown leads to alterations in the microbiological milieu, with subsequent bacterial and fungal overgrowth. Candidiasis in the diaper area seems to have become more common, possibly with the more frequent use of oral anti­ biotics and subsequent diarrhea in infants. Systemic antibiotic therapy with amoxicillin is a known risk factor for development of diaper dermatitis, suggesting a provocative role for C. albicans in diaper dermatitis.411 Young children are particularly prone to Candida infection with 3% of infants affected from the 2nd to the 4th month.412 A direct correlation between IDD and the level of stool Candida albicans has been clearly shown; however, skin maceration must occur for Candida albicans to cause skin infection.405 It

411. Halbert AR, Chan JJ. Anogenital and buttock ulceration in infancy. Australas J Dermatol. 2002;43:1–6; quiz 7–8. 412. Bound JP. Thrush napkin rashes. BMJ. 1956;1:782–784. 413. Honig PJ, Gribetz B, Leyden JJ, et al. Amoxicillin and diaper dermatitis. J Am Acad Dermatol. 1988;19:275–279.

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is likely, therefore that this microorganism becomes established in the diapered area of infants who have primary irritant diaper dermatitis if it is present in the feces. A study by Honig et al.413 showed increased rates of recovery of Candida albicans from the rectum of children after 10 days of oral amoxicillin. Recovery of Candida albicans correlated with the presence of a perianal rash.414 Other studies have not confirmed this finding. Whether Candida albicans has a causative or secondary role in IDD remains unclear. Treatment with topical anticandidal therapy such as nystatin one of the imidazoles, or other topical antifungals two or three times daily produces resolution in under 2 weeks. Adding hydrocortisone 1% to the above agents may provide an antiinflammatory effect and promote more rapid resolution of erythema. Burow’s solution or normal saline compresses may also be useful in inflammatory lesions. Potent corticosteroids should be avoided. In a double-blind study, the use of oral nystatin to eliminate Candida from the bowel in conjunction with topical nystatin did not affect the outcome of the dermatitis more favorably than topical nystatin alone.415

Jacquet’s diaper dermatitis Jacquet’s erosive dermatitis is a rare form of IDD, most commonly seen in the setting of infrequent diaper changes and/or use of poor quality diapers. Punched-out ulcers with elevated, erythematous borders are seen over the penis, labia or concave skin of the perianal area. The ulcers may be preceded by a vesicular phase, resembling acute herpes simplex virus (HSV) infection. Patients may also develop well-demarcated 2–5 mm papules and nodules, with central umbilication and ulceration (Fig. 14.23).411 This entity represents the severe end of the spectrum of IDD. Preventative and conservative measures,

414. Jordan WE, Lawson KD, Berg RW, et al. Diaper dermatitis: frequency and severity among a general infant population. Pediatr Dermatol. 1986;3: 198–207. 415. Munz D, Powell KR, Pai CH. Treatment of candidal diaper dermatitis: a double-blind placebo-controlled comparison of topical nystatin with topical plus oral nystatin. J Pediatr. 1982;101:1022–1025.

Eczematous dermatitis

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Perianal pseudoverrucous papules and nodules (PPPN)

Figure 14.24  An example of granuloma gluteale infantum.

such as those used to treat IDD, should be employed. Addition of a mild corticosteroid and a topical antibiotic preparation should be considered.416 In infants with chronic frequent stooling, such as those with short bowel syndrome, this type of dermatitis is nearly impossible to clear unless the stooling is brought under control.

Granuloma gluteale infantum Granuloma gluteale infantum (GGI) is a rare condition characterized by large, firm, reddish-purple, oval or elongated nodules and plaques appearing on the inguinal folds, scrotum, perineum, and inner thigh, often sparing the buttocks (Fig. 14.24). This condition is most commonly seen in infants aged 2–9 months old. GGI classically begins as a generalized inflammation of the diaper area which has been treated with potent topical corticosteroids, and subsequent development of reddishpurple nodules. The histology of the lesions consists of a massive infiltrate of neutrophils, histiocytes, lymphocytes, and eosinophils in the dermis with minimal epidermal changes. While the pathogenesis of GGI has not been fully established, occlusion from the diaper and use of potent corticosteroids are known predisposing factors. Bonifazi et al.417 reviewed a series of 11 infants, and found no correlation between the severity of the pre-existing diaper dermatitis and the development of the ‘granulomatous’ lesions.418 The differential diagnosis includes scabetic nodules, urticaria pigmentosa, and xanthogranulomas. It is also important to differentiate this benign process from that of a lymphomatous or histiocytic infiltrate. Treatment is conservative, with the majority of lesions resolving spontaneously over a period of a few months.

416. Schachner LA, Hansen RC. Pediatric dermatology. 3rd ed. Edinburgh: Elsevier; 2003. 417. Bonifazi E, Garofalo L, Lospalluti M, et al. Granuloma gluteale infantum with atrophic scars: clinical and histological observations in eleven cases. Clin Exp Dermatol. 1981;6:23–29. 418. De Zeeuw R, Van Praag MC, et al. Granuloma gluteale infantum: a case report. Pediatr Dermatol. 2000;17:141–143. 419. Goldberg NS, Esterly NB, Rothman KF, et al. Perianal pseudoverrucous papules and nodules in children. Arch Dermatol. 1992.

DIAPER DERMATITIS

This condition was originally thought to be a reaction from chafing associated with urostomies, but it has also been described on the perianal skin in children with longstanding encopresis and around colostomies. The classic appearance consists of 2–10 mm high, domed, red-brown solitary and confluent papules and nodules. The tissue is usually friable and bleeds easily (Fig. 14.25). Histologically, acanthosis and hyperkeratosis predominate. Contributing factors appear to be similar to the erosive variant of IDD (Jacquet’s dermatitis). Lesions regress spontaneously after removal of known irritants. Therapy should focus most on identification and protection from the source of irritation.419

Allergic contact diaper dermatitis (ACDD) ACDD results from specific allergic reactions to detergents, fabric softeners, or to components of the diaper itself. The disposable diaper was introduced in the 1960s and has become almost universally popular in the USA. Alberta et al. reported five cases of ACDD due to dyes (disperse red 17, blue 106, red 1, blue 124, and orange 3) used in diapers.420 True ACDD may look identical to IDD but is much rarer. A change in detergent or type of diaper with resolution of the dermatitis would confirm a suspicion of ACDD.

Intertrigo Intertrigo is an inflammation caused by friction of adjacent skin folds on opposing cutaneous or mucocutaneous surfaces, such as those in the diaper area. Treatment should aim to decrease wetness and treat concurrent infection with yeast and/or bacteria if present. Emollient barriers to reduce friction should be applied after gentle cleansing. Topical antifungal and/or antibacterial preparations may be added when infection is present.421 Erythema and maceration of the skin are common findings in intertrigo, in particular intertrigo caused by Group A β-hemolytic Streptococcus which has a tender, fiery-red, shiny and exudative surface, with well-defined borders and the absence of satellite lesions or scale.422

Crohn’s disease in the diaper region Crohn’s disease presenting in infancy is rare, and seen in only 3% of infants with non-infectious colitis.423 Perianal skin fissuring and ulceration are seen in 47% of older children with Crohn’s disease. Skin findings are found before the diagnosis of Crohn’s disease in 25% of children.423 Crohn’s disease is associated with pyoderma gangrenosum in 1–2% of adults and older children.

420. Alberta L, Sweeney SM, Wiss K. Diaper dye dermatitis. Pediatrics. 2005;116:e450–e452. 421. Janniger CK, Schwartz RA, Szepietowski JC, et al. Intertrigo and common secondary skin infections. Am Fam Phys. 2005;72:833–838. 422. Neri I, Savoia F, Giacomini F, et al. Streptococcal intertrigo. Pediatr Dermatol. 2007;24:577–578. 423. Dinulos JG, Darmstadt GL, Len MK, et al. Infantile Crohn disease presenting with diarrhea and pyoderma gangrenosum. Pediatr Dermatol. 2006;23:43–48.

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A B

D C

Figure 14.25  (A) Erosive diaper dermatitis, usually secondary to frequent stooling (Courtesy Dr A. Torrelo). (B) Verrucous dermatitis in a girl with chronic incontinence of urine (Courtesy Dr. A. Lucky). (C) Erosive diaper dermatitis in a girl with short gut and continuous stooling (Courtesy Dr A. Lucky). (D) Chronic diaper dermatitis in a girl with short gut syndrome and continuous stooling (Courtesy Dr A. Lucky).

In rare cases, PG can present in infants as anal fissuring and ulcerations that can be mistaken for child abuse.

INFECTIOUS CAUSES OF DIAPER ERUPTIONS Candida diaper dermatitis has been discussed with irritant contact dermatitis.

Bullous impetigo of the diaper region Bullous impetigo is caused by Staphylococcus aureus, most commonly phage group 2, and often presents in the diaper area in the neonate. It typically presents with soft, flaccid bullae that easily break leaving superficial erosions with collarettes of scale. Bullae occur due to an exfoliative toxin that cleaves desmoglein I, producing a superficial break through the granular region of

424. Amren DP, Anderson AS, Wannamaker LW. Perianal cellulitis associated with group A streptococci. Am J Dis Child. 1966;112:546–552.

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the epidermis. Bullous impetigo should be treated with systemic antimicrobial agents in infants, since the toxin producing organism may advance rapidly. Although cephalexin, nafcillin, oxacillin, and methicillin have been treatments of choice, skin cultures should be obtained in infants with bullous impetigo, because of the rise in methicillin resistant Staphylococcus aureus. Antibiotics that inhibit toxin production such as clindamycin should be considered. Topical agents may be useful adjuncts to systemic therapy, but should not be utilized as monotherapy for bullous impetigo.

Perianal streptococcal dermatitis (PSD) In 1966, Amren et al. described a group of children with a distinctive perianal eruption caused by beta-hemolytic streptococci.424 The typical age range of affected patients is from 6

Eczematous dermatitis

and all children were afebrile. No specific treatment is required other than bland emollients.

Nutritional deficiencies Eruptions in the diaper area may be caused by nutritional deficiencies. In particular, zinc deficiency, essential fatty acid deficiency and cystic fibrosis often present with diaper dermatitis. These are discussed in detail in Chapter 22.

Langerhans cell histiocytosis Langerhans cell histiocytosis is a rare, potentially fatal disorder of histiocytes that can be seen in infants and young children. Cutaneous findings range from diffuse nodules, resembling a ‘blueberry muffin’, eroded purpuric papules and vesicles to a diffuse weeping seborrheic dermatitis-like eruption. The seborrheic dermatitis-like rash favors the scalp, retro-auricular area, and diaper area, especially the inguinal folds. Small erythematous scaly papules with erosions and areas of purpura or hemorrhagic crusting, which are unresponsive to standard therapy for IDD and Candida diaper dermatitis, are characteristic. Ulceration in the diaper or buttock area may develop as well as on the gingivae and oral mucosa. It is important to differentiate LCH from seborrheic dermatitis and other causes of diaper dermatitis. Infants presenting with recalcitrant diaper dermatitis should be evaluated for Langerhans cell histiocytosis with a skin biopsy.416,433

Seborrheic dermatitis

Recurrent toxin-mediated perineal erythema (RTPE) is a benign self-limited condition characterized by perineal redness and is thought to be similar to other toxin and super-antigen mediated disorders such as staphylococcal scaled skin syndrome, scarlet fever, and Kawasaki syndrome. Erythema of the perineum is a consistent finding in these conditions.416,430,432 Patrizi et al. reported 11 children 3–6 years of age with RTPE.432 All children were in good health before the onset of the cutaneous eruption,

First described by Unna in 1887,434 seborrhea means flow of sebum; the name is a misnomer as there is no evidence showing increased sebum production associated with this eruption in infants. Seborrheic dermatitis (SD) is a disease of unknown etiology that affects infants from about 3 weeks of age, with a distinct clinical picture. Many physicians use the term SD to describe ‘cradle cap’ (retention hyperkeratosis) on the vertex of the scalp, whereas others imply inflammation with erythema and scaling on the scalp and intertriginous areas. Although the age of occurrence may suggest a role for excessive sebaceous gland activity from maternal and endogenous hormones, there is no evidence that this is the case, nor have nutritional factors such as biotin deficiency been validated.435 The term SD is also used to describe similar findings in adults, but there is no indication that infants with SD are more likely to suffer from the adult form of the disease. There is an

425. Krol A. Perianal streptococcal dermatitis. Pediatr Dermatol. 1990. 426. Ulger Z, Gelenava T, Kosay Y, et al. Acute guttate psoriasis associated with streptococcal perianal dermatitis. Clin Pediatr. 2007;46:70–72. 427. Shouval DS, Schurr D, Nussinovitch M. Presentation of perianal group A streptococcal infection as irritability among children. Pediatr Dermatol. 2008;25:568–570. 428. Meury SN, Erb T, Schaad UB, et al. Randomized, comparative efficacy trial of oral penicillin versus cefuroxime for perianal streptococcal dermatitis in children. J Pediatr. 2008;153:799–802. 429. Jongen J, Eberstein A, Peleikis HG, et al. Perianal streptococcal dermatitis: an important differential diagnosis in pediatric patients. Dis Colon Rectum. 2008;51:584–587.

430. Manders SM, Heymann WR, Atillasoy E, et al. Recurrent toxin-mediated perineal erythema. Arch Dermatol. 1996;132:57–60. 431. Patrizi A, Costa AM, Fiorillo L, et al. Perianal streptococcal dermatitis associated with guttate psoriasis and/or balanoposthitis: a study of five cases. Pediatr Dermatol. 1994;11:168–171. 432. Patrizi A, Raone B, Savoia F, et al. Recurrent toxin-mediated perineal erythema: eleven pediatric cases. Arch Dermatol. 2008;144:239–243. 433. Chu T. Langerhans cell histiocytosis. Australas J Dermatol. 2001;42:237–242. 434. Unna PG. Seborrhoeae eczema. J Cutan Dis. 1887;5:499. 435. Keipert JA. Oral use of biotin in seborrhoeic dermatitis of infancy: a controlled trial. Med J Aust. 1976;1:584–585.

Recurrent toxin-mediated perineal eruption

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months to 10 years, and boys are affected more often than girls. The eruption is a form of dermatitis, appearing as a pink to red, moist, superficial perianal patch.425 The signs and symptoms observed in PSD have included perianal dermatitis (90%), itching (78%), rectal pain (52%), blood-streaked stools (35%), and cellulitis.426 Shouval et al. reported a case series of 11 children who presented to a pediatrician’s office with the chief complaint of irritability, but were found to have intense perianal erythema on examination.427 The skin surrounding the anus is generally tender or pruritic and infants may experience painful defecation with or without anal fissuring. Some patients with PSD may present with minimal erythema, but develop painful anal fissuring with dried mucoid or cheesy, white-yellow discharge. Other children develop a beefy red, psoriasiform eruption with a yellow superficial peripheral crust extending several centimeters from the anal skin. PSD is contracted through direct contact with infected individuals, autoinoculation by oral–perianal digital contact or swallowing of GABHS. Interfamily spread has been extensively documented, as has transmission in day-care centers. Confirmation of the diagnosis is accomplished by culturing a moderate to heavy growth of Group A beta-hemolytic streptococci on 5% sheep blood agar. First-line treatment has been 14–21 days of oral penicillin, or erythromycin in penicillin allergic patients. Meury et al. recently compared the efficacy of 10 days of penicillin versus 7 days of cefuroxime and found that a 7-day course of cefuroxime was more efficacious than a 10-day course of penicillin.428 Additional topical therapy with antiseptics or topical antibiotics such as mupirocin penetrates the folds of the perianal mucosa and may accelerate bacterial clearance and decrease the rate of recurrence.429 Children with PSD and/or balanoposthitis have the potential to develop guttate psoriasis. In new or recurrent cases of guttate psoriasis pediatric patients should be examined thoroughly and cultures should be taken from both the pharyngeal and perianal areas.430,431

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Figure 14.27  Flexural involvement in seborrheic dermatitis (Courtesy Dr A. Torrelo).

DIAPER DERMATITIS

Figure 14.26  Typical greasy scale of seborrheic dermatitis in the head and face (Courtesy Dr A. Torrelo).

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impression that SD is not seen in the Western world as frequently as in previous years, but it is still common in other countries.436 The eruption in infants begins between the ages of 3 and 12 weeks; it is uncommon after 6 months of age. Infants are usually asymptomatic and it is the parents who are dismayed by the cosmetic appearance. Nevertheless, in a study by Yates et al., 33% were pruritic.437 The scalp is generally the first area of involvement and lesions appear as greasy yellow or white scales, known as ‘cradle cap’ (Fig. 14.26). Hair loss is not seen and erythema is variable. Lesions may involve the face, particularly the hairline and eyebrows, and the intertriginous areas are involved in more severe cases, with erythema and some scale. In the diaper area well-demarcated erythematous plaques are topped by a thin white scale. The condition often remains confined to the scalp and diaper areas but may spread to involve other flexural creases, the axillae (Fig. 14.27), retro-auricular area, and neck (Fig. 14.28). These may become macerated, crusted, and superinfected with Candida albicans. The lesions respond quickly to treatment with bathing in soothing oatmeal baths, once or twice a day, and shampooing with a tar shampoo daily, followed by hydrocortisone 1% cream two or three times a day to the affected areas. Shampoos containing salicylic acid should be avoided, as they may be irritating and absorption may cause problems with salicylism. Remission is accomplished within 10 days to 2 weeks, and recurrences are unusual. The prognosis in SD is excellent. The pathogenesis of the disease is unknown. It has been shown that the organism Pityrosporum ovale (P. ovale), (Malassezia furfur)

is implicated in the etiology of adult SD. Two studies have shown an increased incidence of P. ovale in the lesions of infants with SD. Broberg and Faergemann438 isolated the organism in 18 of 20 patients and in only four of 20 controls. Ruiz-Maldonado et al.439 detected P. ovale in 73% of patients with infantile SD, 33% in AD and other dermatoses, and 53% in normal controls. Treatment of the SD group with ketoconazole 2% resulted in clinical cure in 11 of 15 infants in 2 weeks and mycologic cure in 13 of the 15 infants. The improvement of SD with ketoconazole cream was corroborated in another study.440 Tollesson et al.441 implicated an abnormality of essential fatty acids in the etiology of infantile SD, but this study has not been corroborated. Histology of the lesions is not diagnostic and consists of a subacute dermatitis with elongation of the rete ridges. It is important to differentiate SD from AD, which may also begin on the scalp early in life; AD has itchy crusted areas and a dry scale. A study found that the two entities may occasionally be difficult to differentiate from one another, with pruritus in SD in one-third of cases.437 SD is the more likely diagnosis when

436. Sardana K, Mahajan S, Sarkar R, et al. The spectrum of skin disease among Indian children. Pediatr Dermatol. 2009;26:6–13. 437. Yates VM, Kerr EI, Frier K, et al. Early diagnosis of infantile seborrhoeic dermatitis and atopic dermatitis total and specific IgE levels. Br J Dermatol. 1983;108:639–645. 438. Broberg A, Faergemann J. Infantile seborrheic dermatitis and Pityrosporum ovale. Presented at the 3rd International Symposium on pediatric dermatology. Mazara del Vallo, Sicily, September 14–17, 1988.

439. Ruiz-Maldonado R, Lopez-Matinez R, Perez Chavariea EL, et al. Pityrosporum ovale in infantile seborrheic dermatitis. Pediatr Dermatol. 1989;6:16–20. 440. Wannanukul S, Chiabunkana J. Comparative study of 2% ketoconazole cream and 1% hydrocortisone cream in the treatment of infantile seborrheic dermatitis. J Med Assoc Thai. 2004;87(Suppl 2):S68–S71. 441. Tollesson A, Frithz A, Berg A, et al. Essential fatty acids in infantile seborrheic dermatitis. J Am Acad Dermatol. 1993;28:957–961.

Figure 14.28  Seborrheic dermatitis of the neck (Courtesy Dr A. Torrelo).

Eczematous dermatitis

the axillae are affected and AD when the shins and forearms are involved. SD should be differentiated from other scaling eruptions, particularly psoriasis. Napkin psoriasis (Fig. 14.29) and psoriasis in general are more common in infants than was previously recognized.442 If the disease is persistent, or if crusting and petechial lesions occur, it is important to rule out the possibility of disseminated Langerhans cell histiocytosis Follow-up studies of patients with infantile SD have produced a variety of findings. Podmore et al.,443 in a follow-up study after 11 years, concluded that many of the cases of infantile SD eventually developed AD. This was also the conclusion of RuizMaldonado et al.439 These cases were probably AD at the onset and were diagnosed on the basis of cradle cap alone. Other studies have shown an increased tendency to develop psoriasis. This is particularly true of napkin psoriasis that was thought to be a variant of SD.444 Since the recognition that psoriasis is not rare in infancy and may occur in the diaper area, the previous diagnosis of SD was probably erroneous, and psoriasis was the correct diagnosis.

CONTACT DERMATITIS Sharon Jacob INTRODUCTION Contact dermatitis is a common diagnosis, being equally prevalent in children and adults.445 Both allergic contact dermatitis

442. Al-Hamdi Psoriasis. Modes of presentations among children in southern Iraq. Saudi Med J. 2008;29(6):892–895. 443. Podmore O, Burrows D, Eedy DJ, et al. Seborrheic eczema – a disease entity or a clinical variant of atopic eczema? Br J Dermatol. 1986;115: 341–350. 444. Neville EA, Finn OA. Psoriasiform napkin dermatitis: a follow-up study. Br J Dermatol. 1975;92:279–285. 445. Fernández Vozmediano JM, Armario Hita JC. Allergic contact dermatitis in children. J Eur Acad Dermatol Venereol. 2005;19:42–46. 446. Fisher AA. Childhood allergic contact dermatitis. Cutis. 1975;15:635. 447. Weston WL, Weston JA. Allergic contact dermatitis in children. Am J Dis Child. 1984;138:932–936. 448. Rajagopalan R, Anderson R. Impact of patch testing on dermatologyspecific quality of life in patients with allergic contact dermatitis. Am J Contact Dermat. 1997;8:215–221.

(ACD) and irritant contact dermatitis (ICD) have been shown to occur in the pediatric population.446 Current data suggest that ACD accounts for as much as 20% of all dermatitis seen in childhood,447 but this may be a significant underestimate given that most children are not patch tested. This is unfortunate since appropriate allergen identification through proper epicutaneous patch testing has been demonstrated to improve quality of life measurements,448,449 as it allows for appropriate avoidance of inciting allergens. Reported rates of clinically relevant positive patch tests in a series of affected children referred to a tertiary care center for suspected ACD have been reported to be as high as 77%.450 That said, the rates of positive responses to contact allergens (contact allergy) vary with referral patterns, selection criteria for patch testing, regional and social variations in allergen exposure, and the allergens tested.451 Recognition of the presenting signs and symptoms, and referral for patch testing are crucial when evaluating children with potential ACD.452 Contact urticaria (CU) a wheal and flare reaction, represents an immunoglobulin E (IgE) and mast cell-mediated, immediatetype hypersensitivity reaction that can lead to anaphylaxis. The foremost example of this is latex protein hypersensitivity.453

CONTACT DERMATITIS

Figure 14.29  Diaper involvement in psoriasis in an infant.

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PATHOPHYSIOLOGY Contact dermatitis is defined as an adverse cutaneous reaction that results from the contact of an exogenous agent with the surface of the skin or mucous membrane. Subsequent to contact with an agent, the skin can react with both immunologic (ACD and CU) and/or non-immunologic mechanisms (contact urticaria (NICU) and ICD) resulting in the clinical expression of either an eczematous inflammation, or wheals in the case of CU. In ACD and ICD the severity of the dermatitis can range from a mild, short-lived eruption to one that is severe, persistent and chronic.

Irritant contact dermatitis Irritant contact dermatitis accounts for approximately 80% of all contact dermatitis cases.454 It is caused by direct injury to the skin cells after contact with a chemical that abrades, irritates or damages the skin. Damage to the keratinocytes induces inflammation, but this reaction does not activate an immune cascade; thus no prior sensitization is required for this type of response to occur.455 ICD can appear in any location on the skin or

449. Jacob SE, Brod B, Crawford GH. Clinically relevant patch test reactions in children – a United States based study. Pediatr Dermatol. 2008;25: 520–527. 450. Besnier EM. Premiere note et observations preliminaires pour servir d’ introduction a l’etude des prurigos diathesiques. Ann de Dermat et Syph. 1892;3:634–648. 451. de Waard-van der Spek FB, Oranje AP. Patch tests in children with suspected allergic contact dermatitis: A prospective study and review of the literature. Dermatology. 2008;218:119–125. 452. Militello G, Jacob SE, Crawford GH. Allergic contact dermatitis in children. Curr Opin Pediatr. 2006;18:385–390. 453. Warshaw E. Latex allergy. Skin Med. 2003;2:359–366. 454. Mark BJ, Slavin RG. Allergic contact dermatitis. Med Clin North Am. 2006; 90:169–185. 455. Mydlarski PR, Katz AM, Mamelak AJ, et al. Contact dermatitis. In: Adkinson NF, Yunginger JW, Busse WW, et al, eds. Middleton’s allergy principles and practice. Philadelphia: Mosby; 2003:1581–1593.

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mucosa and can present in anyone, whether or not there has been previous exposure to a particular chemical. Onset of symptoms varies from a few minutes to 48 hours. The concentration of the irritating substance and the duration of the exposure have a significant effect on the severity of the reaction.456 A common example of ICD in childhood includes liplicker dermatitis, a perioral eruption, where the initial event is usually irritation from cold dry weather, and subsequent licking of the lips to counteract the dryness leading to a secondary reaction from exposure to drying saliva. The diagnosis of ICD depends on the patient history and clinical presentation, but it is not always possible to clinically differentiate irritant from allergic contact dermatitis, especially in chronic cases where lichenification of the involved skin further complicates the clinical and histopathologic picture. Classically, acute ICD presents as a discrete patch of erythema that corresponds to the area of skin exposed to the offending agent. In general, burning and pain are more common than pruritus. With strong or prolonged exposure, blistering and erosions may occur.

ALLERGIC CONTACT DERMATITIS Allergic contact dermatitis (ACD) is a T-cell mediated, type IV, delayed hypersensitivity reaction that results from exposure and subsequent sensitization to an environmental chemical. It accounts for approximately 20% of new incident cases of contact dermatitis.455 This reaction results primarily from epicutaneous exposure to small lipophilic chemicals (haptens) with a low molecular weight ( Vitamin D analogues >> Coal tar preparations >> Anthralin >> Tazarotene >> Salicylic acid preparations >> Phototherapy – UVB – Narrow band UVB – PUVA Systemic therapy

>> Antibiotics >> Acitretin >> Methotrexate >> Cyclosporin

scalp, trunk, and limbs. They are usually used twice or three times a day for maximal effect. Weaker preparations (e.g., hydrocortisone) are used for psoriasis on sensitive sites such as the face, around the ears, in the flexures, and on the genitalia. The most common side-effects of potent topical steroid therapy are atrophy and striae at the site of application following prolonged use. A rare side-effect is suppression of the hypothalamic-pituitary-adrenal axis following prolonged, widespread application of a potent topical steroid in infants and young children.123 The risk of side-effects can be minimized by monitoring the amount of steroid used, ensuring the steroid is applied to the correct site, and discouraging continuous use of topical steroids over a long period of time. Strategies to minimize continuous use include intermittent or cyclic therapy, and combination or rotational therapy. Topical steroids have been combined with calcitriol124–126 and tazarotene127 in adult patients with greater efficacy, increased duration of remission, and reduction in steroid use. Rotational therapy for mild to moderate psoriasis involves alternating topical steroids with one of the topical treatments listed in Box 15.1. Although the continuous use of topical steroids is to be discouraged the side-effects of mid-strength topical steroids are uncommon.

Calcipotriol (vitamin D) with topical therapy. Phototherapy is the preferred option for older children with widespread plaque psoriasis not responding to topical therapy. Systemic therapy is reserved for children with severe disease not responding to topical and phototherapy.

Topical therapy Topical steroids Topical corticosteroids are the most commonly prescribed topical therapy for pediatric psoriasis.122 Their popularity is due to availability, cosmetic acceptability, efficacy, and ease of application. They are particularly useful when pruritus is a problem and for psoriasis on the face, in the flexures, on the genitalia, and around the ears. Creams and ointment preparations are used on the body and lotions and foams are preferred for the scalp. The site of psoriasis determines the strength of the topical steroid. Moderately potent (e.g., betamethasone valerate or triamcinolone acetonide) or potent (e.g., fluocinonide acetonide) steroids are needed for clinical improvement of psoriasis on the 122. Stern KS. Utilization of outpatient care for psoriasis. J Am Acad Dermatol. 1996;35:543–545. 123. McGibbon DH. Infantile pustular psoriasis. Clin Exp Dermatol. 1979;4:115–118. 124. Lebwohl M, Siskin SB, Epinette W, et al. A multicenter trial of calcipotriene ointment and halobetasol ointment compared with either agent alone for the treatment of psoriasis. J Am Acad Dermatol. 1996;35:268–269. 125. Kragballe K, Barnes L, Hamberg KJ, et al. Calcipotriol cream with or without concurrent topical corticosteroids in psoriasis: tolerability and efficacy. Br J Dermatol. 1998;139:649–664. 126. Lebwohl M, Yoles A, Lombardi K, et al. Calcipotriene ointment and halbetasol ointment in the long term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol. 1998;39:447–450. 127. Lebwohl MG, Breneman DL, Goffe BS, et al. Tazarotene 0.1% gel plus corticosteroid cream in the treatment of plaque psoriasis. J Am Acad Dermatol. 1998;39:590–596. 128. Highton A, Quell J, Calcipotriene Study Group. Calcipotriene ointment 0.005% for psoriasis: a safety and efficacy study. J Am Acad Dermatol. 1995;32:67–72. 129. Harrington CI, Goldin D, Lovell CR, et al. Comparative effects of two different calcipotriol (MC903) formulations versus placebo in psoriasis

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Calcipotriol (vitamin D3) is an effective treatment for mild to moderate plaque psoriasis in adults128,129 and children.130 It is available as a cream, ointment, and lotion. A systematic review of the comparative efficacy and tolerability of topical calcipotriol found it to be as effective as potent topical steroids and more effective than tar cream and anthralin in the treatment of mild to moderate plaque psoriasis.131 Increased efficacy was noted when calcipotriol and potent topical steroids were both applied once a day,124,125 when calcipotriol was applied twice daily on weekdays with a potent topical steroid applied twice daily on weekends126 and with twice daily application of calcipotriol with broad band UVB phototherapy.132,133 The most common side-effect is lesional and perilesional irritation, particularly when used on the face, scalp, and flexures. To prevent hypercalcemia, the maximum recommended dose of 50 g/week per m2 should not be exceeded during treatment.134 Calcipotriol has also been combined with betamethasone dipropionate (Dovobet; Taclonex), and is found to be more effective than either component alone or its vehicle in randomized, double blind, controlled studies.135 vulgaris: a randomised, double-blind, placebo controlled, parallel group multicentre study. J Eur Acad Dermatol Venereol. 1996;6:152–158. 130. Darley CR, Cunliffe WJ, Green CM, et al. Safety and efficacy of calcipotriol ointment (Dovonex) in treating children with psoriasis vulgaris. Br J Dermatol. 1996;135:390–393. 131. Ashcroft DM, Li Wan Po A, Williams HC, et al. Systematic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis. BMJ. 2000;320:963–967. 132. Kragballe K. Combination of topical calcipotriol (MC903) and UVB radiation for psoriasis vulgaris. Dermatologica. 1990;181:211–214. 133. Ramsay CA, Schwartz BE, Lowson D, et al. Calcipotriol cream combined with twice weekly broad-band UVB phototherapy: a safe, effective and UVB-sparing antipsoriatic combination treatment. The Canadian Calcipotriol and UVB Study Group. Dermatology. 2000;200:17–24. 134. Oranje AP, Marcoux D, Svensson A, et al. Topical calcipotriol in childhood psoriasis. J Am Acad Dermatol. 1997;36:203–208. 135. Kragballe K, Austad J, Barnes L, et al. Efficacy results of a 52-week, randomised, double-blind, safety study of a calcipotriol/betamethasone dipropionate two-compound product (Daivobet/Dovobet/Taclonex) in the treatment of psoriasis vulgaris. Dermatology. 2006;213(4):319–326.

Papulosquamous diseases

Coal tar preparations and shampoos are a useful treatment for mild psoriasis of the skin and scalp.136 Use in older children and adolescents is limited because of poor compliance related to the smell and staining properties of coal tar. Coal tar preparations can be used on any site and are most effective with plaque psoriasis that has fine rather than thick surface scale. Coal tar is traditionally mixed with salicylic acid in a cream base and applied 2–3 times a day until clear. The strength of the cream is dependent on the age of the patient and the site of the psoriasis. Crude coal tar 2–4% is usually ordered in petrolatum and is applied bid. Because it is so messy, it is usually only used in a hospital setting. Refined tar (liquor carbonis detergens) is often mixed with salicylic acid and a topical steroid. Tar shampoo is used daily as monotherapy for scalp psoriasis or in combination with topical therapy such as tar preparations and steroid lotions. Crude coal tar cream was traditionally combined with UVB therapy (Goeckerman therapy) in a psoriasis day treatment center or hospital for severe widespread plaque psoriasis.137 A modified Goeckerman treatment can be used at home during the warmer months of the year for school-aged children with the overnight application of tar cream and daily sunlight exposure. The duration of sunlight exposure should be increased slowly to minimize the chances of a phototoxicity reaction between the UVA component of sunlight and the tar cream.

Anthralin Anthralin is an old and effective treatment for chronic plaque psoriasis.138 It is traditionally applied as short contact therapy that involves the application of anthralin cream or ointment 0.1–1% to the psoriatic plaques for a short period (10–60 min) before wiping or washing off.139 Clearance is accompanied by temporary staining of perilesional skin. In view of the risk of burning perilesional skin if carelessly applied and permanent staining of any object (e.g., clothing) with which it is in contact, use is restricted to older, cooperative children with large plaque psoriasis. Perilesional staining and irritation can be minimized by the use of a topical spray-on preparation containing triethanolamine (CuraStain) which is applied before and after removing the anthralin.140 The second option involves an anthralin formulation (Micanol) that encapsulates anthralin in a matrix of semicrystalline monoglycerides known as crystalip.141 The monoglycerides protect the anthralin from oxidation resulting in reduced perilesional staining. The anthralin is only released from the vehicle at a temperature higher than

136. Farber EM, Jacobs AH. Infantile psoriasis. Am J Dis Child. 1977;131:1266–1269. 137. Menter A, Cram DL. The Goeckerman regimen in two psoriasis day care centers. J Am Acad Dermatol. 1983;9:59–65. 138. Zvulunov A, Anisfeld A, Metzker A. Efficacy of short-contact therapy with dithranol in childhood psoriasis. Int J Dermatol. 1994;33:808–810. 139. Schaefer H. Short-contact therapy. Arch Dermatol. 1985;121:1505–1508. 140. Ramsey B, Lawrence CM, Bruce JM, et al. The effect of triethanolamine application on anthralin-induced inflammation and therapeutic effect in psoriasis. J Am Acad Dermatol. 1986;15:1247–1252. 141. Lindahl A. Embedding of dithranol in lipid crystals. Acta Derm Venereol. 1992;172:13–16. 142. Volden G, Bjornberg A, Tegner E, et al. Short contact treatment at home with Micanol. Acta Derm Venereol. 1992;172:20–22. 143. Lebwohl MG, Ast E, Callen JP, et al. Once-daily tazarotene gel versus twice-daily fluocinonide cream in the treatment of plaque psoriasis. J Am Acad Dermatol. 1998;38:705–711.

normal skin temperature, which minimizes release on normal skin. The higher temperature is achieved as the cream is rubbed into the psoriatic plaque. The cream is left on for 10–30 min before removing with lukewarm water.142 Anthralin therapy can be combined with other topical therapies and UVB phototherapy.

Tazarotene Tazarotene is the only topical retinoid approved for the treatment of psoriasis vulgaris. It is available as a 0.05% and 0.1% gel and cream. All of the data regarding efficacy and safety relate to adult patients. Although tazarotene monotherapy compares favorably with mid-potency topical steroid therapy,143 local irritation is a common problem that limits its use. Increased efficacy, reduced local irritation, and longer duration of remission is achieved when tazarotene 0.1% gel is combined with a potent topical steroid.127 Preliminary data suggest greater efficacy when combined with topical calcipotriol.144 Tazarotene 0.1% gel therapy enhances the response to broad-band UVB,145 narrowband UVB,146 and PUVA bath phototherapy147 with the potential benefit of reducing the total dose of ultraviolet light exposure, long-term photodamage, and carcinogenicity.

PSORIASIS VULGARIS

Coal tar preparations

15

Miscellaneous Keratolytic preparations (5–10% salicylic acid in an oil, lotion, cream, or ointment base) are needed when scalp scale is thick and firmly adherent (tinea amiantacea). The keratolytics are used on a daily basis until the thick scale has lifted. This may be used overnight, shampooed out, and then followed by an active ingredient or continued with other agents. Onycholysis and nail bed hyperkeratosis in children can be treated with steroid lotions, calcipotriol lotion, or a potent topical steroid cream/ointment applied to the nail fold above the matrix. Intralesional steroid injection of the nail matrix is not suitable for pediatric patients.

Phototherapy and systemic therapy Phototherapy and systemic therapies are reserved for use in those children with moderate to severe psoriasis; this is defined in adults as those patients with a significant extent of disease (body surface area >10% or Psoriasis Area of Severity Index ≥10), involvement of key areas (for example, face, hands or feet), and/or a significant impact on the quality of life (Dermatology Life Quality Index ≥10). In addition, the presence of psoriatic

144. Tahnghetti EA. Photographic tracking study of tazarotene treatment alone and in conjunction with mometasone furoate cream or calcipotriene ointment, in mild to moderate plaque psoriasis. Poster presented at the 57th Annual Meeting of the American Academy of Dermatology, March 19–24, New Orleans, LA; 1999. 145. Lowe NJ. Ultraviolet B phototherapy plus topical retinoid therapy. Cutis. 1999;63:6–7. 146. Stege H, Reifenberger J, Bruch-Gerharz D, et al. UVB-311-nmphototherapie in kombination mit topischer applikation von tazaroten zur behandlung der psoriasis vulgaris. Z Hautkrank H 1 G. 1998;73(10):708–709. 147. Krutmann J. Combination therapy of psoriasis with 311nm UVB phototherapy plus tazarotene. Oral presentation at the Joint Meeting of the 5th European Congress on Psoriasis at the 7th International Psoriasis Symposium, September 3, Milan, Italy; 1998.

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arthritis may be considered as an indication for the use of systemic agents.

Phototherapy

PSORIASIS VULGARIS

Phototherapy is the most frequent initial choice of most clinicians in treating children with moderate to severe psoriasis who have failed topical therapy. UVB is the preferred form of phototherapy with narrow-band UVB more effective than broad band,148 and less erythrogenic.148–150 Informed consent is essential to ensure the patient and their family are fully aware of the potential short-term (burning) and long-term (photoaging, carcinogenicity) side-effects of phototherapy. There are three main types of phototherapy: ultraviolet A (UVA: 320–400 nm); ultraviolet B (UVB: 280–320 nm); and narrowband (NB UVB: 311 ± 1 nm): the latter is more effective and less erytherogenic.148–150 UVB phototherapy is usually administered three times a week until clearance occurs. A series involving 20 children treated with narrowband UVB resulted in good to excellent results in 65% of patients; they required approximately 19 treatments for clearance with the mean UVB dose of 6.6 J/cm2.151 The efficacy of UVB phototherapy can be enhanced and total dose reduced when combined with tar preparations,137 short contact anthralin,152 topical tazarotene146,147 and Acitretin.153–155 PUVA phototherapy is not recommended for pre-adolescent pediatric psoriasis because of the risk of ocular damage during treatment and the long-term risk of skin cancer.156

Systemic therapy Antibiotics Pharyngeal and perianal streptococcal infections have been associated with psoriasis, particularly the guttate form. This association has led physicians to treat acute guttate psoriasis with penicillin, erythromycin and cephalosporins for 7–10 days: yet there is no evidence that antibiotic therapy alters the natural course of streptococcal induced guttate psoriasis. Systematic reviews including a Cochrane report of antistreptococcal therapy for guttate and chronic plaque psoriasis have not provided any further evidence to support the use of oral antibiotics or tonsillectomy in this setting.157–159

148. Green C, Ferguson J, Lakshmipathi T, et al. 311 nm UVB phototherapy – an effective treatment for psoriasis. Br J Dermatol. 1988;119:691–696. 149. Larko O. Treatment of psoriasis with a new UVB lamp. Acta Derm Venerol. 1989;69:357–359. 150. Kist JM, Van Voorhees AS. Narrowband ultraviolet B therapy for psoriasis and other skin disorders. Adv Dermatol. 2005;21:235–250. 151. Pasic A, Ceovic R, Lipozencic J, et al. Phototherapy in pediatric patients. Pediat Dermatol. 2003;20:71–77. 152. Vella-Briffa D, Greaves MW, Warin AP, et al. Relapse rate and long-term management of plaque psoriasis after treatment with photochemotherapy and dithranol. Br Med J Clin Res Ed. 1981;282:937–940. 153. Ruzicka T, Sommerburg C, Braun-Falco O, et al. Efficiency of acitretin in combination with UV-B in the treatment of psoriasis. Arch Dermatol. 1990;126:482–486. 154. Lowe N, Prystowsky JH, Bourget T, et al. Acitretin plus UVB therapy for psoriasis: comparisons with placebo plus UVB and acitretin. J Am Acad Dermatol. 1991;24:591–594. 155. Iest J, Boer J. Combined treatment of psoriasis with acitretin and UVB phototherapy compared with acitretin alone and UVB alone. Br J Dermatol. 1989;120:665–670. 156. Stern RS, Liebman EJ, Vakeva L, et al. Oral psoralen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer. J Natl Cancer Inst. 1998;90:1278–1284.

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Other systemic treatment The most commonly used systemic medications for pediatric psoriasis include: acitretin, methotrexate, and cyclosporin. There are no randomized, controlled trials using these agents in pediatric patients. Information regarding the dose and long-term safety is typically extrapolated from other indications in pediatrics (such as rheumatoid arthritis) or from adult studies. Systemic therapy is reserved for infants, children, and teenagers with severe plaque psoriasis that has failed to respond to topical and photo therapy and is of sufficiently significant physical and/or cosmetic concern. Informed consent is crucial because of the risk of significant side effects with oral treatment.

Retinoids Retinoids are synthetic and natural compounds that have activity similar to vitamin A.160 Acitretin, an aromatic retinoid, is the most commonly used oral medication in pediatric psoriasis. It can be used as monotherapy in the treatment of chronic plaque psoriasis,161–163 but it is most effective when combined with UVB phototherapy.153–155 Menstruating females must be informed of the teratogenic potential of acitretin and the need to avoid pregnancy with adequate contraception for a minimum of 2 years after stopping the medication. After ensuring the patient’s liver function tests, fasting lipids, and pregnancy test (when appropriate) are normal or negative, the patient is started on a dose of 0.5–0.75 mg/kg per day. Routine follow-up investigations (liver function tests, fasting lipids) are needed at regular intervals to monitor for abnormal liver function and elevated serum lipids. When clearance occurs, the UVB and acitretin are stopped. Prolonged acitretin therapy should be avoided because of the risk of premature epiphyseal closure and impaired bone growth.164 When given in combination with UVB phototherapy, acitretin is usually started 2 weeks before the start of light therapy. It can be started during the course of UVB therapy if needed, provided the dose of UVB is reduced to prevent burning. After baseline liver function and serum lipid levels, blood tests are repeated 1 month after the initiation of treatment and every 3 months thereafter.165 Routine follow-up investigations are needed at regular intervals to monitor for abnormal liver function and elevated serum lipids. Baseline and yearly bone studies should be advised in

157. Owen CM, Chalmers RJ, O’Sullivan T, et al. A systematic review of antistreptococcal interventions for guttate and chronic plaque psoriasis. Br J Dermatol. 2001;145:886–890. 158. Wilson JK, Al-Suwaidan SN, Krowchuk D, et al. Treatment of psoriasis in children: is there a role for antibiotic therapy and tonsillectomy? Pediatr Dermatol. 2003;20:11–15. 159. Owen CM, Chalmers RJ, O’Sullivan T, et al. Antistreptococcal interventions for guttate and chronic plaque psoriasis. Cochrane Database Syst Rev. 2000;(2):CD001976. 160. Wolverton SE, Nguyen EH. Comprehensive dermatologic drug therapy 2001; Chapter 13. 161. Rosinska B, Wolska H, Jablonska S, et al. Etretinate in severe psoriasis in children. Pediat Dermatol. 1988;5:266–272. 162. Judge MR, McDonald A, Black MM. Pustular psoriasis in childhood. Clin Exp Dermatol. 1993;18:97–99. 163. Shelnikz LS, Esterly NB, Honig PJ. Etretinate therapy for generalized pustular psoriasis in children. Arch Dermatol. 1987;123:230–233. 164. Paige DG, Judge MR, Shaw DG, et al. Bone changes and their significance in children with ichthyosis long-term etretinate therapy. Br J Dermatol. 1992;127:387–391. 165. Brecher AR, Orlow SJ. Oral retinoid therapy for dermatologic conditions in children and adolescents. J Am Acad Dermatol. 2003;49:171–182.

Papulosquamous diseases

166. Ruiz-Maldonado R. Tamayol retinoids in keratinizing diseases and acne in children. Pediatr Clin North Am. 1983;30:721–734. 167. Lacour M, Mehta-Nikhar B, Atherton DJ, et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029. 168. Khan SA, Grant Peterkin GA, Mitchell PC. Juvenile generalised pustularpsoriasis. Arch Dermatol. 1972;105:67–72. 169. Kumar B, Dhar S, Handa S, et al. Methotrexate in childhood psoriasis. Pediatr Dermatol. 1994;11:271–273. 170. Juanquin G, Conejomir JS, Ruiz AP, et al. Evaluation of the effectiveness of childhood generalised pustular psoriasis. Pediatr Dermatol. 1998;15:144–146. 171. Kaur I, Dogra S, De D, et al. Systemic methotrexate treatment in childhood psoriasis: further experience in 24 children from India. Pediatr Dermatol. 2008;25(2):184–188. 172. Collin B, Vani A, Ogboli M, et al. Methotrexate treatment in 13 children with severe plaque psoriasis. Clin Exp Dermatol. 2009;34(3):295–298.

Cyclosporin Cyclosporin is an immunosuppressant that inhibits T cell activation and the production of interleukin 2 and interferon γ by activated T cells, through inhibition of calcineurin. Despite the presence of well designed, randomized, controlled trials using cyclosporin in adults with psoriasis, the data in children is limited to small case series.173,174 Cyclosporin has been used extensively in pediatric atopic dermatitis175 where the initial dose in adults is 2.5  mg/kg, increased by 0.5–1  mg/kg every 4 weeks to a maximal dose of 5  mg/kg per day. Treatment is discontinued after remission is achieved and restarted if needed or the dose can be gradually reduced to 0.5  mg/kg per day for every month until the patient is on the lowest dose needed to maintain long-term control. If monitored for side-effects, treatment may be continued for 1–2 years.176 Cyclosporin was reported to be ineffective in two infants with severe plaque psoriasis.173 Another small series of children with plaque type psoriasis was reported with clearance in all three patients at a dose of 3–3.5  mg/kg per day.174 Several small series have been published with cyclosporin in pediatric pustular psoriasis (see below). The most important side-effects include abnormal renal function tests (raised serum creatinine), hypertension and the risks associated with immunosuppression (infection and long-term malignancy.177

PSORIASIS VULGARIS

patients requiring prolonged treatment with retinoids, but exact recommendations of the frequency and type of imaging are not clear.165 Frequently recommended regimens of investigation include annual wrist X-ray for bone age and femur, for epiphyseal changes; spine X-rays may show exostoses. Erythrodermic psoriasis may respond to a lower dose of retinoid.166 Preliminary long-term safety studies from children with keratinizing disorders have been encouraging.167 Mucocutaneous adverse events are most common, including cheilitis, xerosis, epistaxis, and less commonly hair loss. It has also been shown to be effective in pustular psoriasis in a small series of patients.165 Methotrexate and cyclosporin nay be used in children, teen­ agers, and adult patients with severe psoriasis. Methotrexate is administered once a week as a single dose or divided into two or three doses over a 24-h period. Patients need regular monitoring because of the potential risk of bone marrow suppression and liver dysfunction. There are a number of case reports of methotrexate use in children suffering from severe psoriasis,168–170 but there are no studies detailing the efficacy and safety of the drug in pediatric psoriasis. Kumar et al.169 used a dose of 0.2– 0.4 mg/kg per week to treat seven patients and, apart from nausea and vomiting in three patients, the medication was well tolerated and efficacious in all patients. The dose is generally 0.3–0.5 mg/kg to a maximum weekly dose of 15–20 mg given concurrently with folic acid 1–5 mg daily. A retrospective study from India of 24 children with moderate–severe psoriasis (PASI >10 or disease refractory to conventional therapies, and disabling psoriasis even though the psoriasis area and severity index was 75% decrease in PASI) was reported in the majority of patients (22/24), and the mean time to achieve a 50% reduction in PASI was 5.1 weeks. The side-effects were mild; nine children had nausea, vomiting, and loss of appetite.171 A series of 13 children at the Birmingham Children’s Hospital with severe plaque psoriasis were treated with low-dose once-weekly methotrexate with near clearance in 11/13 patients. The follow-up results indicated that five patients received maintenance methotrexate; four patients needed two-three additional courses of methotrexate, with treatment-free intervals of between 9 and 22 months and two patients discontinued treatment due to elevation in liver enzymes, but the drug was otherwise well tolerated.172

15

Biologics Increased recognition of the molecular biology, and immuno­ biology of psoriasis has provided researchers with specific targets in the pathophysiology of psoriasis. At present, there are five biologic therapies available which target key steps in the path­ ogenesis of psoriasis, including anti-T cell agent (alefacept), anti-TNF agents (etanercept, adalimumab, infliximab) and the anti-P40 monoclonal antibodies directed against the IL12–23 pathway (ustekinumab). Etanercept is the only agent that has been systematically studied in childhood psoriasis with only small case reports demonstrating efficacy for infliximab.178 Tumor necrosis factor (TNF) has been clearly implicated in the pathophysiology of psoriasis and was the target of the first double blind, randomized, controlled trial for a biologic agent in psoriasis. In the study, 211 children aged 4–17 were randomized to receive 12 once weekly subcutaneous injections of placebo or 0.8 mg of etanercept per kilogram of body weight. The maximum dose per week of etanercept was 50 mg. At week 12, a Psoriasis Area of Severity Index 75 (PASI 75) was attained

173. Mahe E, Bodemer C, Pruszkowski A, et al. Cyclosporine in childhood psoriasis. Arch Dermatol. 2001;137:1532–1533. 174. Perrett CM, Alichyshyn A, Berth-Jones J. Cyclosporin in childhood psoriasis. J Dermatal Treat. 2003;14:113–118. 175. Berth-Jones J, Finlay AY, Zaki I, et al. Cyclosporine in severe childhood atopic dermatitis: a multicentre study. J Am Acad Dermatol. 1996;34:1016–1021. 176. Lebwohl M, Ellis C, Gottlieb A, et al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol. 1998;39:464–475. 177. Brecher AR, Orlow SJ. Treatment of children and adolescents with methotrexate, cyclosporin and etanercept: a review of the dermatologic and rheumatologic literature. J Am Acad Dermatol. 2005;52:316–340. 178. Paller AS, Siegfried EC, Langley RG, et al, Etanercept Pediatric Psoriasis Study Group. Etanercept treatment for children and adolescents with plaque psoriasis. N Engl J Med. 2008;358(3):241–251.

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in 57% of the patients receiving etanercept compared with 11% of those receiving placebo (p ≤ 0.001). Following the double blind portion, patients could then follow with 24 weeks of once weekly open label etanercept. After 24 weeks of open label etanercept, at week 36, the PASI 75 was 68% for patients who received etanercept and 65% for those patients that had initially received placebo. At week 36, patients underwent a second randomization to either withdraw or retreat with etanercept; 42% of patients that withdrew from etanercept (29/69) lost response at week 48. The drug was generally well tolerated, with the most common adverse event being upper respiratory tract infection, headache and nasopharyngitis. Of note, four serious adverse events occurred in three patients, including three serious infections.178 PUSTULAR PSORIASIS

Prognosis Most children have mild psoriasis that is responsive to topical therapy. The response varies from improvement with maintenance at a cosmetically acceptable level to complete clearance. Although clearance can be followed by prolonged remission, a chronic relapsing course with intermittent treatment is a feature of most cases. Some children worsen with age, requiring aggressive treatment. Children with guttate psoriasis can clear and have no further problems, redevelop psoriasis only following a streptococcal infection, or gradually develop chronic plaque psoriasis. Pediatric psoriasis differs from adult psoriasis in terms of morphology, distribution, and approach to management. Plaque psoriasis in children often has a finer scale and more commonly manifests on the face, in the flexures, and in a guttate pattern. Nail involvement is less common than with adult patients. Management is more conservative with an emphasis on topical therapy. Phototherapy and systemic therapy are reserved for severe cases. Emotional support of the patient and family is often necessary.

PUSTULAR PSORIASIS The term pustular psoriasis refers to a group of entities charac­ terized by the development of multiple sterile pustules on an

179. Baker H, Ryan TJ. Generalised pustular psoriasis. Br J Dermatol. 1968;80:771–793. 180. Beylot C, Bioulac P, Grupper C, et al. Generalised pustular psoriasis in infants and children: report of 27 cases. In: Farber EM, Cox AJ, Jacobs PH, et al, eds. Psoriasis. Proceedings of the 2nd International Symposium. New York: Yorke Medical Books; 1977:171–179. 181. Marill FG, Vodov I. Psoriasis pustuleux chez des enfants. Remarques a propos de cinq cas. Bull Soc Fr Dermatol Syphyiligr. 1974;81:590–592. 182. Juanqin G, Zhiqiang C, Zuia H. Evaluation of the effectiveness of childhood generalised pustular psoriasis treatment in 30 cases. Pediatr Dermatol. 1998;15:144–146. 183. Khan SA, Peterkin GA, Mitchell PC. Juvenile generalised pustular psoriasis. A report of 5 cases and a review of the literature. Arch Dermatol. 1972;105:67–72. 184. Zelickson BD, Muller SA. Generalised pustular psoriasis in childhood. J Am Acad Dermatol. 1991;24:186–194. 185. Liao PB, Rubinson R, Howard R, et al. Annular pustular psoriasis – most common form of pustular psoriasis in children: Report of three cases and review of the literature. Pediatr Dermatol. 2002;19:19–25. 186. Zachariae H, Peterson HO, Nielsen FK, et al. The HLA antigens in pustular psoriasis. Dermatologica. 1977;154:73.

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erythematous skin, which can be divided clinically into localized and generalized forms. Localized pustular psoriasis is further subdivided into palmoplantar pustulosis, digital pustulosis (acrodermatitis continua of Hallopeau), and plaque psoriasis that develops surface pustules. Generalized pustular psoriasis is subdivided into acute generalized pustular psoriasis (Von Zumbusch), an annular variant, and impetigo herpetiformis, which refers to acute generalized pustular psoriasis during pregnancy. There is considerable overlap between the acute generalized and annular types and this clinical scenario is often referred to as the mixed variant of generalized pustular psoriasis.179 Although one study reported digital pustulosis as the most common type of pustular psoriasis in children,50 the acute generalized and annular forms were the most common types in all other studies.179–185 A review of 39 cases with pustular psoriasis in children by Liao et al.185 found the annular and mixed forms to be more common than the acute generalized form.

EPIDEMIOLOGY Genetics No link has been established between any forms of pustular psoriasis and HLA antigens B13, B17 and Cw6 that are strongly associated with psoriasis vulgaris.186,187 A link has been found between acute generalized pustular psoriasis and HLA B27.187 Pustular psoriasis has been reported in siblings,188 including monozygotic twins189 and a family history of psoriasis is found in up to 25% of patients.180

Statistics All forms of pustular psoriasis are rare in the pediatric age group.50,180,181 Only 68 cases were recorded in one series of 1262 pediatric patients with psoriasis50 and five cases in another series of 479 children.181 In a series of 104 cases of pustular psoriasis involving patients of all ages, there were only five pediatric patients.179 Although most reported cases involve the 2–10-year age group, pustular psoriasis can be present at birth3 or develop at any time during infancy, childhood, or adolescence.50,179–182,190–195 There is a predeliction for males, particularly during the first 2 years of life.180,182

187. Karvonen J, Tiilikainen A, Lassus A. HLA antigens in psoriasis. In: Farber EM, Cox AJ, Jacobs PH, et al, eds. Psoriasis, Proceedings of the 2nd International Symposium. New York: Yorke Medical Books; 1977:405–408. 188. Huber WR. Familial juvenile generalised pustular psoriasis. Arch Dermatol. 1984;120:1174–1178. 189. Takematsu H, Rokugo M, Takahashi K, et al. Juvenile generalised pustular psoriasis in a pair of monozygotic twins presenting strikingly similar clinical courses. Acta Dermatol Venereol. 1992;72:443–444. 190. Chao PH, Cheng YW, Chung MY. Generalized pustular psoriasis in a 6-week-old infant. Pediatr Dermatol. 2009;26(3):352–354. 191. Bellet JS, Chamlin SL, Yan AC, et al. Intertriginous pustular psoriasis. J Am Acad Dermatol. 2009;60(4):679–683. 192. Saeki H, Watanabe A, Tada Y, et al. Juvenile pustular psoriasis associated with steroid withdrawal syndrome due to topical corticosteroid. J Dermatol. 2008;35(9):601–603. 193. Kiszewski AE, De Villa D, Scheibel I, et al. An infant with acrodermatitis continua of Hallopeau: successful treatment with thalidomide and UVB therapy. Pediatr Dermatol. 2009;26(1):105–106. 194. Kirkup ME, Lovell CR. Acquired syndactyly secondary to acrodermatitis continua of Hallopeau. Br J Dermatol. 2005;152(5):1083–1084. 195. Pereira TM, Vieira AP, Fernandes JC, et al. Anti-TNF-alpha therapy in childhood pustular psoriasis. Dermatology. 2006;213(4):350–352.

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Figure 15.13  (A,B) Generalized pustular

A

PUSTULAR PSORIASIS

psoriasis. (B, courtesy of Dr A. Torrelo).

B

PRESENTING HISTORY The acute generalized form of pustular psoriasis presents with the abrupt onset of tender, burning erythema over large areas of the body and/or increased erythema within pre-existing plaques of psoriasis. Surface pustules develop within 24 h. The eruption is accompanied by high fever, malaise, and arthralgias.179–185,190 The annular form presents with scattered erythematous areas that are plaque-like or annular in appearance with overlying surface pustules at the periphery of the lesions. Children can be systemically well or have accompanying fever and malaise, which tends to be less severe than with the acute generalized form.179–185 Many of the acute generalized, annular, and mixed forms have a preceding history of psoriatic diaper rash as babies or an eruption diagnosed as seborrheic dermatitis.179,180,183,184 Patients with the palmoplantar and digital forms present with a pustular eruption on acral sites that is not accompanied by a systemic illness. A personal history of plaque psoriasis and/or family history of pustular or plaque psoriasis may be obtained from patients with all types of pustular psoriasis.

PHYSICAL EXAMINATION In acute generalized pustular psoriasis, the skin is erythematous with superimposed pustules (Fig. 15.13). The extent of skin involvement varies from involvement of large but discrete areas to complete erythroderma. The overlying pustules may remain discrete (1–3 mm) or rapidly coalesce to produce lakes of pus before drying over a 3–4 day period with pronounced desquamation. Successive waves of pustules develop in severely affected patients over several weeks.179–185 A linear pattern of pustular psoriasis following the lines of Blaschko has been reported in two adult patients with acute generalized pustular psoriasis.196,197

196. Kanoh H, Ichihashi N, Kamiya H, et al. Linear pustular psoriasis that developed in a patient with generalised pustular psoriasis. J Am Acad Dermatol. 1998;39:635–637.

Figure 15.14  Annular pustular psoriasis (courtesy of Dr A. Torrelo).

Circinate pustular psoriasis may be localized to the glans penis, and resemble circinate balanitis.192 The annular form is characterized by scattered, welldelineated, erythematous plaques or annular lesions with centrifugal enlargement and central clearing (Fig. 15.14). Pustules and desquamation are scattered over the surface of the plaques or along the advancing edge of the annular lesions.179,180,182–185 Pustular psoriasis can also present during infancy with intertriginous involvement, and possible eventual widespread involvement.191 The intertriginous form may mimic a candidal or bacterial infection, or a dermatitis with erythematous papules, or

197. Ozkaya-Bayazit E, Akasya E, Buyukbabani N, et al. Pustular psoriasis with a striking linear pattern. J Am Acad Dermatol. 2000;42:329–331.

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nail shedding, nail dystrophy,184 and polyarthritis.179,184 Rare complications reported in children are renal failure, cholestatic jaundice,200 lytic bone lesions,201 and sterile multifocal osteomyelitis.202 Rare complications reported in adults with severe acute generalized pustular psoriasis are acute respiratory distress syndrome requiring intubation and ventilation203 and a number of eye changes which include purulent conjunctivitis, iridocyclitis, corneal ulceration, exfoliation of the cornea,204 and uveitis.205 Acute generalized pustular psoriasis was the initial presentation of multiple carboxylase deficiency in a Chinese infant.206

Laboratory findings

PUSTULAR PSORIASIS

Figure 15.15  Acropustulosis continua (courtesy of Dr B. Krafchik). pustules. It is usually localized to the neck and/or other intertriginous areas.191 The palmoplantar form manifests as pustules on the peripheral and/or central aspects of the palms and soles. As the pustules dry, they develop a characteristic reddish-brown color prior to desquamation. Pruritus is a variable feature.198 The digital form (acrodermatitis continua of Hallopeau) is characterized by ‘glazed’ erythema, scaling, and pustules on the distal end of a finger and/or toe with dystrophy of the adjacent nail and swelling of the paronychial area (Fig. 15.15).199 The skin changes are tender and painful rather than pruritic.

Associated findings Severe cases of acute generalized pustular psoriasis in children may be accompanied by geographic tongue,182,184 alopecia,184

198. Baker H. Pustular psoriasis. Dermatol Clin. 1984;2:455–470. 199. Mahowald ML, Parrish RM. Severe osteolytic arthritis mutilans in pustular psoriasis. Arch Dermatol. 1982;118:434–437. 200. Li SP-S, Tang WY-M, Lam W-Y, et al. Renal failure and cholestatic jaundice as unusual complications of childhood pustular psoriasis. Br J Dermatol. 2000;143:1292–1296. 201. Ivker RA, Grin-Jorgensen CM, Vega VK, et al. Infantile generalised pustular psoriasis associated with lytic lesions of the bone. Pediatr Dermatol. 1993;10:277–282. 202. Prose NS, Fahrner L, Miller CR, et al. Pustular psoriasis with chronic recurrent multifocal osteomyelitis and spontaneous fractures. J Am Acad Dermatol. 1994;31:376–379. 203. Sadeh JS, Rudikoff D, Gordon ML, et al. Pustular and erythrodermic psoriasis complicated by acute respiratory distress syndrome. Arch Dermatol. 1997;133:747–750. 204. Lyons JH. Generalised pustular psoriasis. Int J Dermatol. 1987;26:409–418. 205. Yamamoto T, Yokozeki H, Katayama I, et al. Uveitis in patients with generalised pustular psoriasis. Br J Dermatol. 1995;132:1023–1024. 206. Law LK, Lau CY, Pang CP, et al. An unusual case of multiple carboxylase deficiency presenting as generalised pustular psoriasis in a Chinese boy. J Inherit Metab Dis. 1997;20:106–107. 207. Brenner M, Molin S, Ruebsam K, et al. Generalized pustular psoriasis induced by systemic glucocorticosteroids: four cases and recommendations for treatment. Br J Dermatol. 2009;161(4):964–966. 208. Tokuyama Y, Senoh A, Setsu N, et al. Pustular psoriasis induced by terbinafine: differential diagnosis from acute generalized exanthematous pustulosis. Eur J Dermatol. 2008;18(6):725–726. 209. Tamer E, Gur G, Polat M, et al. Flare-up of pustular psoriasis with fluoxetine: possibility of a serotoninergic influence? J Dermatol Treat. 2009;20(3):1–3 Review. 210. Georgala S, Rigopoulos D, Aroni K, et al. Generalised pustular psoriasis precipitated by topical calcipotriol cream. Int J Dermatol. 1994;33:515–516.

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In severe acute generalized pustular psoriasis, investigations reveal a leukocytosis with prominent neutrophilia. Some cases have hypoalbuminemia, hypocalcemia and, rarely, impairment of renal and liver function.

PATHOPHYSIOLOGY AND HISTOGENESIS The development of generalized pustular psoriasis in predisposed children and teenagers can be triggered by an upper respiratory tract infection,182,184 urinary tract infection,184 abrupt cessation of oral steroids,182,184,207 tar cream therapy,184 sunburn,184 terbinafine therapy,208 after fluoxetine administration,209 calcipotriol therapy,210 cessation of cyclosporin therapy,211 vaccination,182 and pregnancy.212 Additional triggering factors in adult cases include withdrawal from potent topical steroid therapy,109,192,213 hydroxychloroquine,214 and recombinant interferon beta injections for multiple sclerosis.215 Palmoplantar pustular psoriasis has been increasingly recognized as a side-effect of biologic therapies, particularly TNF antagonists.216,217 There have been reports of new onset psoriasis in psoriasis patients receiving biologic therapies as well as those with other chronic diseases,216,218 such as psoriatic arthritis,219 and rheumatoid arthritis.220

211. Georgala S, Koumantaki E, Rallis E, et al. Generalised pustular psoriasis developing during withdrawal of short-term cyclosporin therapy. Br J Dermatol. 2000;142:1057–1058. 212. Lee SH, Hunt MJ, Barnetson RS. Pustular psoriasis of pregnancy. Australas J Dermatol. 1995;36:199–200. 213. Tobin AM, Langan SM, Collins P, et al. Generalized pustular psoriasis (von Zumbusch) following the use of calcipotriol and betamethasone dipropionate ointment: a report of two cases. Clin Exp Dermatol. 2009;34(5):629–630. 214. Vine JE, Hymes SR, Warner NB, et al. Pustular psoriasis induced by hydroxychloroquine: a case report and review of the literature. J Dermatol. 1996;23:357–361. 215. Webster GF, Knobler RL, Lublin FD, et al. Cutaneous ulcerations and pustular psoriasis flare caused by recombinant interferon beta injections in patients with multiple sclerosis. J Am Acad Dermatol. 1996;34: 365–367. 216. English PL, Vender R. Occurrence of plantar pustular psoriasis during treatment with infliximab. J Cutan Med Surg. 2009;13(1):40–42. 217. Monteagudo Sánchez B, Cabanillas M, Ortiz-Marin S et al. Infliximabinduced pustular psoriasis in a patient with Crohn’s disease. Gastroenterol Hepatol. 2009;32(3):175–176. 218. Green MG, Bragg J, Rosenman KS, et al. Pustular psoriasis of pregnancy in a patient whose dermatosis showed features of acute generalized exanthematous pustulosis. Int J Dermatol. 2009;48(3):299–303. 219. Rallis E, Korfitis C, Stavropoulou E, et al. Onset of palmoplantar pustular psoriasis while on adalimumab for psoriatic arthritis: A ‘class effect’ of TNF-alpha antagonists or simply an anti-psoriatic treatment adverse reaction? J Dermatolog Treat. 2009;1:1–3. 220. Egnatios G, Warthan MM, Pariser R, et al. Pustular psoriasis following treatment of rheumatoid arthritis with TNF-alpha inhibitors. J Drugs Dermatol. 2008;7(10):975–977.

Papulosquamous diseases

Histologic findings Pustular psoriasis is characterized by epidermal spongiosis and pronounced neutrophilic infiltration resulting in spongioform pustules (of Kogoj). Significant neutrophil collections are also found in the stratum corneum (Munro microabscesses). The epidermal and dermal features are otherwise those of plaque psoriasis.121

Differential diagnosis Acute generalized pustular psoriasis should be distinguished from subcorneal pustular dermatosis, drug induced acute generalized pustular dermatosis (AGEP), and staphylococcal scalded skin syndrome (SSSS). Subcorneal pustular dermatosis is rare in children and does not exhibit spongiform epidermal pustules. This entity may be a variant of pustular psoriasis. Drug induced AGEP is clinically and histologically similar to acute generalized pustular psoriasis. Distinguishing between the two relies on a history of recent drug ingestion. The tender erythema of SSSS can mimic the very early stages of pustular psoriasis. The absence of pustule formation and the crusted moist eruption around the mouth and in the skin flexures distinguishes SSSS from pustular psoriasis. The main differential diagnosis for the annular form

221. Mendez J, Garcia I, Escudero G, et al. Generalized pustular psoriasis induced by tuberculin testing. Actas Dermosifiliogr. 2007;98(7):507–508. 222. Kuijpers AL, Zeeuwen PL, de Jongh GJ, et al. Skin derived antileukoproteinase (SKALP) is decreased in pustular forms of psoriasis. A clue to the pathogenesis of pustule formation. Arch Dermatol Res. 1996;288:641–647. 223. Alkemade JA, Molhuizen HO, Ponec M, et al. SKALP/elafin is an inducible proteinase in hibitor in human epidermal keratinocytes. J Cell Sci. 1994;107:2335–2342. 224. Nonomura K, Yamanishi K, Yasuno H, et al. Up-regulation of elastin/ SKALP gene expression in psoriatic epidermis. J Invest Dermatol. 1994;103:88–91. 225. Wilsmann-Theis D, Hagemann T, Dederer H, et al. Successful treatment of acrodermatitis continua suppurativa with topical tacrolimus 0.1% ointment. Br J Dermatol. 2004;150(6):1194–1197. 226. Murray D, Warin AP. Photochemotherapy for persistent palmoplantar pustulosis (PPP). Br J Dermatol. 1979;101(17):13–14. 227. Zelickson BD, Muller SA. Generalised pustular psoriasis. Arch Dermatol. 1991;127:1339–1345. 228. Ozawa A, Ohkido M, Haruki Y, et al. Treatments of generalised pustular psoriasis: a multicenter study in Japan. J Dermatol. 1999;26:141–149. 229. Yu HJ, Park JW, Park JM, et al. A case of childhood generalised pustular psoriasis treated with dapsone. J Dermatol. 2001;28:316–319. 230. Alli N, Gungor E, Karakayali G, et al. The use of cyclosporin in a child with generalised pustular psoriasis. Br J Dermatol. 1998;139:754–755.

of pustular psoriasis is tinea corporis, erythema annular centrifugum, and Sweet syndrome. Tinea usually manifests as one lesion with positive KOH microscopy and fungal culture. Skin biopsy and routine histology differentiate erythema annulare centrifugum and Sweet syndrome from pustular psoriasis. Tinea manuum and infected dyshidrotic dermatitis can mimic palmoplantar and digital pustulosis. A KOH microscopy and fungal culture help differentiate the two. Persistence of pustules after antibiotic therapy and significant associated itch distinguish this from infected dyshidrotic dermatitis.

THERAPY AND PROGNOSIS Localized pustular psoriasis Localized pustular psoriasis in children is managed adequately in most cases with topical therapy. The choices are potent topical corticosteroids, coal tar preparations, calcipotriol, dithranol used as monotherapy or in combination. Thalidomide and UVB therapy has been used successfully in an infant combined with topical tacrolimus.225 Oral therapy (see below) or PUVA with topically applied psoralen226 is reserved for children with sig­ nificant impairment unresponsive to topical therapy.

PUSTULAR PSORIASIS

Pustular psoriasis is characterized by massive infiltration of neutrophils into the epidermis resulting in pustule formation; the cause of this is unknown. One study, using tuberculin testing,221 found the activity of skin derived antileukoproteinase, also known as elafin, was significantly reduced in the epidermis of pustular psoriasis patients compared with plaque psoriasis patients.222 Elafin is an inducible epidermal serine proteinase inhibitor that protects the epidermis against damage caused by elastase and proteinase-3 released by infiltrating neutrophils.223 Elafin gene expression in plaque psoriasis is greatest around subcorneal microabscesses, which supports a protective or damage-minimization role for elafin.224 The decreased activity of elafin in pustular psoriasis may theoretically promote neutrophil-induced destruction of the epidermis and pustule formation.

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Generalized pustular psoriasis Acute generalized psoriasis is best managed in the early stages in hospital to ensure adequate fluid intake, urine output, stable blood pressure, and to facilitate monitoring of serum electrolytes, albumin, calcium, liver, and renal function. Removal or treatment of a triggering factor may allow the process to settle with bed rest and the application of a weak topical steroid with or without wet dressings.184 For most patients, however, repeated waves of pustulation and the associated toxicity necessitate a more aggressive approach with oral therapy. Oral medications that have been used successfully in the treatment of acute generalized pustular psoriasis in children are retinoids,182,184,190,227,228 methotrexate,182,227,228 dapsone,182,227,229 and cyclosporine.227,228,230 Anti TNF antagonists and anti-T cell agents have also been used in adults with generalized pustular psoriasis,231–240 and in

231. Sheth N, Greenblatt DT, Acland K, et al. Generalized pustular psoriasis of pregnancy treated with infliximab. Clin Exp Dermatol. 2009;34(4):521–522. 232. Jordan J, Bieber T, Wilsmann-Theis D. Adalimumab: safe and successful in severe pustular psoriasis. J Eur Acad Dermatol Venereol. 2009;23(5):592–593. 233. Routhouska SB, Sheth PB, Korman NJ. Long-term management of generalized pustular psoriasis with infliximab: case series. J Cutan Med Surg. 2008;12(4):184–188. 234. Zangrilli A, Papoutsaki M, Talamonti M, et al. Long-term efficacy of adalimumab in generalized pustular psoriasis. J Dermatolog Treat. 2008;19(3):185–187. 235. Carr D, Tusa MG, Carroll CL, et al. Open label trial of alefacept in palmoplantar pustular psoriasis. J Dermatol Treat. 2008;19(2):97–100. 236. Esposito M, Mazzotta A, Casciello C, et al. Etanercept at different dosages in the treatment of generalized pustular psoriasis: a case series. Dermatology. 2008;216(4):355–360. 237. Mikhail M, Weinberg JM, Smith BL. Successful treatment with etanercept of von Zumbusch pustular psoriasis in a patient with human immunodeficiency virus. Arch Dermatol. 2008;144(4):453–456. 238. Weishaupt C, Metze D, Luger TA, et al. Treatment of pustular psoriasis with infliximab. J Dtsch Dermatol Ges. 2007;5(5):397–399. 239. Weisenseel P, Prinz JC. Sequential use of infliximab and etanercept in generalized pustular psoriasis. Cutis. 2006;78(3):197–199. 240. Lewis TG, Tuchinda C, Lim HW, et al. Life-threatening pustular and erythrodermic psoriasis responding to infliximab. J Drugs Dermatol. 2006;5(6):546–548.

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PSORIATIC ARTHRITIS

recalcitrant cases of acrodermatitis continua of Hallopeau.241–250 The choice of oral medication is determined by drug availability, prescriber’s experience, and the patient’s medical status. Particular care is needed when using retinoids in females of childbearing age because of its teratogenicity. As a general principle, treatment is initiated at an adequate dose and maintained until clearance occurs. The lowest possible dose required for disease control is determined and continued for as long as needed. Appropriate pretreatment and follow-up investigations are required, particularly during the early stages of the disease when organ dysfunction may be present. Oral corticosteroids are reserved for pregnant patients and those with evidence of organ dysfunction. One child with cholestatic hepatitis and renal failure required intravenous methylprednisolone therapy to reverse organ dysfunction.200 Three children with generalized pustular psoriasis were treated with cyclosporin in doses from 1–2 mg/kg per day.251 Clearance was reported within 2–4 weeks of therapy and maintenance was continued for 6 months to 1 year. A single case was also reported of a 9-year-old patient with generalized pustular psoriasis achieving disease control after 2 weeks with 3 mg/kg per day.252 In adults, cyclosporin is typically used in the short term to achieve remission and then discontinued. Treatment for the annular and mixed forms of generalized pustular psoriasis is guided by the extent of the eruption and the presence and severity of the associated systemic illness. Topical steroids are sufficient for patients with mild–moderate skin disease and no systemic symptoms.184,185 Patients with extensive skin disease and any patients with systemic symptoms require oral therapy.183–185 This is generally achieved with Acitretin 0.75 mg/kg per day.

Prognosis The course of generalized pustular psoriasis is variable. It may be a once only phenomenon, it may recur at intermittent intervals over many years, it may persist indefinitely (annular form), or evolve into plaque psoriasis. Morbidity and mortality with the acute generalized form is low because of improved medical management and hospital care. Localized pustular psoriasis tends to run a chronic course.

241. Ryan C, Collins P, Kirby B, et al. Treatment of acrodermatitis continua of Hallopeau with adalimumab. Br J Dermatol. 2009;160(1):203–205. 242. Rubio C, Martin MA, Arranz Sánchez DM, et al. Excellent and prolonged response to infliximab in a case of recalcitrant acrodermatitis continua of Hallopeau. J Eur Acad Dermatol Venereol. 2009;23(6):707–708. 243. Thielen AM, Barde C, Marazza G, et al. Long-term control with etanercept (Enbrel) of a severe acrodermatitis continua of Hallopeau refractory to infliximab (Remicade). Dermatology. 2008;217(2):137–139. 244. Weisshaar E, Diepgen TL. Successful etanercept therapy in therapy refractory acrodermatitis continua suppurativa Hallopeau. J Dtsch Dermatol Ges. 2007;5(6):489–492. 245. Bonish B, Rashid RM, Swan J. Etanercept responsive acrodermatitis continua of Hallopeau: is a pattern developing? J Drugs Dermatol. 2006;5(9):903–904. 246. Tobin AM, Kirby B. Successful treatment of recalcitrant acrodermatitis continua of Hallopeau with adalimumab and acitretin. Br J Dermatol. 2005;153(2):445–446. 247. Ahmad K, Rogers S. Three years’ experience with infliximab in recalcitrant psoriasis. Clin Exp Dermatol. 2006;31(5):630–633. 248. Ahmad K, Rogers S. Two years of experience with etanercept in recalcitrant psoriasis. Br J Dermatol. 2007;156(5):1010–1014. 249. Kazinski K, Joyce KM, Hodson D. The successful use of etanercept in combination therapy for treatment of acrodermatitis continua of hallopeau. J Drugs Dermatol. 2005;4(3):360–364.

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BOX 15.2 CLASSIFICATION OF PSORIATIC ARTHRITIS

>> Arthritis of the distal interphalangeal joints of the hands and feet

>> Arthritis mutilans with sacroileitis >> Symmetric arthritis indistinguishable from rheumatoid arthritis (negative rheumatoid factor)

>> Asymmetric pauciarticular arthritis with small joint involvement >> Ankylosing spondylitis

PSORIATIC ARTHRITIS Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis that may occur in childhood or in adult patients.253 Although the first report of a patient with psoriasis and psoriatic arthritis was made by Alibert in 1818,254 it was not recognized as a specific disease entity by the American College of Rheumatology until 1964.255 A formal association between psoriasis and arthritis was reported by Bazin in 1860256 and Bourdillon in 1888.257 It was not until the early 1970s, with the implementation of Moll and Wright’s classification,258 that PsA was reliably distinguished from rheumatoid arthritis. It is grouped with the other seronegative spondyloarthro­ pathies; Reiter syndrome, ankylosing spondylitis and enter­ opathic arthritides and is a heterogeneous disease with five clinical subgroups as proposed by Moll and Wright.258 The subgroups are listed in Box 15.2. There is considerable overlap between the subgroups and patients can evolve from one type to another.

EPIDEMIOLOGY Genetics Studies have identified an association between psoriatic arthritis and HLA alleles Cw6,259 particularly the Cw*0602 allele,260

250. Mang R, Ruzicka T, Stege H. Successful treatment of acrodermatitis continua of Hallopeau by the tumour necrosis factor-alpha inhibitor infliximab (Remicade). Br J Dermatol. 2004;150(2):379–380. 251. Kilic SS, Hacimustafaoglu M, Celebi S, et al. Low dose cyclosporin a treatment in generalized pustular psoriasis. Pediat Dermatol. 2001;18:246–248. 252. Alli N, Gunjur E, Krakayali G, et al. The use of cyclosporin in a child with generalized pustular psoriasis. Br J Dermatol. 1998;139:754–755. 253. Wright V, Moll JM. Psoriatic arthritis. Seronegative polyarthritis. North Holland: Amsterdam; 1976:169–223. 254. Alibert JL. Precis theorique sur les malaides de la peau. Paris: Caille et Ravier; 1818. 255. Brumberg BS, Bunim JJ, Kalkins E, et al. ARA nomenclature and classification of arthritis and rheumatism. Arthritis Rheum. 1964:7:93–97. 256. Bazin P. Leçons theoretiques et cliniques sur les affections cutanées de nature arthritique et arthreux. Paris: Delahaye; 1860. 257. Bourdillon C. Psoriasis et arthropathies. Paris: MD Thesis; 1888. 258. Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum. 1973;3:55–78. 259. Rahman P, Schentag CT, Beaton M, et al. Comparison of clinical and immunogenetic features in familial versus sporadic psoriatic arthritis. Clin Exp Rheumatol. 2000;18:7–12. 260. Gladman DD, Cheung C, Ng C-M, et al. HLA-C locus alleles in patients with psoriatic arthritis (PsA). Hum Immunol. 1999;60:259–261.

Papulosquamous diseases

Statistics The prevalence of PsA has not been clearly defined; estimates have ranged from 0.04% to 1.2%.266 Between 5% and 42% of psoriasis patients will develop psoriatic arthritis.267–269 Historically, it is believed that PsA is infrequent among psoriasis patients, although this may be due to under-recognition of the condition in dermatology practice and lack of standardized criteria.

PRESENTING HISTORY Patients present to primary care physicians, dermatologists, or rheumatologists with pain involving one or more joints. Pain and stiffness is usually worse in the morning on awakening. Many patients exhibit features of one of the five clinical subgroups outlined in Box 15.2. One study found 50% of children have one joint involved at the time of first presentation.270 If psoriasis is not clinically evident, a past or family history of psoriasis should be sought.

PHYSICAL EXAMINATION Joints The findings of joint examination on first presentation are extremely variable. In mild cases, little may be found apart from mild periarticular tenderness and limitation of movement. More severe cases exhibit varying degrees of tenderness, erythema, swelling, and limitation of joint movement. Sausage-like swelling of the digit is a particularly characteristic feature. Chronicity is associated with progressive reduction in range of movement and variable deformity of affected digits. 261. Lambert JR, Wright V, Rajah SM, et al. Histocompatibility antigens in psoriatic arthritis. Ann Rheumatol Dis. 1976;35:526. 262. Gladman DD, Farewell VT. The role of HLA antigens as indicators of disease progression in psoriatic arthritis. Multivariate relative risk model. Arthritis Rheum. 1995;38:845–850. 263. Gladman DD, Anhorn KA, Schachter RK, et al. HLA antigens in psoriatic arthritis. J Rheumatol. 1986;13:586–592. 264. Hamilton ML, Gladman DD, Shore A, et al. Juvenile psoriatic arthritis and HLA antigens. Ann Rheum Dis. 1990;49:694–697. 265. Gonzalez S, Martinez-Borra J, Torre-Alonso JC, et al. The MICA-A9 triplet repeat polymorphism in the transmembrane region confers additional susceptibility to the development of psoriatic arthritis and is independent of the association of Cw*0602 in psoriasis. Arthritis Rheum. 1999;42:1010–1016. 266. Gladman DD. Psoriatic arthritis in psoriasis and psoriatic arthritis. In Gordon KB, Ruderman EM, eds. Psoriatic arthritis. Berlin: Springer; 2004:57–65. 267. Gladman DD, Brockbank J. Psoriatic arthritis. Expert Opin Investig Drugs. 2007;9:1511–1522. 268. Elkayam O, Ophir J, Yaron M, et al. Psoriatic arthritis: interrelationships between skin and joint manifestations related to onset, course and distribution. Clin Rheumatol. 2000;19:301–305.

Hair, nails, teeth, mucous membranes, and associated findings Most patients have evidence of psoriasis vulgaris or pustular psoriasis at the time of initial presentation of the arthritis.271 There is a correlation between the severity of psoriasis and the presence and severity of psoriatic arthritis.271 Psoriatic nail changes are found in 80% of psoriatic patients with arthritis compared with 20–30% of patients with skin disease only.272 Inflammation of the eye can occur and manifests as conjunctivitis (20% cases), uveitis (10% cases), keratoconjunctivitis (3% cases), and episcleritis (2% cases).273 Ophthalmologic assessment is needed if patients complain of eye irritation and/or pain. The CASPAR classification has been developed to provide criteria for the diagnosis of psoriatic arthritis (PsA). Using these criteria, patients must have inflammatory articular disease (joint, spine, or entheseal) with three or more of the following five criteria: 1. Current or personal history of psoriasis, or family history of psoriasis (first or second degree relative). Psoriasis is defined as skin or scalp disease. 2. Psoriatic nail disease, including: onycholysis, pitting, and hyperkeratosis on current physical exam. 3. Negative for rheumatoid factor (by any method except latex). 4. History of recurrent dactylitis recorded by a rheumatologist. 5. Radiographic evidence of juxta-articular new bone formation, appearing as ill-defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand and foot. These criteria have been determined to have a high specificity of 98.7% and a sensitivity of 91.4% for the diagnosis of PsA.274 The CASPAR criteria have also been validated in a family practice setting with a sensitivity of 100% and a specificity of 98.8%.275,276 PsA is equal between the sexes. The peak age of onset is approximately 36 years.266 Psoriasis is the first manifestation in the majority of patients, with arthritis following in approximately 10 years. In 15% of patients, arthritis and psoriasis can occur at the same time, and in 15% arthritis may precede psoriasis.277 The most frequent pattern of PsA is the oligoarticular pattern which is reported in approximately 70% of patients. The least frequent pattern of psoriatic arthritis is the arthritis mutilans pattern, occurring in approximately 5% of patients.266

PSORIATIC ARTHRITIS

B27,261 B39,262 and DR4.263 HLA-B27 is particularly associated with the sacroileitis variant of psoriatic arthritis. HLA-B39 is linked with poor prognosis and HLA-DR4 is associated with the polyarthritis variant of psoriatic arthritis. Other reported associations with psoriatic arthritis involve a polymorphism at position –238 in the promoter region of the tumour necrosis factor (TNF) gene264 and a particular allele (MICA-A9) of the MICA gene265 that encodes for MICA, a major histocompatibility complex-like molecule, whose function remains unknown.42

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269. Gladman DD. Psoriatic arthritis. Rheum Dis Clin North Am. 1998;24:829–844. 270. Wright V. Psoriatic arthritis. Ann Rheum Dis. 1961;20:123–132. 271. Oriente P, Biondi-Oriente C, Scarpa R. Psoriatic arthritis. Clinical manifestations. Baillieres Clin Rheumatol. 1994;8:277–294. 272. Eastwood CJ, Wright V. The nail dystrophy of psoriatic arthritis. Ann Rheumatol Dis. 1979;38:226. 273. Lambert JR, Wright V. Eye inflammation in psoriatic arthritis. Ann Rheum Dis. 1976;35:354–356. 274. Taylor W, Gladman DD, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54:2665–2673. 275. Chandlan V, Chentag CT, Gladman DD. Sensitivity and specificity of the CASPAR criteria for psoriatic arthritis in a family medicine clinic setting. J Rheumatol. 2008;35(10):2069–2070. 276. Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis. 2005;64(2):18–23. 277. Gladman DD, Shuckett R, Russell ML, et al. Psoriatic arthritis – clinical and laboratory analysis of 220 patients. Q J Med. 1987;62:127–141.

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PsA is differentiated from rheumatoid arthritis on a clinical and radiological basis. Rheumatoid arthritis presents as a symmetric polyarthritis with rare spinal involvement and the presence of rheumatoid nodules. In contrast, PsA is typically asymmetric: it affects joints in a ray distribution (in one digit) and spinal involvement is common. In comparison to rheumatoid arthritis, nail involvement is frequent in psoriasis, and psoriasis skin lesions are usually present on the skin and/or scalp of patients with PsA. A red-purple discoloration may occur over joints in PsA. Joint tenderness is more pronounced in rheumatoid arthritis than in PsA. Spine involvement is common in PsA (spondyloarthritis), whereas this is infrequent in rheumatoid arthritis, apart from cervical involvement. The dermatologist plays an important role in the early recognition of psoriatic arthritis. Since the majority of PsA patients present first with skin disease, dermatologists are in the unique position to identify children with psoriasis that subsequently develop PsA. The Toronto Psoriatic Arthritis Screen (ToPAS) has been developed for patients to facilitate the early diagnosis of PsA and the CASPAR criteria have been validated among rheumatologists and family physicians as a highly sensitive and specific tool for the diagnosis of PsA. An interrater diagnostic accuracy study involving dermatologists and rheumatologists demonstrated that dermatologists are able to diagnose the signs and symptoms of psoriatic arthritis with high accuracy.278

Laboratory findings There is no specific laboratory test to establish the diagnosis of psoriatic arthritis. Non-specific laboratory findings include mild anemia, elevated erythrocyte sedimentation rate, elevated C-reactive protein, and negative rheumatoid factor.279 The rheumatoid factor can be weakly positive with the polyarthritis form,280 which may represent a coincidental finding because a positive rheumatoid factor occurs in 5% of the normal population.281 Radiologic changes can be indistinguishable from rheumatoid arthritis with local demineralization, narrowing of joint spaces, articular erosions, and periarticular soft tissue swelling.282 Four characteristic radiologic signs of psoriatic arthropathy noted in one series were: (a) destructive distal interphalangeal arthropathy with bony ankylosis of the interphalangeal joints; (b) destruction of the interphalangeal joints with abnormally wide joint spaces and sharply demarcated adjacent bony surfaces; (c) destruction of the interphalangeal joint of the great toe with bony proliferation of the distal phalanx; and (d) resorption of tufts of the distal phalanges of the hands and feet.283 Fat suppression magnetic resonance imaging (MRI) has identified enthesitis (inflammation at sites of attachment of ligaments,

278. Gladman DD, Rosen CM, Langley RG 2010 (in press). 279. Laurent MR. Psoriatic arthritis. Clin Rheum Dis. 1985;11:50–55. 280. Roberts MET, Wright V, Hill AG, et al. Psoriatic arthritis: follow-up study. Ann Rheum Dis. 1976;35:206–212. 281. Waller M, Toone EC. Normal individuals with positive tests for rheumatoid factor. Arthritis Rheum. 1968;11:50–55. 282. Lassus A, Mustakallio KK, Laine V. Psoriasis arthropathy and rheumatoid arthritis. Acta Rheum Scand. 1964;10:62–68. 283. Avila R, Pugh DG, Slocumb CH, et al. Psoriatic arthritis: a roentgenologic study. Radiology. 1960;75:691–702. 284. McGonagle D, Gibbon W, O’Connor P, et al. Characteristic magnetic resonance imaging entheseal changes in knee synovitis in spondyloarthropathy. Arthritis Rheum. 1998;41:694–700.

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tendons, joint capsule, and fascia to bone) in many patients with PsA.284

PATHOPHYSIOLOGY AND HISTOGENESIS Conventionally, PsA has been considered to be an autoimmune disorder. The primary basis for this concept has related to T-cell-directed response against synovial antigens, which was indirectly supported by the human leucocyte antigen-Cw6 disease association. Evidence that supports the synovium as the primary site of pathology relates to examination of the T-cell infiltrates in synovial fluid. Studies have found oligoclonal expansion of CD4+ and CD8+ T cells within synovial fluid compared with peripheral blood CD4+ and CD8+ T cells. The clonal expansion is more pronounced with CD8+ T cells, resulting in a significant reduction in the CD4+: CD8+ ratio.77,285 This is in contrast with rheumatoid arthritis, which has a high CD4+: CD8+ ratio due to clonal expansion of CD4+ T cells.286 The clonal expansion of T cells within the joint suggests stimulation by an unidentified antigen. The finding of common T-cell clonal expansion in the synovium and skin suggests the involvement of a common antigen in the inflammatory process at both sites.77 Emerging evidence has supported a central role of the enthesis, or the tendon and ligament insertion to bone, in the pathophysiology of PsA.284,287,288 Improvements in imaging have identified subclinical enthesitis in a substantial proportion of PsA patients at presentation.287 In addition, associated osteitis has been documented.289 Fat suppression MRI has also identified enthesitis as the initial process in some patients with early PsA.284 Recent microanatomical studies have suggested that the enthesis may be the primary site for the inflammatory reaction associated with PsA, and that microtrauma results in an innate immune activation.287

Histologic findings Histologically, one cannot distinguish psoriatic arthritis from rheumatoid arthritis, and synovial biopsy has no role in the diagnosis and management of psoriatic arthritis.

Differential diagnosis The diagnosis of psoriatic arthritis is straightforward in patients with definite psoriasis. The polyarthritis form can be difficult to distinguish from rheumatoid arthritis in patients without

285. Costello P, Bresnihan B, O’Farrelly C, et al. Predominance of CD81 T lymphocytes in psoriatic arthritis. J Rheumatol. 1999;26:1117–1124. 286. Goronzy JJ, Bartz-Bazzanella P, Hu W, et al. Dominant clonotypes in the repertoire of peripheral CD41 T-cells in rheumatoid arthritis. J Clin Invest. 1994;94:2068–2076. 287. McGonagle D, Benjamin M, Tan AL. The pathogenesis of psoriatic arthritis and nail disease: not autoimmune after all? Curr Opini Rheum. 2009;21:340–347. 288. McGonagle D, Conaghan PG, Emery P. Psoriatic arthritis: a unified concept twenty years on. Arthritis Rheum. 1999;42:1080–1086. 289. Jevtic T, Watt I, Rozman B, et al. Distinctive radiographical features of small hand joints in rheumatoid arthritis and seronegative spondyloathritis demonstrated by contrast enhanced (Gd-DPTA) magnetic resonance imaging. Skeletal Radiol. 1995;24:351–355.

Papulosquamous diseases

psoriasis and a negative or weakly positive rheumatoid factor. In this situation, the correct diagnosis evolves with time and observation. Distinguishing Reiter disease may be difficult and relies on identification of a triggering illness and the presence or history of urethritis.

a dysenteric illness.299 His name is now eponymously linked to the syndrome of reactive arthritis associated with urethritis and conjunctivitis.

THERAPY AND PROGNOSIS

Genetics

Treatment is usually initiated and supervised by a rheumatologist. Mild cases can usually be managed with non-steroidal anti-inflammatory medication (e.g., naproxen) and intra-articular steroid injections. More severe cases require oral therapy such as methotrexate,290 sulfasalazine,291 retinoids,292 azathioprine,293 or cyclosporine.294 A systematic review of all medications, with the exception of cyclosporine, found that all were better than placebo. Intravenous methotrexate and Salazopyrin were the most efficacious.295 Oral corticosteroids are reserved for severe, fulminant cases with a high risk of irreversible crippling deformities. Physiotherapy is helpful in maintaining full movement in affected joints. Tumor necrosis factor inhibitors, such as etanercept, adalimumab, and infliximab, may be efficacious.296

Most adult300 and pediatric cases301–304 of Reiter syndrome are positive for the HLA-B27 antigen. HLA-B51 has also been associated with Reiter syndrome in one Japanese report.305 It has been reported in children with a family history of ankylosing spondylitis.304 Simultaneous occurrence in parents and children306 and siblings has also been reported.302

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EPIDEMIOLOGY

REITER SYNDROME

Statistics In view of the rarity of Reiter syndrome in children, the incidence in this group is unknown. Most of the reported pediatric cases involve males and the age range at the time of presentation is 1.8–16 years.301–304

PRESENTING HISTORY Prognosis The course of childhood PsA is very unpredictable, with numerous remissions and relapses. Severe cases may be rapidly progressive with marked destruction of many joints. In most children, disease activity is intermittent and long-term prognosis is good with minimal joint disease in adult life.270 Poor prognostic indicators are numerous effusions, peripheral joint involvement, polyarthritis, and elevated erythrocyte sedimentation rate at the time of initial presentation.297,298 Education of patients and parents is essential because of the chronic and intermittent nature of PsA in most children. Early assessment by a rheumatologist is important to ensure optimum treatment.

Children with Reiter disease usually present with conjunctivitis and/or asymmetric arthritis involving one or more joints.301,303,304 Dysuria and mucocutaneous lesions are uncommon presenting features.302 The complete triad of arthritis, conjunctivitis, and urethritis is rarely evident on presentation and can take 4–24 days to manifest.302 Some patients fail to develop the complete triad.301,303,304,307 Fever with anorexia, weight loss, and malaise may occur at the time of initial presentation.302–304 Children and adolescents with Reiter syndrome usually have a history of a preceding gastrointestinal illness.301–303 Adolescents should be questioned about sexual contacts and the presence of symptoms and/or signs suggestive of chlamydia infection.302

PHYSICAL EXAMINATION

REITER SYNDROME

Ocular

In 1916, Hans Reiter reported a case of a young soldier with non-gonococcal urethritis, conjunctivitis, and arthritis following

Conjunctivitis is the most common ocular manifestation of Reiter syndrome. It is bilateral and can vary in severity from mild

290. Willkens RF, Williams HJ, Ward JR, et al. Randomised, double-blind placebo controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum. 1984;27:376–381. 291. Clegg DO, Reda DJ, Mejias E, et al. Comparison of sulphasalazine and placebo in the treatment of psoriatic arthritis: a Department of Veterans Affairs Cooperative Study. Arthritis Rheum. 1996;39:2013–2020. 292. Hopkins R, Bird HA, Jones H, et al. A double-blind controlled trial of etretinate (Tigason) and ibuprofen in psoriatic arthritis. Ann Rheum Dis. 1985;44:189–193. 293. Levy J, Paulus HE, Barrett EV, et al. A double-blind controlled evaluation of azathioprine treatment in rheumatoid arthritis and psoriatic arthritis. Arthritis Rheum. 1972;15:116–117. 294. Mahrle G, Schulze H-J, Brautigam M, et al. Anti-inflammatory efficacy of low-dose cyclosporin A in psoriatic arthritis. A prospective multicentre study. Br J Dermatol. 1996;135:752–757. 295. Jones G, Crotty M, Brooks P. Interventions for psoriatic arthritis. Cochrane Database Syst Rev. 2000;3:CD000212. 296. Helliwell PS, Taylor WJ, CASPAR Study Group. Treatment of psoriatic arthritis and rheumatoid arthritis with desease modifying drugs – comparison of drugs and adverse reactions. J Rheumatol. 2008;35(3):472–476. 297. Jones SM, Armas JM, Cohen MG, et al. Psoriatic arthritis: outcome of disease subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol. 1994;33:834–839.

298. Gladman DD, Fareqell VT, Nadeau C. Clinical indicators of progression in psoriatic arthritis: multivariate relative risk model. J Rheumatol. 1995;22:675–679. 299. Reiter H. Ueber eine bisher unerkannte Spirochaeteninfektion. Dtsch Med Wochenschr. 1916;42:1535–1536. 300. Morris R, Metzger AL, Bluestone R, et al. HLA-B27: A clue to the diagnosis and pathogenesis of Reiter’s syndrome. N Engl J Med. 1974;290:554. 301. Singsen BH, Bernstein BH, Koster-King KG, et al. Reiter’s syndrome in childhood. Arthritis Rheum. 1977;20:402–407. 302. Rosenberg AM, Petty RE. Reiter’s disease in children. Am J Dis Child. 1979;133:394–398. 303. Zivony D, Nocton J, Wortmann D, et al. Juvenile Reiter’s syndrome: a report of four cases. J Am Acad Dermatol. 1998;38:32–37. 304. Liao CH, Huang JL, Yeh KW. Juvenile Reiter’s syndrome: a case report. J Microbiol Immunol Infect. 2004;37:379–381. 305. Shimamoto Y, Sugiyama H, Hirohata S. Reiter’s syndrome associated with HLA-B51. Intern Med. 2000;39:182–184. 306. Gough KR. Reiter’s syndrome in father and son. Ann Rheum Dis. 1962;21:292–294. 307. Jacobs J, Berdon W, Johnston A. HLA-B27 associated spondyloarthritis and enthesopathy in childhood: clinical, pathologic and radiographic observations in 58 patients. Pediatr. 1982;100:521–528.

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injection to mucopurulent inflammation of the conjunctiva.301–304 Infrequent ocular findings in pediatric cases are iritis,308 keratitis,309 corneal ulceration,302 and optic neuritis.310 Ocular manifestations are self-limited and no long-term sequelae have been reported.302,303

Joints

REITER SYNDROME

Although large weight-bearing joints (e.g., knee, ankle, hip) are the most commonly affected, any large (e.g., wrist) or small joint (e.g., metatarsophalangeal joint) can be affected.301,303,304,308 Most pediatric cases have more than one joint involved in an asymmetric or, less commonly, symmetric distribution.301–304,308 The affected joints exhibit warmth, tenderness, swelling, and limitation of movement. Unlike adult cases, sacroileitis is uncommon in pediatric cases.311,312 Many patients also have enthesitis (inflammation at the site of attachment of tendons and ligaments to bone).302,304,307 The enthesitis gives rise to pain and focal tenderness. In most patients, the arthritis and enthesitis are selflimited with resolution occurring within a few months of onset. Occasionally, it lasts for several years as a chronic persistent or chronic recurring problem.303

Figure 15.16  Keratoderma blenorrhagica of Reiter’s syndrome.

and an evanescent erythematous eruption on the trunk and limbs.302,303

Other clinical findings Genitourinary Most children have asymptomatic urethritis with sterile pyuria as the only evidence of urethral inflammation.301–303 If there is a history of dysuria, examination may reveal inflammation of the meatus301,302 and/or urethral discharge.308

Mucocutaneous Circinate balanitis/vulvitis and keratoderma blenorrhagica are the characteristic mucocutaneous findings of Reiter syndrome. Circinate balanitis manifests as shallow, sharply marginated ulcers in females309 and uncircumcised males.303 Circumcised males exhibit hyperkeratotic (psoriasiform) patches or plaques.302,303 Circinate balanitis developed in 15% of pediatric patients in one study302 and 50% of pediatric patients in another study.312 In a more recent report, three of four cases were affected.303 Keratoderma blenorrhagica develops in a minority of children with Reiter’s syndrome. It manifests on the palms and soles as yellow, hyperkeratotic papules that can coalesce to form scaly, psoriasiform plaques (Fig. 15.16). Vesicules and/or pustules may be evident in the early stages of development. Psoriasiform changes can develop on the extensor surface of the hands, feet, and limbs.303,306 Keratoderma blenorrhagica was present in 8% of patients in one study,302 25% of pediatric patients in another study,312 and two of four patients in another study.303 Additional nonspecific mucocutaneous findings include oral ulceration301,304,309

308. Iveson JMI, Nanda BS, Hancock JA, et al. Reiter’s disease in three boys. Ann Rheum Dis. 1975;34:364–368. 309. Russell AS. Reiter’s syndrome in children following infection with Yersinia enterocolitica and shigella. Arthritis Rheum. 1977;20:471–472. 310. Zewi M. Morbut reiteri. Acta Ophthalmol. 1947;25:47–60. 311. Ansell B. Reactive arthritis/Reiter’s syndrome in children. Clin Exp Rheumatol. 1994;12:581–582.

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Rare manifestations of Reiter syndrome in children are pleuritis,302 epistaxis,302 aortic root dilation,301 generalized lymphadenopathy,313 and splenomegaly.313

Laboratory findings Most pediatric patients with Reiter disease are positive for the HLA-B27 antigen.301–303 Stool cultures and urethral cultures may be positive for the triggering factor if collected at the appropriate time.302 Non-specific findings include sterile pyuria, mild anemia, mild leukocytosis, and significantly elevated erythrocyte sedimentation rate.302 Radiographs of the affected joints are unremarkable in the early stages. Chronicity is associated with periosteal new bone formation secondary to periostitis, heel lucencies, spurs at the attachment of the plantar fascia or Achilles tendon, and demineralization around affected joints.307

PATHOPHYSIOLOGY AND HISTOGENESIS Reiter disease is triggered in predisposed pediatric patients by an infectious illness in the gastrointestinal tract or urethra. Predisposition in most patients is linked to the HLA-B27 antigen. Gastrointestinal infections known to trigger Reiter syndrome in children involve Shigella flexneri,301,309 Yersinia enterocolitica,309 and various Salmonella species (enteritidis, oranienburg, typhimurium).301,308,314 Chlamydia has been isolated from the urethra of pediatric patients with post-urethritis Reiter syndrome.302 Other

312. Cuttica R, Scheines E, Garay M, et al. Juvenile onset Reiter’s syndrome. A retrospective study of 26 patients. Clin Exp Rheumatol. 1992;10: 285–288. 313. Lockie GN, Hunder GG. Reiter’s syndrome in children. Arthritis Rheum. 1971;14:767–772. 314. Jones RA. Reiter’s disease after Salmonella typhimurium enteritis. BMJ. 1977;1:1391.

Papulosquamous diseases

Histologic findings The early lesions of circinate balanitis and keratoderma blenorrhagica exhibit a spongiform pustule in the upper epidermis similar to psoriasis. The pustule is replaced by non-specific acanthosis, parakeratosis, and hyperkeratosis in established lesions.121

Differential diagnosis The differential diagnosis includes juvenile rheumatoid arthritis, other seronegative arthropathies (e.g., psoriatic arthritis, inflammatory bowel disease associated arthritis), infectious arthropathies (e.g., Lyme disease, post viral, gonococcal), Behçet disease, Kawasaki disease and rheumatic fever. Distinguishing the various conditions depends on other clinical features (e.g., symptoms of inflammatory bowel disease, criteria for Kawasaki disease), the pattern of joint involvement, serology to exclude particular infections (e.g., Lyme disease), serum rheumatoid factor, and HLA-B27 status.

THERAPY AND PROGNOSIS Therapy is directed at removing the triggering factor and implementing anti-inflammatory therapy to settle the various manifestations of the disease. Antibiotic therapy for the infectious trigger is guided by the results of microbial cultures. Arthritis and enthesitis usually respond to aspirin or a non-steroidal antiinflammatory medication (e.g., naproxen) given in appropriate doses for as long as needed.301–304 Occasionally, intra-articular steroids or more aggressive oral therapy is needed. Sulfasalazine

315. Winchester R, Bernstein D, Fischer H, et al. The co-occurrence of Reiter’s syndrome and acquired immunodeficiency. Ann Intern Med. 1978;123:1622–1632. 316. Natarajan UR, Tan TL, Lau R. Reiter’s disease following Mycoplasma pneumoniae infection. Int J STD AIDS. 2001;12:349–350. 317. Pavlica L, Draskovic N. Isolation of Chlamydia trachomatis or Ureaplasma urealyticum from the synovial fluid of patients with Reiter’s syndrome. Vojnosanitetski Pregled. 2003;60:5–10. 318. Huang DF, Tsai CY, Tsai YY, et al. Reiter’s syndrome caused by Streptococcus viridans in a patient with HLA-B27 antigen. Clin Exp Rheumatol. 2000;18:394–396. 319. Sloan VS. Reiter syndrome following protracted symptoms of Cyclospora infection. Emerg Infect Dis. 2001;7:1070. 320. Toussirot E, Plesiat P, Wendling D. Reiter’s syndrome induced by Gardnerella vaginalis. Scand J Rheumatol. 1998;27:316–317. 321. Eapen BR. A new insight into the pathogenesis of Reiter’s syndrome using bioinformatics tools. Int J Dermatol. 2003;42:242–243.

has been used successfully in combination with aspirin in one child.303 Methotrexate,322 acitretin,323 cyclosporin324 and infliximab325 have been used successfully in adult patients with difficult-to-control joint disease. The ocular manifestations should be managed with the assistance of an ophthalmologist. Circinate balanitis and early keratoderma blenorrhagica may respond to appropriate topical steroid therapy.303,322 Salicylic acid 10% ointment worked well in one patient with established keratoderma blenorrhagica.303

Prognosis In most children, the disease is self-limiting and clears with no residual sequelae. A small percentage has persistent or recurring arthritis particularly in the sacroiliac area.303 Reiter disease in children is usually triggered by a gastrointestinal infection. Mucocutaneous lesions are not commonly seen. Unlike adults, Reiter syndrome in children is usually self-limited and responds to simple anti-inflammatory therapy.

REITER SYNDROME

infectious agents reported as triggering factors in adult patients are human immunodeficiency virus infection,315 mycoplasma pneumonia,316 ureaplasma urealyticum,317 Streptococcus viridans,318 Cyclospora,319 and Gardnerella vaginalis.320 A study identified Chlamydia trachomatis or Ureaplasma urealyticum in the synovial fluid collected from the affected joints of some adult patients with Reiter’s disease.317 The link between HLA-B27 antigen located on chromosome 6p and the development of clinical disease is unknown. Another study found homology between a short segment of gene Ly 95 on 6p21.1 and a segment of Salmonella enterica serovar typhi. The gene y95 encodes for NKp44, a surface receptor involved in the triggering of NK cell activity during the process of tumor cell lysis.321

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Geographic tongue (benign migratory glossitis, annulus migrans) The term geographic tongue describes a fluctuating eruption on the anterior two-thirds of the dorsum of the tongue. The eruption conveys the impression of a geographic map.

EPIDEMIOLOGY Genetics Familial clustering of cases has been reported326 but the majority of cases are sporadic.

Statistics The Third National Health and Nutrition Examination Survey (1988–1994) examined 10 030 individuals aged between 2 and 17 years for a variety of oral conditions. The prevalence of geographic tongue was 1.05%.327

PRESENTING HISTORY Geographic tongue can manifest at any age.327,328 The clinical appearance of the tongue and/or symptoms of burning and

322. Rothe M, Kerdel F. Reiter syndrome. Int J Dermatol. 1991;30:173–180. 323. Blanche P. Acitretin and AIDS-related Reiter’s disease. Clin Exp Rheumatol. 1999;17:105–106. 324. Kiyohara A, Takamori K, Ogawa H. Successful treatment of severe recurrent Reiter’s syndrome with cyclosporine. J Am Acad Dermatol. 1997;36:482–483. 325. Gill H, Majithia V. Successful use of infliximab in the treatment of Reiter’s syndrome: a case report and discussion. Clin Rheumatol. 2008;27: 121–123. 326. Eidelman E, Chosack A, Cohen T, et al. Scrotal tongue and geographic tongue: polygenic and associated traits. Oral Surg Oral Med Oral Pathol. 1976;42:591. 327. Shulman JD. Prevalence of oral mucosal lesions in children and youths in the USA. Int J Pediatr Dent. 2005;15:89–97. 328. Jainkittivong A, Langlais RP. Geographic tongue: clinical characteristics of 188 cases. J Contemp Dent Pract. 2005;6:123–135.

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intra-oral hygiene. Symptomatic cases may respond to an intraoral topical steroid preparation (e.g., Kenalog in Orabase). Cyclosporin was used successfully to treat an adult with geographic tongue associated with severe and persistent pain.331 The clinical course of geographic tongue is variable; it can last from months to years.

Figure 15.17  Geographic tongue.

SEBORRHEIC DERMATITIS

tenderness are the usual reasons for presentation. The problem is asymptomatic in the majority of patients.328 It can also be an incidental finding in patients with pustular psoriasis182,184 and plaque psoriasis.329

SEBORRHEIC DERMATITIS Seborrheic dermatitis refers to an erythematous, scaly eruption that preferentially involves the scalp, face, and skin folds, which are regarded as the seborrheic areas of the body. An eruption referred to as seborrheic dermatitis may occur during the first year of life (infantile seborrheic dermatitis, ISD) or in postpubertal individuals (adolescent or adult seborrheic dermatitis). Whether the two conditions are the same or different is yet to be determined; there is no evidence that ISD will develop into seborrheic dermatitis in an adolescent or adult.

PHYSICAL EXAMINATION Geographic tongue is characterized by flat, smooth, erythematous patches, which contrast with the normal, off-white, furry appearance of the adjacent tongue mucosa (Fig. 15.17). The patches expand and coalesce to produce an appearance that resembles a geographic map. The number of patches, their size, and shape constantly change from day to day, even within hours; this is a typical feature of the disease.328,330

PATHOPHYSIOLOGY AND HISTOGENESIS The etiology and underlying pathophysiology are unknown. Early reports of a link with atopy or psoriasis have never been substantiated.

EPIDEMIOLOGY Genetics Although there is no evidence implicating genetic factors in the development of ISD, patients with adolescent or adult onset seborrheic dermatitis will often give a history of family members with the disease.

Statistics The incidence of ISD in the general population is unknown. The incidence of adolescent and adult seborrheic dermatitis in the general population is estimated to be 2–5%. Males are more commonly affected than females.

Histologic findings The active, expanding border is characterized by acanthosis with overlying parakeratosis and intraepithelial microabscesses that are indistinguishable from the spongiform pustules of Kogoj seen in pustular psoriasis. The flat smooth center exhibits epithelial thinning.121

Differential diagnosis The geographic appearance and recognition of the changing pattern distinguish geographic tongue from lichen planus, candidiasis, nutritional deficiency, or the mucus patches seen with secondary syphilis.

THERAPY AND PROGNOSIS There is no effective treatment for geographic tongue. Most patients only require reassurance and maintenance of good

329. Cambiaghi S, Colonna C, Cavalli R. Geographic tongue in two children with nonpustular psoriasis. Pediatr Dermatol. 2005;22:83–85. 330. Brooks JK, Balciunas BA. Geographic stomatitis: review of the literature and report of five cases. J Am Dent Assoc. 1987;115:421–424.

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PRESENTING HISTORY In ISD, the eruption develops during the first few months of life with asymptomatic red, scaly lesions in the diaper area, skin folds, and scalp. In adolescent or adult seborrheic dermatitis, patients present at any time after the onset of puberty with a history of dandruff, scalp pruritus, and/or a facial eruption.

PHYSICAL EXAMINATION ISD usually presents with erythema on the scalp, in the diaper area, skin folds, retro-auricular folds, neck, axillae, umbilicus, antecubital fossae and popliteal fossae, and occasionally the face (Fig. 15.18). The erythema on the scalp, face, and behind the ears is typically covered with greasy, yellow-colored scale. The scaling on the scalp can vary from fine to thick and plate-

331. Abe M, Sogabe Y, Syuto T, et al. Successful treatment with cyclosporin administration for persistent benign migratory glossitis. J Dermatol. 2007;34:340–343.

Papulosquamous diseases

15

B C SEBORRHEIC DERMATITIS

A

Figure 15.18  (A) Infantile seborrheic dermatitis on the scalp. (B) Infantile seborrheic dermatitis on the face. (C) Infantile seborrheic dermatitis on his flexures.

Figure 15.20  Adolescent seborrheic dermatitis on the face.

Figure 15.19  Widespread infantile seborrheic dermatitis (courtesy of Dr A. Torrelo).

like. The facial changes are most prominent on the forehead, in the eyebrows, and around the nose. The skin folds are erythematous with mild to moderate scale. Occasionally, the changes extend beyond the flexures, involving the trunk and limbs (Fig. 15.19). Adolescent seborrheic dermatitis presents with changes on the scalp that consist of scaling with varying degrees of erythema. Pruritus is a variable feature. Some patients develop changes on

the face (Fig. 15.20), presternal area, and skin folds. The facial changes are symmetric and consist of erythema and scaling involving the eyebrows, sides of the nose, the nasolabial folds, the malar area of the face, retro-auricular folds, ears, and external auditory canal. Involvement of the presternal area consists of well-defined, scaly, erythematous patches. Skin fold involvement is characterized by confluent moist erythema. Severe cases can manifest with a blepharitis.

Laboratory findings There are no consistent laboratory abnormalities in either form of seborrheic dermatitis. 925

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PATHOPHYSIOLOGY AND HISTOGENESIS

SEBORRHEIC DERMATITIS

The link between Malassezia furfur (M. furfur) and dandruff was first proposed by Malassez in 1874.332 Some 30 years later, Sabouroud suggested a role for the organism in the pathogenesis of adolescent and adult seborrheic dermatitis.333 M. furfur is a normal member of the skin flora of post-pubertal individuals. Colonization of the skin begins with the onset of sebaceous gland activity in the early stages of puberty. Although M. furfur can be isolated from any part of the skin, its levels are highest in the sebaceous gland-rich areas such as the scalp and face. Clinical improvement that occurs with a reduction in M. furfur levels with topical and oral antifungal therapy supports a role for M. furfur in the pathogenesis of adolescent and adult seborrheic dermatitis.334,335 Although total levels of M. furfur on the skin surface do not correlate with the presence of seborrheic dermatitis,336 one study suggests that pathogenicity may be related to the presence of particular M. furfur subtypes on the skin surface.337 Another study found a difference between M. furfur subtypes isolated from patients with pityriasis versicolor compared with patients with seborrheic dermatitis.338 The mechanism through which M. furfur induces the development of seborrheic dermatitis remains unclear. Immune factors are probably important because of the high incidence of seborrheic dermatitis in patients with human immunodeficiency virus (HIV) infection.339 There is no evidence of defective humoral and cellular immunity to M. furfur in non-HIV patients with seborrheic dermatitis compared with control patients.340 The immunohistochemistry profile of inflammatory cells and inflammatory mediators in the affected skin of patients with the adult form of seborrheic dermatitis is consistent with an irritant, nonimmunogenic stimulation of the immune response.341 The stimulus may involve free fatty acids (e.g., oleic acid) generated by Malassezia metabolism of triglycerides in sebum342 and/or bioactive indoles released by M. furfur.343 One study found that particular bioactive indoles (malassezin, indolocarbazole) were selectively produced by M. furfur strains isolated from patients with seborrheic dermatitis.343 Indolocarbazole is a potent ligand of the aryl hydrocarbon receptor.343 The etiology of ISD is unclear. Although there is no quantitative difference in sebum production between infants with ISD and unaffected controls, one study found a temporary alteration in serum fatty acids in infants with ISD consistent with transient

332. Malassez L. Notes sur le champignon de la pilade. Arch Physiol Norm Pathol. 1874;1:203–212. 333. Sabouroud R. Pityriasis et Alopecies Peliculaire. Les maladies desquamatives. 1st ed. Paris: Massonet; 1904:205. 334. Skinner Jr RB, Noah PW, Taylor RM, et al. Double blind treatment of seborrhoeic dermatitis with 2% ketaconazole cream. J Am Acad Dermatol. 1985;12:852–856. 335. Scaparro E, Quadri G, Virno G. Evaluation of the efficacy and tolerability of oral terbinafine (Daskil) in patients with seborrhoeic dermatitis. A multicentre, randomised, investigator-blinded controlled trial. Br J Dermatol. 2001;144:854–857. 336. McGinley KJ, Leyden JJ, Marples RR, et al. Quantitive microbiology of the scalp in non-dandruff, dandruff and seborrhoeic dermatitis. J Invest Dermatol. 1975;64:401–405. 337. Peschere M, Krischer J, Renondat C. Malassezia spp. Carriage in patients with seborrhoeic dermatitis. J Dermatol. 1999;26:558–561. 338. Gandra RF, Simao RC, Matsumoto FE, et al. Genotyping by RAPD-PCR analyses of Malassezia furfur strains from pityriasis versicolor and seborrheic dermatitis patients. Mycopathologica. 2006;162:273–280.

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impaired function of the enzyme delta-6-desaturase.344 M. furfur has been isolated from the skin of ISD patients at a frequency higher than in patients with atopic dermatitis and unaffected controls.345 Clinical improvement with topical antifungal therapy suggests a pathogenic role for M. furfur in ISD.345

Histologic findings The histopathologic findings in seborrheic dermatitis are non­ diagnostic. These consist of focal parakeratosis, moderate acanthosis, and mild to moderate spongiosis with exocytosis of mononuclear cells. A mild superficial perivascular lymphohistiocytic infiltrate is usually present in the dermis.121

Differential diagnosis Conditions to consider in the differential diagnosis of ISD are atopic dermatitis, psoriasis, and Langerhans histiocytosis. Atopic dermatitis can initially manifest with an ISD-like pattern. The eventual development of itch and weepy eczematous lesions outside the skin folds will distinguish infants with atopic dermatitis. Psoriasis should be considered in the presence of welldefined scaly plaques on the trunk, limbs, and diaper area. Langerhans histiocytosis must be excluded if purpura, erosions, and/or crusting is evident. The principal differential diagnosis for adolescent seborrheic dermatitis is psoriasis. Distinguishing the two can be difficult when the changes are confined to the scalp and face. A diagnosis of psoriasis is more likely if there are typical plaques on the scalp, plaques on the trunk or limbs, and/ or pitting of the nails.

THERAPY AND PROGNOSIS Topical ISD responds well to topical therapy. Hydrocortisone (1%) is used on the face and skin folds. This may be combined with an antifungal agent for affected skin folds. A mid-potency topical steroid (e.g., Betamethasone valerate 0.05%) may be required for the trunk and limbs if hydrocortisone 1% fails to have the desired effect. Scalp scale can be removed after softening with an oil preparation or a weak keratolytic agent. The application of

339. Smith KJ, Skelton HG, Yeager J, et al. Cutaneous findings in HIV-1-positive patients: a 42-month prospective study. J Am Acad Dermatol. 1994;31:746–754. 340. Parry ME, Shapre GR. Seborrhoeic dermatitis is not caused by an altered immune response to Malassezia yeast. Br J Dermatol. 1998;139:254–263. 341. Faergemann J, Bergbrant IM, Dohse M, et al. Seborrhoeic dermatitis and pityrosporum (Malassezia) folliculitis: characterisation of inflammatory cells and mediators in the skin by immunohistochemistry. Br J Dermatol. 2001;144:549–556. 342. DeAngelis YM, Gemmer EM, Kaczvinsky JR, et al. Three etiologic facets of dandruff and seborrheic dermatitis: Malassezia fungi, sebaceous lipids and individual sensitivity. J Invest Dermatol. 2005;10:295–297. 343. Gaitanis G, Magiatis P, Stathopoulou K, et al. AhR ligands, malassezin, and indolo(3,2-b) carbazole are selectively produced by Malassezia furfur strains isolated from seborrheic dermatitis. J Invest Dermatol. 2008;128:1620–1625. 344. Tollesson A, Frithz A, Berg, et al. Essential fatty acids in infantile seborrhoeic dermatitis. J Am Acad Dermatol. 1993;22:957–961. 345. Ruiz-Maldonado R, Lopez-Martinez R, Chavarria P, et al. Pityrosporum ovale in infantile seborrhoeic dermatitis. Pediatr Dermatol. 1989;6:16–20.

Papulosquamous diseases

Prognosis ISD has a good prognosis. Most cases quickly clear with appropriate topical therapy. Adolescent seborrheic dermatitis requires ongoing therapy to maintain disease control. Although no figures are available, there appears to be a marked decrease in the incidence of ISD.

SEBOPSORIASIS Seborrheic psoriasis (sebopsoriasis) (seborrhiasis) refers to a scaly erythematous eruption on the scalp, face, and skin folds with features that are consistent with both seborrheic dermatitis and psoriasis. A final diagnosis can only be made when typical lesions of psoriasis develop elsewhere on the body. The principles of treatment are identical to those outlined for seborrheic dermatitis and psoriasis. Some suggest that seboatopic dermatitis also exists.

346. Ratnavel RC, Squire RA, Boorman GC. Clinical efficacies of shampoos containing ciclopirox olamine (1.5%) and ketoconazole (2.0%) in the treatment of seborrheic dermatitis. J Dermtol Treat. 2007;18:88–96. 347. Satchell AC, Saurajen A, Bell C, et al. Treatment of dandruff with 5% tea tree oil shampoo. J Am Acad Dermatol. 2002;47:852–855. 348. Faergemann J, Borgers M, Degreef H. A new ketoconazole topical gel formulation in seborrheic dermatitis: an updated review of the mechanism. Exp Opin Pharmacotherapy. 2007;8:1365–1371. 349. Warshaw EM, Wohlhuter RJ, Liu A, et al. Results of a randomized, double-blind, vehicle controlled efficacy trial of pimecrolimus cream 1% for the treatment of moderate to severe facial seborrheic dermatitis. J Am Acad Dermatol. 2007;57:257–264. 350. Seckin D, Gurbuz O, Akin O. Metronidazole 0.75% gel vs. Ketoconazole 2% cream in the treatment of facial seborrheic dermatitis: a randomized, double-blind study. J Eur Acad Dermatol Venereol. 2007;21:345–350. 351. Dreno B, Chosidow O, Revuz J, et al. Lithium gluconate 8% vs ketoconazole 2% in the treatment of seborrheic dermatitis: a multicentre, randomized study. Br J Dermatol. 2003;148:1230–1236. 352. Kose O, Erbil H, Gur AR. Oral itraconazole for the treatment of seborrheic dermatitis: an open, non comparative trial. J Eur J Dermatol Venereol. 2005;19:172–175. 353. Wilson E. On Leichen planus. J Cutan Med Dis Skin. 1869;3:117–321. 354. Wickham LF. Sur un signe pathognomique de Lichen du Wilson (lichen plan) stries et ponctuations grisatres. Ann Dermatol Syph. 1895;6:517–520. 355. Gibstine CF, Esterly NB. Lichen planus in monozygotic twins, letter to editor. Arch Dermatol. 1984;120:580. 356. Mahood JM. Familial lichen planus. A report of nine cases from four families with a brief review of the literature. Arch Dermatol. 1983;119:292–294.

LICHEN PLANUS Lichen planus (LP) is a distinctive dermatosis aptly summarized by the four Ps: purple, polygonal, pruritic papules. The name lichen planus was first proposed by Wilson in 1869.353 The reticulate, white lines on the surface of lichen planus papules, eponymously known as Wickham’s striae, were first described by Wickham in 1895.354

EPIDEMIOLOGY Genetics Although LP has been reported in monozygotic twins355 and families,356–358 most cases are sporadic. Studies examining links between LP and HLA antigens have found an association with a variety of HLA alleles (A3, Bw35, B8, B16, DR1, DQw1), which are of doubtful significance.359–361 HLA-DRB1*0101 was closely associated withe development of lichen planus in the Mexican Mestizo population.362

LICHEN PLANUS

hydrocortisone prevents the reappearance of erythema and the re-accumulation of scalp scale. Adolescent seborrheic dermatitis of the scalp is usually controlled with the regular use of a medicated shampoo containing zinc pyrithione, selenium sulfide, coal tar, ketoconazole, ciclopirox olamine346 and tea tree oil.347 If pruritus remains a problem, topical steroid scalp lotions and foams can be used on an intermittent basis. Patients with severe scaling may benefit from the application of coal tar-salicylic acid preparations. Facial seborrheic dermatitis in adolescents is usually treated with intermittent hydrocortisone cream and/or ketoconazole cream. Alternative topical options reported to be of benefit are ketoconazole 2% gel,348 pimecrolimus 1% cream,349 metronidazole 0.75% gel350 and lithium gluconate 8% ointment.351 Oral itraconazole was found to be of benefit in an open trial involving adults with severe seborrheic dermatitis.352

15

Statistics The incidence and prevalence of pediatric LP in the general community are unknown. Several large series of cutaneous LP found the number of pediatric cases to be very small. Little reported 12 pediatric cases in a total of 150 cases,363 Samman reported two pediatric patients in a total of 200 cases;364 Singh and Kanwar reported 76 cases (10 cases were under 10 years; 56 cases were aged 10–18 years) in a total of 441 cases;365 Milligan and GrahamBrown reported six pediatric cases in a total of 154 patients;357 and Cottoni et al. reported five pediatric patients in a total of 234 cases.366 Only six pediatric cases were identified in one review of 1062 cases of oral LP367 and five pediatric cases were noted in another series of 723 cases of LP.368 The seven largest series

357. Milligan A, Graham-Brown RAC. Lichen planus in children – a review of six cases. Clin Exp Dermatol. 1990;15:340–342. 358. Huang C, Chen S, Liu Z, et al. Familial bullous lichen planus (FBLP): pedigree analysis and clinical characteristics. J Cutan Med Surg. 2005;9:217–222. 359. Simon M, Djawari D, Schonberger A. HLA antigens associated with lichen planus. Clin Exp Dermatol. 1984;9:435. 360. Powell FC, Rogers RS, Dickson ER, et al. An association between HLA DR1 and lichen planus. Br J Dermatol. 1986;114:473–478. 361. Valsecchi R, Bontempelli M, Rossi A, et al. HLA-DR and DQ antigens in lichen planus. Acta Dermatol Venereol (Stockh). 1988;68:77–80. 362. Luis-Montoya P, Yamamoto-Furosho JK, Vega-Memije E, et al. HLADRB1*0101 is associated with the genetic susceptibility to develop lichen planus in the Mexican Mestizo population. Arch Dermatol Res. 2007;299:405–407. 363. Little EG. Lichen planus. J Cutan Dis. 1919;37:639–670. 364. Samman PD. Lichen planus. An analysis of 200 cases. Trans St Johns Dermatol Soc. 1961;46:36–38. 365. Singh DVD, Kanwar AJ. Lichen planus in India: an appraisal of 441 cases. Int J Dermatol. 1976;15:752–756. 366. Cottoni F, Ena P, Tedde G, et al. Lichen planus in children: a case report. Pediatr Dermatol. 1993;10:132–135. 367. Alam F, Hamburger J. Oral mucosal lichen planus in children. Int J Paediatr Dent. 2001;11:209–214. 368. Eisen D. The clinical features, malignant potential and systemic associations of oral lichen planus; a study of 723 patients. J Am Acad Dermatol. 2002;46:207–214.

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LICHEN PLANUS

Figure 15.21  Classic lichen planus; polygonal purple papules. of pediatric cases revealed a predeliction for males.365,369–374 The age of onset extended from the first year through to adolescence.365,369–374

Figure 15.22  Oral lichen planus in a boy (courtesy of Dr A. Torrelo).

PRESENTING HISTORY Pediatric patients usually present with the typical skin eruption that is usually but not always pruritic.365,369–374 Rarely, patients present with nail357,369,373,375 or oral manifestations367,368,373 of LP.

PHYSICAL EXAMINATION Skin

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Classic LP manifests as extremely pruritic, flat-topped, violaceous-colored, polygonal papules which measure 3–15 mm in diameter (Fig. 15.21). Wickham’s striae are evident on the surface of the papules as a reticulate network of fine white lines (Fig. 15.22). Although lesions are usually symmetrically distributed on the limbs (especially the wrists), lower back, and pre­ tibial areas, any site can be involved, including the face, scalp, and palmoplantar surfaces.366,369–374 Papules can also develop at sites of trauma, which represents the Koebner phenomenon (Fig. 15.23).370,373,374 The morphologic variants of cutaneous LP seen in pediatric patients are linear, hypertrophic, annular, follicular, erosive, actinic, and bullous. Linear LP is the most common variant seen in children. It is characterized by typical papules arranged in a linear or zosteriform pattern on the limbs and, less commonly, the trunk (Fig. 15.24). It can be distributed in the lines of Blaschko.376 It is distinct from linear LP that develops at sites of trauma (Koebner phenomenon).357,363,369–374 Hypertrophic LP refers to large papules or plaques of LP that develop a verrucous surface (Fig. 15.25). It usually occurs on the pretibial areas and is

extremely pruritic.369–371,373,374 Annular LP is characterized by a ring-like cluster of typical papules with a clear or slightly atrophic center (Fig. 15.26). It usually occurs on the penis and trunk.370,373 Follicular LP manifests on any hair-bearing area as follicular papules that measure 1–2 mm in diameter.357,369,371 Scalp involvement may be accompanied by scarring alopecia.369,371 Erosive LP is characterized by the development of erosions on the surface of papular lesions. The palms and soles are the most common

369. Kanwar AJ, Handa S, Ghosh S, et al. Lichen planus in childhood: a report of 17 patients. Pediatr Dermatol. 1991;8:288–291. 370. Sharma R, Maheshwari V. Childhood lichen planus: a report of fifty cases. Pediatr Dermatol. 1999;16:345–348. 371. Nanda A, Al-Ajami HS, Al-Sabah H, et al. Childhood lichen planus: a report of 23 cases. Pediatr Dermatol. 2001;18:1–4. 372. Luis-Montoya P, Dominguez-Soto L, Vega-Memije E. Lichen planus in 24 children with review of the literature. Pediatr Dermatol. 2005;22:295–298.

373. Nnoruka EN. Lichen planus in African children: a study of 13 patients. Pediatr Dermatol. 2007;24:495–498. 374. Balasubramaniam P, Ogboli M, Moss C. Lichen planus in children: review of 26 cases. Clin Exp Dermatol. 2008;33:457–459. 375. Al-Ajroush N, Al-Khenaizan S. Isolated nail lichen planus with primary sclerosing cholangitis in a child. Saudi Med J. 2007;28:1441–1442. 376. Kabbash C, Laude TA, Weinberg JM, et al. Lichen planus in the lines of Blaschko. Pediatr Dermatol. 2002;19:541–545.

Figure 15.23  Lichen planus Koebnerizing at the site of trauma.

Papulosquamous diseases

site for erosive changes. It has been rarely reported in children.366 Actinic LP develops on sun-exposed and, to a lesser extent, protected areas, as bluish-brown macules or patches with welldefined borders. Shortly after onset, there is central clearing and induration of the periphery, resulting in an annular lesion with a hyperpigmented center. Most cases have been reported from the Middle East, Italy, India, and Africa.371,372,377 This variant of LP accounted for 2% of cases in Sharma and Maheshwari’s series of 50 cases.370 Bullous LP refers to the development of blistering within papules of LP. Blister formation is subepidermal and is due to severe liquefaction and vacuolation of the basal layer of the epidermis. It is rarely seen in pediatric patients with LP.358,366,378 Bullous LP can be confused with LP pemphigoides, which refers to a mixed eruption of LP papules and blisters that develop within the papules and on unaffected skin. While the papules have the histologic features of LP, the blisters have the histologic and immunofluorescence features of bullous pemphigoid.379 There have been several reported cases in children.380,381 Resolution of cutaneous LP is accompanied by the development of post-inflammatory hyperpigmentation in all except those with very fair skin. Atrophy may be found following resolution of the hypertrophic and annular variants.

LICHEN PLANUS

Figure 15.24  Linear lichen planus (courtesy of Dr A. Torrelo).

15

Mucosa

Figure 15.25  Hypertrophic lichen planus.

Involvement of the oral mucosa is very uncommon in pediatric patients. Although Sharma and Maheshwari370 found 30% of their patients with cutaneous LP to have oral manifestations of the disease, only one of Kanwar et al.’s369 17 patients, nine of Nanda et al.’s371 series of 23 patients, one of Luis-Montoya et al.’s series of 24 patients372 and three of Nnoruka’s 13 patients373 had oral involvement. In addition, Epidermolysis bullosa simplex – Dowling–Meara* >> Epidermolysis bullosa simplex – localized (Weber–Cockayne)* >> Epidermolysis bullosa simplex – generalized, other (Köbner)* >> Epidermolysis bullosa simplex – muscular dystrophy >> Epidermolysis bullosa simplex – mottled pigmentation >> Epidermolysis bullosa simplex – autosomal recessive Epidermolysis bullosa simplex – suprabasal forms

INHERITED VESICULOBULLOUS DISEASE

>> Epidermolysis bullosa superficialis >> Skin fragility – ectodermal dysplasia syndrome >> Acantholytic EB Junctional epidermolysis bullosa

>> Junctional epidermolysis bullosa – Herlitz* >> Junctional epidermolysis bullosa – non-Herlitz* >> Junctional epidermolysis bullosa – pyloric atresia* >> Junctional epidermolysis bullosa – inversa >> Junctional epidermolysis bullosa – late onset >> Laryngo-onycho-cutaneous syndrome Dystrophic epidermolysis bullosa

>> Dominant dystrophic epidermolysis bullosa* >> Dominant dystrophic epidermolysis bullosa – pretibial >> Dominant dystrophic epidermolysis bullosa – bullous

Figure 16.3  EB simplex Weber-Cockayne: bullae on the foot (Courtesy Dr A. Torrelo).

dermolysis of the newborn

>> Dominant dystrophic epidermolysis bullosa – pruriginosa >> Recessive dystrophic epidermolysis bullosa – severe generalized (Hallopeau–Siemens)*

>> Recessive dystrophic epidermolysis bullosa – generalized, other (non-Hallopeau–Siemens)*

>> Recessive dystrophic epidermolysis bullosa – inversa >> Recessive dystrophic epidermolysis bullosa – pretibial >> Recessive dystrophic epidermolysis bullosa – bullous dermolysis of the newborn

>> Recessive dystrophic epidermolysis bullosa – pruriginosa Mixed epidermolysis bullosa

>> Kindler syndrome Adapted with permission from Fine JD, Eady RA, Bauer EA et al. The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 2008; 58:931–950.

sufficient friction or trauma to non-acral sites will, however, also result in blistering. Occasionally, intra-oral blistering occurs. Palmoplantar involvement is sometimes associated with focal hyperkeratosis which becomes more apparent over time. The condition is much worse during the summer months and is exacerbated by frictional trauma such as occurs with manual labor and walking, especially with ill-fitting shoes. Thickening and dystrophy of the nails may occur as a result of trauma. As a rule, the blistering tendency continues throughout life, although patients will often modify their lifestyle to minimize the impact it has on their skin. 954

The effect of localized EBS on quality of life is often underestimated.10 The discomfort from bullae on the feet may limit walking to very short distances and some individuals may be confined to a wheelchair during the summer months. Affected children often try to avoid walking and may prefer to crawl or bottom-shuffle when at home. Teenagers may have problems with frequent changes of classroom during their school day, and the less motivated children may have poor school attendance records.

Epidermolysis bullosa simplex – generalized, other (Köbner) In EBS-generalized, other (Köbner), non-scarring blisters occur in a generalized distribution without predominantly acral involvement, especially at sites of friction, for example in skin flexures and extensor surfaces and from clothing. The generalized subtype tends towards an earlier onset than localized EBS, but in most respects the two conditions are very similar and differ principally in their extent. Intraoral blistering is more common in the generalized variant, whereas hyperkeratosis and toenail dystrophy are similar.10 Heat is an important predisposing factor to blistering and the warmer months of the year are generally the most troublesome. Improvement may occur with age. Both the generalized and localized forms of EBS may rarely be associated with localized congenital absence of skin (formerly known as Bart syndrome), usually involving a limb, which heals leaving subtle atrophic scarring.10

Vesiculobullous disease

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Epidermolysis bullosa simplex – Dowling–Meara

A INHERITED VESICULOBULLOUS DISEASE

The Dowling–Meara variant of EBS has the most severe blistering tendency of the basal EBS subtypes. It presents at birth or within the first week of postnatal life with extensive blistering, which may occasionally be life-threatening. In around 50% of cases there is no previous family history of the condition, the affected child presenting a de novo mutation which subsequently is transmitted in an autosomal dominant fashion. Although EBS Dowling–Meara develops distinctive clinical and pathological features,11 at the outset it is not possible to distinguish it with certainty from the severe forms of dystrophic and junctional EB on the basis of the clinical features, but ultrastructural examination enables a rapid diagnosis. After the first few months, bullae tend to assume a clustered, ‘herpetiform’ distribution on the trunk and limbs (Fig. 16.4A), hence a former alternative name ‘EBS herpetiformis.’ Blisters are non-scarring but often result in post-inflammatory hyperor hypopigmentation. Intraoral blistering in infants is very common, and a hoarse cry, the result of laryngeal involvement, may be a prominent feature during the first 2 years. Gastroesophageal reflux may be marked in infants with this form of EBS.12 Friction from clothing is an important precipitant of bullae, although they often appear to develop spontaneously, and the seasonal variation tends not to be as great as in the other forms of EBS. The severity of blistering lessens during childhood and adolescence although may still be troublesome in adulthood. A mild degree of palmoplantar hyperkeratosis is common, but occasionally it may be florid and be associated with flexion deformities of the digits. Nail involvement is usual and of variable degree. In infants, periodic shedding of finger- and toenails occurs and adults tend to develop thickening of the nails. Congenital absence of skin has been recorded.10

B

Figure 16.4  (A) EB simplex Dowling-Meara: characteristic clustered bullae (Courtesy Dr A. Torrelo). (B) Multiple small pigmented macules on the thigh of a child with EB simplex with mottled pigmentation (Courtesy Dr A. Lucky).

Epidermolysis bullosa simplex with mottled pigmentation EBS with mottled pigmentation is a very rare subtype first reported in 1979.13,14 Patients typically present with acral, nonscarring, heat-exacerbated blistering in early childhood and develop a characteristic mottled macular pigmentation on the trunk and limbs, which may persist or improve over time (Fig. 16.4B). They also develop punctate palmoplantar keratoderma later in life and most have nail abnormalities.

Epidermolysis bullosa simplex with muscular dystrophy EBS with muscular dystrophy is a very rare autosomal recessive condition with a wide range of clinical severity.15,16 Generalized blistering is evident at birth or appears shortly thereafter, with

11. McGrath JA, Ishida-Yamamoto A, Tidman MJ, et al. Epidermolysis bullosa simplex (Dowling–Meara). A clinicopathological review. Br J Dermatol. 1992;126:421–430. 12. Freeman EB, Köglmeier J, Martinez AE, et al. Gastrointestinal complications of epidermolysis bullosa in children. Br J Dermatol. 2008;158:1308–1314. 13. Fischer T, Gedde-Dahl T. Epidermolysis bullosa simplex and mottled pigmentation: a new dominant syndrome. Clin Genet. 1979;15:228–238. 14. Irvine AD, Rugg EL, Lane EB, et al. Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol. 2001;144:40–45. 15. Niemi KM, Sommer H, Kero M, et al. Epidermolysis bullosa simplex associated with muscular dystrophy with recessive inheritance. Arch Dermatol. 1988;124:551–554.

accentuation over acral sites, leaving atrophic scarring. Nail thickening is usual and teeth are often abnormal. The age of onset of muscle weakness ranges widely, from congenital involvement to onset in the fourth decade. There may be associated cerebral and cerebellar atrophy,17 urethral stricture, scarring alopecia and, occasionally, respiratory symptoms.18

Epidermolysis bullosa simplex – Ogna The Ogna variant of EBS is inherited in an autosomal dominant fashion and has been described in only two pedigrees.19,20 Nonscarring blistering that tends to be worse in warm weather occurs on the palms and soles in association with generalized non-

16. Shimizu H, Takizawa Y, Pulkkinen L, et al. Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature. J Am Acad Dermatol. 1999;41:950–956. 17. Smith FJ, Eady RA, Leigh IM, et al. Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet. 1996;13:450–457. 18. Mellerio JE, Smith FJ, McMillan JR, et al. Recessive epidermolysis bullosa simplex associated with plectin mutations: infantile respiratory complications in two unrelated cases. Br J Dermatol. 1997;137:898–906. 19. Gedde-Dahl T. Epidermolysis bullosa. A clinical, genetic and epidemiological study. Oslo-Bergen-Tromso: Universitetsforlaget; 1970. 20. Koss-Harnes D, Høyheim B, Anton-Lamprecht I, et al. A site specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. J Invest Dermatol. 2002;118:87–93.

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seasonal skin fragility, resulting in small transient erosions on limbs, face and trunk. Dystrophic great toenails are frequent in this condition.

Pathophysiology

INHERITED VESICULOBULLOUS DISEASE

It is now well established that the localized, generalized other and Dowling–Meara variants of EBS are caused by missense mutations in the genes encoding keratin 5 or 14 (KRT5 or KRT14, respectively),21,22 both of which are expressed by, and constitute, the cytoskeleton of the basal keratinocytes. The degree of impairment of the structural integrity of the keratin molecule is determined by the site and nature of the keratin mutation and this influences the phenotype. The Dowling–Meara subtype is the most severe form of EBS and is characterized by mutations within the highly conserved helix initiation or termination motifs, whereas milder forms of EBS are associated with mutations at other sites in the keratin genes.23 Almost all cases of EBS with mottled pigmentation that have been described have been due to a specific missense mutation in the non-helical rod domain of the keratin 5 gene,14 although another mutation in the tail domain of the same gene has also been implicated.24 Autosomal recessive forms of EBS have been described in a small number of consanguineous families arising from mutations in the keratin 14 gene.6,25 EBS associated with muscular dystrophy is caused by mutations of varying disruptive potential in the gene encoding plectin (PLEC1). Plectin is a component of hemidesmosomes in the skin and mucosae, and is also expressed in the sarcolemma and sarcomeres of skeletal muscle.16,17 The Ogna variant is also caused by a mutation in the plectin gene but is not associated with muscular dystrophy.20

Differential diagnosis The localized form of EBS rarely causes diagnostic difficulty, particularly if there is a family history and by virtue of its distinctive clinical features; histological and ultrastructural examination is usually not necessary. Dowling–Meara EBS, presenting as it usually does with widespread blistering in the neonatal period, cannot be clinically distinguished from junctional or severe recessive forms of EB. However, ultrastructural examination in Dowling–Meara EBS shows the pathognomonic combination of cytolytic blistering in the lower pole of the basal keratinocytes and clumping of tonofilaments.

21. Bonifas JM, Rothman AL, Epstein EH. Epidermolysis bullosa simplex: evidence in two families for keratin gene abnormalities. Science. 1991;254:1202–1205. 22. Lane EB, Rugg EL, Navsaria H, et al. A mutation in the conserved helix termination peptide of keratin 5 in hereditary skin blistering. Nature (London). 1992;356:244–246. 23. Irvine AD, McLean WHI. Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation. Br J Dermatol. 1999;140:815–828. 24. Horiguchi Y, Sawamura D, Mori R, et al. Clinical heterogeneity of 1649delG mutation in the tail domain of keratin 5: a Japanese family with epidermolysis bullosa simplex with mottled pigmentation. J Invest Dermatol. 2005;125:83–85. 25. Chan Y, Anton-Lamprecht I, Yu QC, et al. A human keratin 14 ‘knockout’: the absence of K14 leads to severe epidermolysis bullosa simplex and a

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Epidermolysis bullosa simplex: suprabasal forms Three rare disorders, characterized by suprabasal skin blistering, have been recognized under the most recent classification scheme as suprabasal forms of EBS: EBS superficialis, skin fragilityectodermal dysplasia syndrome and lethal acantholytic EB.

Epidermolysis bullosa simplex superficialis EB superficialis is a rare autosomal dominant form of suprabasal EBS in which blistering arises just below the stratum corneum.26 Intact bullae are rarely noted and individuals frequently present with erosions and crusts which may be generalized or acral. Milia formation, atrophic scarring and dystrophic nails are common. The underlying molecular basis for this form of EB has not yet been determined.

Ectodermal dysplasia/skin fragility syndrome Ectodermal dysplasia/skin fragility syndrome is a rare, recently described disorder characterized by features that are reminiscent of both ectodermal dysplasia and EB. It is caused by a deficiency of plakophilin-1, a structural component of desmosomes,27 and presents in the newborn period with variable degrees of erythema, bullae and desquamation. The hair is short and sparse, and the nails become thickened and dystrophic. Affected individuals also have perioral erythema and fissuring. The tendency to blistering improves with time and becomes more localized, particularly to the flexures. Subsequently, hyperkeratotic plaques develop on the extremities with focal palmoplantar hyperkeratosis and fissuring. A reduced ability to sweat may also be present.28,29 Histological examination reveals acantholysis and widening of intercellular spaces between the keratinocytes of the mid-spinous layer of the epidermis. Immunohistochemical analysis shows absent staining for plakophilin-1 and an altered distribution of desmoplakin.

Pathophysiology Individuals with ectodermal dysplasia/skin fragility syndrome have autosomal recessive mutations in the gene encoding the desmosomal protein plakophilin-1 (PKP1). Plakophilin-1 is an important structural protein involved in cell–cell adhesion and also plays an important role in signal transduction pathways and epidermal morphogenesis. An absence of plakophilin-1 leads to abnormal cell–cell adhesion and retraction of the keratin filaments in suprabasal keratinocytes, resulting in skin fragility and

26.

27. 28. 29.

function for an intermediate filament protein. Genes Dev. 1994;8:2574– 2587. Fine JD, Johnson L, Wright T. Epidermolysis bullosa simplex superficialis. A new variant of epidermolysis bullosa characterized by subcorneal skin cleavage mimicking peeling skin syndrome. Arch Dermatol. 1989;125:633–638. McGrath JA, McMillan JR, Shemanko CS, et al. Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nat Genet. 1997;17:240–244. McGrath JA. A novel genodermatosis caused by mutations in plakophilin 1, a structural component of desmosomes. J Dermatol. 1999;26:764–769. McGrath JA, Hoeger PH, Christiano AM, et al. Skin fragility and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin I. Br J Dermatol. 1999;140:297–307.

Vesiculobullous disease

16

blistering. The absence of plakophilin-1 probably leads to abnormalities of patterning in embryonic ectodermal development which results in the hair, nail and sweating abnormalities.28

Prognosis The prognosis of this rare genodermatosis is uncertain. Blister formation improves over time, although the palmoplantar keratoderma tends to become more troublesome. Management is supportive.

A severe form of suprabasal EB with generalized acantholysis, alopecia, nail loss and natal teeth has been described in one neonate in whom the outcome was rapidly fatal.30 The proband was a compound heterozygote for mutations in the desmoplakin gene (DSP) leading to the loss of the tail domain of this desmosomal component.

INHERITED VESICULOBULLOUS DISEASE

Lethal acantholytic epidermolysis bullosa

Figure 16.5  JEB-Herlitz: bullae on the buttocks and thighs.

JUNCTIONAL EPIDERMOLYSIS BULLOSA Introduction In 1935, Herlitz described a non-scarring variant of EB which was lethal in infancy.31 Initially, this was considered to be a severe form of dystrophic EB (DEB) until 1974 when it was demonstrated by ultrastructural examination that the cleavage plane in this condition was within the lamina lucida of the epidermal basement membrane,32 thereby distinguishing it from DEB. The term junctional EB (JEB) was coined and the lethal form is now known as JEB-Herlitz. However, JEB can be compatible with survival into adulthood and this subtype is designated JEB-non-Herlitz. Rarer variants of JEB include a type associated with pyloric atresia (JEB-pyloric atresia), an inverse form (JEBinversa), a type manifesting at an older age (JEB-late onset) and the laryngo-onycho-cutaneous syndrome.1

Figure 16.6  JEB Herlitz paronychial inflammation with excessive granulation tissue (Courtesy Dr A. Lucky).

Genetics and epidemiology All variants of JEB are inherited in an autosomal recessive manner. JEB is the rarest of the three main forms of EB, with the Scottish data giving a prevalence of 0.3 cases per million of the population and an incidence of 3.2 new cases per million live births.8 The equivalent US figures are 0.44 and 2.04.9

Clinical features Junctional epidermolysis bullosa – Herlitz JEB-Herlitz presents at birth with tense bullae affecting skin and oral mucous membranes. Occasionally, there may be localized absence of skin on a limb. The degree of blistering in the first week or two of postnatal life is no guide to the ultimate prog-

30. Jonkman MF, Pasmooij AM, Pasmans SG, et al. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet. 2005;77:653–660. 31. Herlitz O. Kongenitaler nicht syphilitischer Pemphigus. Einc übersicht nebst Beschreibung einer neuen Krankheitsform (Epidermolysis bullosa hereditaria letalis). Acta Paediatr. 1935;17:315–371.

nosis, and the presence of only a few bullae on an otherwise healthy-looking baby can be the harbinger of an ultimately lethal outcome. Provided bullae are not excoriated or infected, they are non-scarring and milia are not a prominent feature. There is no specific pattern of blistering, but involvement of the buttocks (Fig. 16.5) and the pinnae of the ears is quite characteristic in JEB, as is a hoarse cry reflecting laryngeal involvement.33 Early on, a paronychial inflammation often occurs (Fig. 16.6), followed by nail dystrophy and loss, with granulation tissue of the nail beds being evident. Dental enamel hypoplasia results in pitting of the tooth surfaces if survival is prolonged (Fig. 16.7).34 A non-scarring hair loss is common. The gradual development of a distinctive perioral, and occasionally occipital,

32. Pearson RW, Potter B, Strauss F. Epidermolysis bullosa hereditaria letalis. Arch Dermatol. 1974;109:349–355. 33. Hore I, Bajaj Y, Denyer J, et al. The management of general and disease specific ENT problems in children with epidermolysis bullosa – a retrospective case note review. Int J Otorhinolaryngol. 2007;71:385–391. 34. Wright JT, Fine JD, Johnson L. Hereditary epidermolysis bullosa: oral manifestations and dental management. Pediatr Dent. 1993;15:242–248.

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Figure 16.9  JEB-non-Herlitz: toenail loss and dystrophy. INHERITED VESICULOBULLOUS DISEASE

Figure 16.7  JEB-Herlitz: dental enamel hypoplasia.

cause sudden death. Post-mortem examination often reveals widespread mucous membrane involvement of the upper aerodigestive tract, lower alimentary tract and the urinary tract.

Junctional epidermolysis bullosa – non-Herlitz

Figure 16.8  JEB-Herlitz: persistent facial erosions.

distribution of granulation tissue occurs in those individuals who survive beyond 6 months of age (Fig. 16.8). This granulation tissue is extremely friable and may bleed copiously. It is very difficult to heal although ultrapotent topical steroids may be of benefit. Conjunctival involvement may result in corneal erosions, pannus and symblepharon formation.35 Affected infants fail to thrive, and usually become anemic, despite nutritional supplementation. Death, often as the result of septicemia, usually occurs within the first few years after a gradual decline. However, bullae in the larynx or trachea may

35. Fine JD, Johnson LB, Weiner M, et al. Eye involvement in inherited epidermolysis bullosa: experience of the National Epidermolysis Bullosa Registry. Am J Ophthalmol. 2004;138:254–262. 36. Bauer JW, Schaeppi H, Kaserer C, et al. Large melanocytic nevi in hereditary epidermolysis bullosa. J Am Acad Dermatol. 2001;135:1243–1247. 37. Fine JD, Johnson LB, Weiner M, et al. Genitourinary complications of inherited epidermolysis bullosa: experience of the national

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Some patients with extensive junctional blistering in infancy survive to adulthood, and identification of this subtype in infancy on the basis of the clinical features is usually not possible. Compared with JEB-Herlitz, excessive granulation tissue is less of a feature. Another phenotype, originally termed ‘generalized atrophic benign EB,’ is characterized by a normal lifespan and blistering which heals to leave atrophic scarring; in hairbearing regions the scarring causes alopecia. Pigmentation may occur at sites of previous bullae, so-called ‘EB nevi,’ although these can also be observed in other types of EB.36 Nail dystrophy (Fig. 16.9) and dental enamel hypoplasia are common features.34 Conjunctival and eyelid involvement may result in scarring or blepharitis. Corneal erosions and scarring, with subsequently impaired vision, are features of JEB-non-Herlitz.35 Genitourinary tract abnormalities include urinary retention and urethral stenosis.37

Junctional epidermolysis bullosa – pyloric atresia This variant of JEB is characterized by congenital blistering and gastrointestinal atresia, usually affecting the pylorus. It tends to carry a poor prognosis even after surgical correction of the gastrointestinal abnormality. A minority of children have milder cutaneous involvement and have a better prognosis. Survivors may develop significant urogenital tract disease, including urethral strictures, vesicoureteric reflux and bladder wall involvement, leading to hydronephrosis and renal failure.38,39 Although blister formation in this form of EB is usually within the lamina

epidermolysis bullosa registry and review of the literature. J Urol. 2004;172:2040–2044. 38. Dank JP, Kim S, Parisi MA, et al. Outcome after surgical repair of junctional epidermolysis bullosa-pyloric atresia syndrome: a report of 3 cases and review of the literature. Arch Dermatol. 1999;135:1243–1247. 39. Chan SM, Dillon MJ, Duffy PG, et al. Nephro-urological complications of epidermolysis bullosa in paediatric patients. Br J Dermatol. 2007;156:143–147.

Vesiculobullous disease

lucida, occasionally a simplex plane of cleavage through the basal keratinocytes is seen.40

of skin blistering (herpes simplex, staphylococcal infections, candidiasis, and sepsis-related bullae) should be excluded.

Laryngo-onycho-cutaneous syndrome

DYSTROPHIC EPIDERMOLYSIS BULLOSA

The laryngo-onycho-cutaneous (LOC or Shabbir) syndrome is a rare variant of JEB, occurring in individuals of Punjabi Muslim origin.41 It is characterized by cutaneous erosions, nail dystrophy and exuberant granulation tissue affecting the skin, larynx and conjunctivae. The condition may be lethal in childhood due to laryngeal involvement.

Introduction

JEB is a genetically heterogeneous disorder caused by mutations in several different genes encoding different proteins expressed at the dermal–epidermal junction. JEB-Herlitz is associated with severely disruptive mutations, usually premature termination codons, on both alleles of any of the three genes (LAMA3, LAMB3 or LAMC2) encoding, respectively the three constituent polypeptide chains (α3, β3 and γ2) of laminin 332 (formerly laminin 5),42 the morphological equivalent of which are the anchoring filaments that cross the lamina lucida. JEB-nonHerlitz is usually also the result of laminin 332 mutations, most frequently a premature termination codon on one allele combined with a less disruptive mutation on the paired allele.42 Some cases of JEB-non-Herlitz, corresponding to the former clinical description of generalized atrophic benign EB, are caused by mutations, usually premature termination codons or missense mutations, in the gene (COL17A1 or BPAG2) encoding type XVII collagen (the 180 kDa bullous pemphigoid antigen),43 a constituent of hemidesmosomes. Mutations in the genes (ITGA6 and ITGB4) for another hemidesmosome-associated transmembrane protein system, the α6β4 integrin, are responsible for JEB-pyloric atresia,44 although mutations in the plectin gene have also rarely been implicated in this form of EB.45 LOC syndrome results from a frameshift mutation in LAMA3 encoding the laminin α3a isoform that is specific to basal cells of stratified epithelia.46

Inherited blistering conditions with consequent scarring as a prominent clinical feature were described from the late 19th century by, among others, Tilbury Fox (1879)47 and Hallopeau (1898).48 These disorders would now be classified as forms of dystrophic EB (DEB). In addition to scarring, milia frequently occur at sites of previous blistering (although are by no means restricted solely to DEB), and nail dystrophy and loss are common. A number of older classification systems used eponymous names to describe different forms of DEB; these have gradually been used less over recent years and have been removed entirely in the latest classification system.1

Genetics and epidemiology DEB may be dominantly or recessively inherited: in general terms, dominant DEB (DDEB) is milder than the recessive disease (RDEB), although there may be considerable phenotypic overlap between DDEB and milder forms of RDEB. The Scottish prevalence is 20.4 cases per million of the population (compared with 2.4 cases per million of the population in the USA), and the incidence 26.4 new cases per million live births.8 The majority of these have DDEB (prevalence 17.4 per million of the population).

Clinical features Bullae in DEB heal with scarring and milia, and are usually associated with nail dystrophy of variable degree.

Dominant dystrophic epidermolysis bullosa

The diagnosis of EB should be considered for any infant presenting with skin fragility, but the differential is quite broad (Box 16.2). JEB cannot usually be distinguished from other severe variants of EB in the neonatal period merely on the basis of clinical features, and early laboratory-based diagnosis is recommended. In the immediate postnatal period, infectious causes

DDEB is the most common subtype of DEB and usually presents from birth to 5 years of age. The spectrum of clinical severity is wide, even within a particular pedigree, and the condition may be expressed by as little as dystrophy of the great toenails. DDEB may be generalized (encompassing the types formerly known as Pasini and Cockayne-Touraine DDEB), with bullae charac­ teristically occurring over the trunk, limbs and bony prominences (knuckles, elbows, knees and malleolar regions) (Figs 16.10, 16.11), or it may be more limited to an acral distribution. Atrophic scarring and milia both occur during the healing process. Thickened, discolored nail plates are common,

40. Puvabanditsin S, Garrow E, Kim DU, et al. Junctional epidermolysis bullosa associated with congenital localized absence of skin, and pyloric atresia in two newborn siblings. J Am Acad Dermatol. 2001;44:330–335. 41. Phillips RJ, Atherton DJ, Gibbs ML, et al. Laryngo-onycho-cutaneous syndrome: an inherited epithelial defect. Arch Dis Child. 1994;70:319– 326. 42. Nakano A, Chao SC, Pulkkinen L, et al. Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs non-Herlitz phenotypes. Hum Genet. 2002;110:41–51. 43. Pulkkinen L, Marinkovich MP, Tran HT, et al. Compound heterozygosity for novel splice site mutations in the BPAG2/COL17A1 gene underlies generalised atrophic benign epidermolysis bullosa. J Invest Dermatol. 1999;113:1114–1118.

44. Mellerio JE, Pulkkinen L, McMillan JR, et al. Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the β4 gene (ITGB4) in two unrelated patients with mild disease. Br J Dermatol. 1998;139:862–871. 45. Pfendner E, Uitto J. Plectin gene mutations can cause epidermolysis bullosa with pyloric atresia. J Invest Dermatol. 2005;124:111–115. 46. McLean WH, Irvine AD, Hamill KJ, et al. An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome. Hum Mol Genet. 2003;12:2395–2409. 47. Fox T. Notes on unusual or rare forms of skin disease. Lancet. 1879;1: 766–767. 48. Hallopeau MH. Nouvelle note sur la dermatose bulleuse hereditaire et traumatique. Ann Dermatol Syph. 1898;9:721–728.

Differential diagnosis

INHERITED VESICULOBULLOUS DISEASE

Pathophysiology

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BOX 16.2 DIFFERENTIAL DIAGNOSIS OF EPIDERMOLYSIS BULLOSA IN INFANTS AND CHILDREN Genetic conditions

INHERITED VESICULOBULLOUS DISEASE

>> Bullous congenital ichthyosiform erythroderma (bullae, erosions) >> Ichthyosis bullosa of Siemens (bullae, erosions) >> Porphyrias – Congenital erythropoietic porphyria (bullae, erosions) – Familial porphyria cutanea tarda (bullae, erosions) >> Mendes da Costa syndrome (bullae, erosions) >> Pachyonychia congenita (bullae) >> Hailey–Hailey disease (bullae, erosions) >> Hay–Wells syndrome (erosions) >> Incontinentia pigmenti (vesicles, bullae erosions) >> Focal dermal hypoplasia (erosions) >> Microphthalmia and linear skin defects (linear atrophic scars) >> Methylmalonic acidemia (erosions) >> Acrodermatitis enteropathica (erosions) Infections

>> Viral – Herpes simplex virus (vesicles) – Varicella zoster virus (vesicles) – Hand, foot and mouth syndrome (Coxsackie A 16) (vesicles, erosions)

>> Bacterial – Staphylococcal pyoderma/bullous impetigo (bullae, erosions) – Staphylococcal scalded skin syndrome (bullae, erosions) – Blistering distal dactylitis (bullae) – Group B streptococcal infection (vesicles, bullae, erosions) – Congenital syphilis (bullae) >> Yeast – Candidiasis (pustules, erythroderma, bullae, erosions)

>> Parasitic – Scabies (vesicopustules) Autoimmune blistering disorders

>> Bullous pemphigoid (bullae, erosions) >> Linear IgA disease (chronic bullous disease of childhood) (bullae and erosions)

>> Dermatitis herpetiformis (vesicopapules) >> Pemphigus (bullae, erosions) >> Maternal blistering disease (transplacental antibodies,

pemphigoid gestationis, pemphigus) (bullae, erosions)

>> Epidermolysis bullosa acquisita (bullae, erosions) >> Bullous systemic lupus erythematosus (bullae) Miscellaneous

>> Diffuse cutaneous mastocytosis (bullae, erosions) >> Aplasia cutis congenita (erosions) >> Sucking blisters (bullae, erosions) >> Transient neonatal pustular melanosis (vesicopustules) >> Infantile acropustulosis (vesicopustules) >> Trauma (bullae, erosions) >> Congenital erosive and vesicular dermatosis (vesicles, erosions, reticulate scarring)

>> Erythema multiforme (bullae) >> Stevens–Johnson syndrome/toxic epidermal necrolysis (erythema, bullae, erosions)

>> Acute contact dermatitis (vesicles, bullae) >> Actinic prurigo (vesicopapules) >> Hydroa vacciniforme (vesicles) >> Miliaria crystallina (vesicles)

Adapted with permission from Fine JD, Eady RAJ, Bauer EA et al. Revised classification system for inherited epidermolysis bullosa: Report of the Second International Consensus Meeting on diagnosis and classification of epidermolysis bullosa. J Am Acad Dermatol 2000; 42(6):1051–1066.

Figure 16.10  Dominant DEB: bullae and scarring on the knee. 960

Figure 16.11  Milia on the ankle of a child with DDEB (Courtesy Dr A. Lucky).

Vesiculobullous disease

16

especially on the toes, although some nails may remain normal (Fig. 16.12). Scarring of the nail bed often results in loss of the affected nail. Scarring does not lead to pseudosyndactyly in this type of DEB, but occasionally flexion contractures of the fingers may be seen.49 The presence of albopapuloid lesions, typically over the lower back, is common in, but not specific to, DDEB. Albopapuloid lesions vary from being rather subtle, discrete, hypopigmented, atrophic areas, with a finely wrinkled surface, to more prominent, ivory–white papules. Their significance is uncertain. Occasionally, DDEB may be associated with localized congenital absence of skin, formerly called Bart syndrome. Oral bullae are not uncommon in children or adults and may be associated with dental caries if oral hygiene is compromised.34,49,50 Gastrointestinal tract involvement occurs in up to 55% of cases of DDEB and includes dysphagia, microstomia, constipation, and anal fissures.12,50 Esophageal strictures and webs may occur but are not typical of DDEB. Tracheobronchial and ocular involvement is not characteristic. Anemia occurs in less than 25% of patients, and growth retardation is an uncommon feature of DDEB. The incidence of cutaneous squamous cell carcinoma is increased in older patients with DDEB, although there is no increased incidence of basal cell carcinoma or malignant melanoma in this group.51,52 For the majority, DDEB does not cause serious difficulties, and for many the cosmetic consequences of scarring and nail problems are the most troublesome aspect, resulting in psychological difficulty and social embarrassment rather than physical disability. Most experience improvement of the blistering tendency during early adult life.

Figure 16.13  Congenital absence of skin on the foot of a girl with RDEB (Courtesy Dr A. Lucky).

RDEB generalized, other (formerly non-Hallopeau–Siemens). Other minor subtypes are recognized (see below).1

Severe generalized RDEB

The most recent consensus classification divides RDEB into a severe generalized form (previously Hallopeau–Siemens) and

Severe generalized RDEB presents at birth with generalized blistering. Congenital localized absence of skin is commonly a feature (Fig. 16.13). The skin is very fragile and blistering is easily induced by frictional trauma. Milia are usual, although may not be a prominent feature. Scarring follows skin blistering, and may also affect the gastrointestinal tract after trauma. Nail loss is inevitable and early, quickly followed by inexorably progressive flexion contractures of the digits and fusion of the fingers and toes until the hands and feet become encased in a mitten of scar tissue (pseudosyndactyly; Fig. 16.14). Flexion contractures of the limbs often contribute to immobility (Fig. 16.15) so that affected individuals are not infrequently partially or wholly wheelchair reliant by adolescence or young adulthood. Scarring alopecia often develops during childhood, as does scarring of the external ear. Corneal erosions, ocular scarring causing pannus, symblepharon, and ectropion may occur.

49. Horn HM, Tidman MJ. The clinical spectrum of epidermolysis bullosa. Br J Dermatol. 2002;146:267–274. 50. Fine JD, Johnson LB, Weiner M, et al. Gastrointestinal complications of inherited epidermolysis bullosa: cumulative experience of the National Epidermolysis Bullosa Registry. J Pediatr Gastroenterol Nutr. 2008;46:147–158.

51. Schwartz RA, Birnkrant AP, Rubenstein DJ, et al. Squamous cell carcinoma in dominant type epidermolysis bullosa dystrophica. Cancer. 1981;47: 615–620. 52. Fine JD, Johnson LB, Weiner M, et al. Epidermolysis bullosa and the risk of life-threatening cancers: The National EB Registry experience, 1986–2006. J Am Acad Dermatol. 2008;60(2):203–211.

Recessive dystrophic epidermolysis bullosa

INHERITED VESICULOBULLOUS DISEASE

Figure 16.12  Dominant DEB: fingernail dystrophy.

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INHERITED VESICULOBULLOUS DISEASE

Figure 16.14  Recessive

DEB-Hallopeau–Siemens: pseudosyndactyly of

hands.

Figure 16.15  Recessive DEB-Hallopeau–Siemens: fixed flexion deformity at knees.

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Figure 16.16  Recessive DEB-Hallopeau–Siemens: squamous cell carcinoma.

calcanei and vertebral bodies may also occur. Patients with RDEB may have delayed puberty, further compromising bone health. Anemia, resulting from an inadequate diet, chronic blood loss from the gastrointestinal tract and skin, and the consequence of chronic disease, is the rule. It may prove relatively refractory to oral iron supplements, with many patients requiring intravenous iron or regular blood transfusions to maintain an adequate hemoglobin level. Dilated cardiomyopathy may rarely occur: the causes of this are not fully understood although nutritional deficiencies have been suggested as a possible cause.54,55 Urogenital tract disease resulting from outflow obstruction (such as urethral meatal stenosis) or renal parenchymal disease (post-infectious glomerulonephritis, renal amyloid or IgA nephropathy) is well described, and may ultimately result in renal failure.37,56 There is a greatly increased likelihood of squamous cell carcinoma (SCC) (Fig. 16.16) in patients with severe generalized RDEB, and this is the leading cause of death in this condition. SCC may arise as early as the second decade of life, but the incidence increases with age: the cumulative risk of developing SCC by age 35 years was 67.8% in the United States National EB Registry, rising to 90.1% by age 55 years.52 Patients tend to develop multiple primary SCCs which are often highly aggressive locally and metastasize early, despite often being well differentiated histologically. Differentiation of an SCC from a chronic EB wound on purely clinical grounds may be extremely difficult and repeated biopsies may be necessary.

Oral blistering always occurs and even very gentle brushing of teeth results in gingival bleeding and erosions. The teeth are normal but dental caries is common and a function of poor oral hygiene and exposure of teeth as a result of intraoral scarring. Microstomia further contributes to the difficulty in maintaining oral hygiene. Dysphagia is a common symptom and may be due to a combination of ankyloglossia, esophageal dysmotility, and esophageal webs or strictures. Over 50% of children with this form of RDEB have symptoms of dysphagia by age 10 years.12,50 Constipation is also common and may have multifactorial causes, including anal fissuring and inadequate levels of dietary fiber.12,49 Patients with severe generalized RDEB frequently have reduced bone mineral density which is probably multifactorial in nature, including immobility, low vitamin D levels and a generally proinflammatory state.53 Bone pain is common and fractures of the

RDEB generalized, other (non-Hallopeau–Siemens) has a phenotype which may be indistinguishable from DDEB, with blisters, milia and subsequent atrophic scars localized to acral bony prominences. Nail dystrophy or loss is usual. Congenital absence of skin may occur. As with DDEB, skin fragility usually improves in adulthood. A mild degree of flexion contractures of the fingers

53. Fewtrell MS, Allgrove J, Gordon I, et al. Bone mineralization in children with epidermolysis bullosa. Br J Dermatol. 2006;154:959–962. 54. Sidwell RU, Yates R, Atherton D. Dilated cardiomyopathy in dystrophic epidermolysis bullosa. Arch Dis Child. 2000;83:59–63.

55. Fine JD, Hall M, Weiner M, et al. The risk of cardiomyopathy in inherited epidermolysis bullosa. Br J Dermatol. 2008;159:677–682. 56. Burgu B, Duffy PG, Wilcox DT. Single-centre experience of genitourinary complications of epidermolysis bullosa. J Pediatr Urol. 2006;2:583–586.

Recessive dystrophic epidermolysis bullosa – generalized, other

Vesiculobullous disease

16

may be present. Oral blistering, dental caries, and anal fissures may arise, as may a restricted oral aperture and ankyloglossia. Esophageal webs and strictures may cause dysphagia.

Inversa form of recessive dystrophic epidermolysis bullosa

Pretibial dystrophic epidermolysis bullosa Pretibial DEB is rare and is characterized by recurrent blistering, predominantly involving pretibial regions, resulting in milia formation and scarring, and usually associated with nail dystrophy.1,57 Pruritus is a common feature and it may be associated with a prurigo morphology and albopapuloid lesions. Onset may be delayed until the second or third decade. There tends to be significant phenotypic variation even within individual pedigrees. Autosomal dominant transmission is the norm, although some cases may be the result of recessive inheritance. It remains to be determined whether this phenotype is distinct from EB pruriginosa.

Epidermolysis bullosa pruriginosa EB pruriginosa appears to be a clinically distinct subset of DEB, which may be inherited in either a dominant or recessive manner49,58,59: it is characterized by intense pruritus associated with the formation of lichenified nodules or plaques. Traumainduced blistering occurs but may not be a prominent feature. Violaceous linear lesions, excoriations, milia, nail dystrophy and occasional albopapuloid lesions are also features. EB pruriginosa may cause clinical confusion with both lichen planus and nodular prurigo (Fig. 16.17). This form of DEB may rarely be associated with the development of cutaneous SCC in affected areas of skin. There may be co-existence of more conventional DEB phenotypes and EB pruriginosa within individual families, although the reason for such phenotypic variability is not fully understood.

Bullous dermolysis of the newborn This is a rare subtype of DEB which in the majority of cases is transmitted in an autosomal dominant manner, but which may

57. Lee JY, Chen HC, Lin SJ. Pretibial epidermolysis bullosa: a clinicopathologic study. J Am Acad Dermatol. 1993;29:974–981. 58. McGrath JA, Schofield OM, Eady RA. Epidermolysis bullosa pruriginosa: dystrophic epidermolysis bullosa with distinctive clinicopathological features. Br J Dermatol. 1994;130:617–625. 59. Mellerio JE, Ashton GH, Mohammedi R, et al. Allelic heterogeneity of dominant and recessive COL 7A1 mutations underlying epidermolysis bullosa pruriginosa. J Invest Dermatol. 1999;112:984–987. 60. Fine JD, Johnson LB, Cronce D, et al. Intracytoplasmic retention of type VII collagen and dominant dystrophic epidermolysis bullosa: reversal of

INHERITED VESICULOBULLOUS DISEASE

The ‘inversa’ variant of RDEB is characterized by a combination of flexural and acral bullae and erosions. The inguinal, axillary and, in adulthood, submammary regions are particularly affected. The hands and feet are also involved; the nails are lost and scarring of the hands and feet occur. Flexion contractures of the fingers may result. Secondary dental disease, ankyloglossia, microstomia, anal fissures and esophageal strictures also occur. Other body regions frequently blister and scar although not to the same degree or extent as in severe generalized RDEB. Figure 16.17  EB pruriginosa: lichenoid lesions on legs and feet (Courtesy Dr A. Torrelo).

less commonly be recessive. It is characterized by extensive blistering or areas of raw skin at birth which resolve or dramatically improve over the succeeding months to years. Intracytoplasmic retention of type VII collagen within basal and suprabasal keratinocytes typifies this condition during the blistering period.60

Pathophysiology All variants of DEB are the result of mutations in the gene that encodes type VII collagen (COL7A1), the morphological expression of which are the anchoring fibrils that appear to function in uniting the lamina densa with underlying elements of the papillary dermis. The anchoring fibrils are reduced in number, rudimentary, or absent in DEB. The cleavage plane in DEB coincides with the region normally occupied by anchoring fibrils. The severe generalized RDEB phenotype is usually associated with premature termination codons on both alleles, either homozygous or compound heterozygous,61 resulting in marked reduction or absence of structurally normal anchoring fibrils. RDEB generalized, other is usually associated with compound heterozygosity for a premature termination codon and a different type of mutation, such as a missense or splice site mutation, resulting in somewhat less disruption of the structural integrity and assembly of the collagen VII molecule. DDEB is caused by mutations in COL7A1 that result in either a glycine substitution or, less frequently, other mutations, such as splice-site mutations,62,63 which may have a destabilizing effect on the triple helical type VII collagen molecule. However, the presence of a wild-type allele in DDEB allows a small percentage of normal polypeptides to assemble into collagen VII molecules that can

defect following cessation of or marked improvement in disease activity. J Invest Dermatol. 1993;101:232–236. 61. Pulkkinen L, Uitto J. Mutation analysis and molecular genetics of epidermolysis bullosa. Matrix Biology. 1999;18:29–42. 62. Christiano AM, Ryynänen M, Uitto J. Dominant dystrophic epidermolysis bullosa: identification of a glycine-to-serine substitution in the triple helical domain of type VII collagen. Proc Natl Acad Sci USA. 1994;91:3549–3553. 63. Jiang W, Bu D, Yang Y, et al. A novel splice site mutation in collagen type VII gene in a Chinese family with dominant dystrophic epidermolysis bullosa pruriginosa. Acta Derm Venereol. 2002;82:187–191.

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form anchoring fibrils. Dermolysis of the newborn results from a variety of different types of COL7A1 mutation.64,65

Differential diagnosis Severe generalized RDEB is a unique clinical picture and unlikely to be confused with other conditions once the typical consequences of scarring have developed. In infancy, it may be difficult to distinguish from other severe variants of EB, and infections have to be excluded. The localized variants of DEB are also quite typical, although in the older child there is the possibility of confusion with conditions such as porphyria cutanea tarda, variegate porphyria, EB acquisita, and pseudoporphyria, all of which can result in very similar appearances of the hands. INHERITED VESICULOBULLOUS DISEASE

MANAGEMENT AND PROGNOSIS The treatment of all forms of EB is supportive. The establishment of an appropriate regimen for the immediate care of a neonate with one of the severe generalized forms of EB, which include JEB-Herlitz, EBS-Dowling–Meara and severe generalized RDEB, will minimize unnecessary damage to the skin and thus help to limit permanent disability. The Dystrophic Epidermolysis Bullosa Research Association (DEBRA) provides invaluable support to parents and nursing staff caring for people with EB and, later, to patients themselves. Current treatment strategies are focused on preventing new blisters, preventing and treating infections, enhancing wound healing, providing nutritional support, managing extracutaneous complications, preserving function and providing psychological support to patients and family members. For the localized and generalized variants of EBS, prevention of blistering is paramount. Keeping the soles and palms cool and dry, especially during the summer months, can be helpful in minimizing the blistering, and, if hyperhidrosis is a feature, a topical antiperspirant containing 20% aluminum chloride hexa­ hydrate, applied last thing at night and gently dried with a hairdryer, may be useful. Well-fitting footwear is very important and leather shoes with leather linings, ideally with external seams, are generally recommended. Several pairs of shoes should be worn in rotation to vary the sites of friction and it may be helpful for patient or parent to carry a spare pair of shoes for children to change into partway through the day. During the summer, alternatives to leather shoes are canvas shoes or jelly sandals. Another measure to reduce frictional forces on the soles is to wear two pairs of cotton socks, although this has to be balanced against the possibility of increasing the temperature of the skin. Cornflour sprinkled into the shoes or socks may also help reduce friction. In the worst cases of EBS, children may benefit from having assistance with transportation to and from school. A careful explanation of the nature of EBS to the teaching staff at school will usually ensure that the child is treated sympathetically.

64. Christiano AM, Fine JD, Uitto J. Genetic basis of dominantly inherited transient dermolysis of the newborn: a splice site mutation in the type VII collagen gene. J Invest Dermatol. 1997;109:811–814. 65. Fassihi H, Diba VC, Wessagowit V, et al. Transient bullous dermolysis of the newborn In three generations. Br J Dermatol. 2005;153:1058–1063.

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In most cases of EBS, discomfort is reduced by puncturing bullae using sterile scissors or needles, and retaining the roof of the bulla which acts as a biological dressing. Antibiotic or antiseptic ointment at the incision site reduces the risk of secondary infection. Soaking hands and feet in cold water or an antiseptic solution such as potassium permanganate (1 : 10 000) for 20– 30 min once or twice each day may be helpful. Some patients prefer the application of a non-adherent dressing, held in place with a bandage, whereas others find dressings unnecessary or deleterious, by actually increasing blistering beneath them or around their edges. Cornflour can also be useful in this setting to help dry up blisters that have been punctured. As with all forms of EB, attention should be paid to adequate pain control, and a nocturnal dose of amitriptyline (0.5 mg per kg body weight) may be beneficial, particularly during the summer months. Dowling–Meara EBS is managed in the initial weeks in a similar fashion to the severe generalized forms of JEB and DEB (see below). Septicemia is a particular risk in infancy,66 and management in an intensive care unit may be required. In later years, troublesome palmoplantar hyperkeratosis may respond to low-dose acitretin or isotretinoin, although this may increase skin fragility and worsen the tendency to blistering. The essence of caring for the skin of infants and young children with severe EB, notably Dowling–Meara EBS, JEB and severe recessive DEB, is careful handling to minimize blister formation, and the prevention of infection.66 Babies should be lifted and moved on to a soft pad such as a folded towel inside a pillowcase, trying to avoid applying shearing forces to the skin. Clothing should be soft, pads may be sewn in at the interiors of shirts and pants over elbows and knees, and it is helpful to turn them inside out to avoid rubbing of the skin from seams and labels. Cotton mittens may reduce self-inflicted trauma. Nonblistered skin should be kept well moisturized with a greasy emollient such as a 50 : 50 mixture of white soft paraffin and liquid paraffin. When bathing, the bath should be lined with a thick towel. Rigid plastic cord clamps should be removed and the cord tied with a ligature. Similarly, plastic namebands may damage skin of the wrists and ankles, and should be avoided. Adhesive tapes to secure intravenous lines, for example, should not be used; specialized soft silicone dressings or soft bandages are generally adequate for this purpose. A variety of different wound care strategies have been employed to manage EB, but the basic principles are similar.66 Dressing choices are often determined by parental, and later personal, preference. Probably the best technique of care, to prevent bullae from enlarging, is to puncture them with a sterile needle, leaving the roof intact and allowing it to settle on the floor of the bulla. Dusting the area with cornflour dries up the bullae and limits their spread. A topical antibiotic applied to the ruptured area may be used: mupirocin ointment is reserved for treatment of small areas for limited periods of time to prevent bacterial resistance. The use of topical antiseptics, such as hydrogen peroxide in a lipidstabilized formulation (Crystacide™ cream), may be helpful.

66. Denyer J. Management of severe blistering disorders. Semin Neonatal. 2000;5:321–324.

Silver sulfadiazine cream and silver-containing dressings are probably best avoided in infants and used for only limited periods of time in older children due to the potential for silver absorption and toxicity.67 Systemic antibiotics should be used when significant cutaneous or extracutaneous infection is suspected. A wide range of different atraumatic wound dressings are available and which to use depends on patient or carer preference, the state of the wound and its location. Many patients will use different dressings at different times and at different sites. Lowadherent soft silicone dressings are widely used in EB (Mepitel™, Mepilex™, Mepilex Transfer™, Mepitac™). Mepitel™ is often used as a primary dressing as it is atraumatic and enables exudate to pass through to a secondary dressing such as Mepilex™ or Mepilex Transfer™. In open exuding wounds, a non-occlusive hydrocolloid fiber dressing may be useful as a primary dressing, covered with a soft silicone secondary dressing. Conformable or tubular bandages can be used to secure dressings but care should be taken not to apply tape directly to the skin. Additional protection may be afforded with the use of padding over the secondary dressing. The primary dressing may be changed every 4–7 days in order to minimize the discomfort of the dressing process and to allow the wound to heal undisturbed, although it may be necessary to change the dressing more frequently if the wound is infected or heavily exudative. The secondary dressing may be changed daily if required. Care should be taken to give adequate analgesia prior to dressing changes.66 There have been several reports of using tissue-engineered skin (Apligraf™) and autologous epidermal grafts for wounds in individuals with inherited EB.68 However, the costs are high and graft take is poor when infection is present. The role of tissueengineered skin grafts in the routine management of various forms of inherited EB remains to be fully evaluated. Severe forms of EB are associated with protean problems that demand a multidisciplinary management approach, including dermatologists, nurses, plastic surgeons, pediatricians, gastro­ enterologists, hematologists, ophthalmic surgeons, dentists, dietitians, and physiotherapists. The treatment of systemic involvement, including oral, gastrointestinal, and musculoskeletal manifestations, should be individualized. A comprehensive discussion of the management of these issues is beyond the scope of this text, but has been reviewed recently.69,70 Perhaps the single most important aspect of managing DEB, especially severe generalized RDEB, is the regular monitoring for cutaneous SCC, with biopsy of any ulcers with unusual features.

In the past, phenytoin has been advocated for the treatment of DEB,71 but there is insufficient evidence of its efficacy to support its use.72 Isotretinoin has been advocated as a chemoprophylactic agent for SCC in RDEB, and appears to be tolerated,73 although evidence that this is effective is lacking. Feeding an EB patient at any age is a problem if there is oral involvement. The lips should be protected with petroleum jelly, and, if the mouth is ulcerated, teething gels may be beneficial. The teat can be moistened prior to feeding to avoid it sticking to ulcerated areas. A Haberman feeder is often helpful if the mouth is very uncomfortable, as this reduces the need for strong sucking, and the length of the teat avoids trauma to the nose.66 Breast-feeding tends to be more beneficial in terms of general wellbeing than bottle-feeding if soreness of the mouth permits. Nasogastric tubes are best avoided, but, if required, a tube suitable for long-term feeding should be used, thereby reducing the need for frequent tube changes. If a pacifier is used, it is helpful to avoid those with a plastic ring as this may damage the lips and surrounding skin. In older children, a local anesthetic spray or mouthwash may be helpful for oral ulceration. Genetic counseling is extremely important for affected individuals and their families. DNA-based prenatal diagnosis is available for junctional and dystrophic forms of EB in families in which there is a known history of EB and for which the mutations or informative markers have been characterized. It is performed using DNA obtained from chorionic villus sampling or amniocentesis at around 11–12 weeks’ gestation.74 More recently, preimplantation genetic diagnosis (PGD), an alternative approach that avoids the termination of an affected pregnancy, has been developed for EB. This technique permits the genotype to be determined in an embryo produced by in vitro fertilization techniques at an eight-cell stage from analysis of DNA from one or two cells,75,76 following which one or two unaffected embryos are then placed in the uterus to establish a pregnancy. PGD has been successfully applied in a family with ectodermal dysplasia/ skin fragility syndrome76 and should become more widely available in other forms of EB. Gene therapy remains the future hope for treatment of EB. An ex vivo approach in a patient with JEB-non-Herlitz successfully gene-corrected the patient’s own epidermal stem cells which were then cultured and grafted back on to the skin with longlasting rescue of the phenotype at the graft site.77 This important proof of principle study is forming the basis for further studies in JEB and DEB. Other approaches using allogeneic keratinocytes or fibroblasts are currently under evaluation, and early work in

67. Flohr C, Heague J, Leach I, et al. Topical silver sulfadiazine-induced argyria in a patient with severe generalized dystrophic epidermolysis bullosa. Br J Dermatol. 2008;159:740–741. 68. Falabella AF, Valencia IC, Eaglstein WH, et al. Tissue-engineered skin (Apligraf) in the healing of patients with epidermolysis bullosa wounds. Arch Dermatol. 2000;136:1225–1230. 69. Fine JD, Mellerio JE. Extracutaneous manifestations and complications of epidermolysis bullosa. Part I. Epithelial associated tissues. J Am Acad Dermatol. 2009;61:367–384. 70. Fine JD, Mellerio JE. Extracutaneous manifestations and complications of epidermolysis bullosa. Part II. Other organs. J Am Acad Dermatol. 2009;61: 387–402. 71. Bauer EA, Cooper TW, Tucker DR, et al. Phenytoin therapy of recessive dystrophic epidermolysis bullosa: clinical trial and proposed mechanism of action on collagenase. N Engl J Med. 1980;303:776–781. 72. Caldwell-Brown D, Stern RS, Lin AN, et al. Lack of efficacy of phenytoin in recessive dystrophic epidermolysis bullosa. N Engl J Med. 1992;327: 163–167.

73. Fine JD, Johnson LB, Weiner M, et al. Chemoprevention of squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: results of a phase 1 trial of systemic isotretinoin. J Am Acad Dermatol. 2004;50:563–571. 74. Holbrook KA, Christiano AM, Elias S, et al. Prenatal diagnosis of inherited epidermolysis bullosa: ultrastructural, antigenic and molecular approaches. In: Fine JD, Bauer EA, McGuire J, Moshell A, eds. Epidermolysis bullosa: clinical, epidemiologic and laboratory advances and the findings of the National Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999:351–373. 75. Cserhalmi-Friedman PB, Tang Y, Adler A, et al. Preimplantation genetic diagnosis in two families at risk for recurrence of Herlitz junctional epidermolysis bullosa. Exp Dermatol. 2000;9:290–297. 76. Fassihi H, Grace J, Lashwood A, et al. Preimplantation genetic diagnosis of skin fragility-ectodermal dysplasia syndrome. Br J Dermatol. 2006;154:546–550. 77. Mavilio F, Pellegrini G, Ferrari S, et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med. 2006;12:1397–1402.

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animal models may indicate a potential role for bone marrow or stem cell transplantation in the future.78,79 Determining the prognosis in infants with JEB on purely clinical grounds is very difficult, especially in the early weeks. Laboratory investigations usually prove extremely helpful in distinguishing JEB-Herlitz and non-Herlitz subtypes. Although JEB-Herlitz is usually fatal within the first year or two of life, some individuals may survive beyond the first decade. Conversely, infants with JEB-non-Herlitz may be very severely affected and may succumb despite optimal medical care. The cause of death in JEB-Herlitz is not always clear, although failure to thrive, infection and laryngeal involvement may all contribute. Patients with DDEB have a normal life expectancy and, in general, the condition may improve in adulthood. Nonetheless, patient and physician should be aware of the possibility of SCC arising on chronically scarred skin. In individuals with severe generalized RDEB, skin fragility and blister formation continue unabated and there is a greatly increased risk of early death from SCC, sepsis, renal failure and pneumonia.

LABORATORY INVESTIGATIONS If EB is suspected, samples should be taken for ultrastructural confirmation of the cleavage plane and for immunohistochemistry. Routine light microscopy is not helpful for establishing the type of EB, but may exclude other inflammatory blistering disorders. The biopsy should be taken from an unblistered area of skin that has been gently rubbed with a finger tip or pencil eraser for a minute: this is to induce microscopic cleavage in the skin but without causing macroscopic separation that would detach the epidermis from the underlying dermis completely. A technique of shave biopsy is most appropriate as it provides a long stretch of the dermal–epidermal junction for analysis. Punch biopsying may cause rotational shearing on the biopsy and lead to complete separation of the epidermis from the dermis. The biopsy should be gently divided for ultrastructural and immunohistochemical analysis. Electron microscopy is the gold standard for defining the cleavage plane, but if this is not available immunohistochemical antigen mapping will reveal the level of the split by defining its location relative to proteins that are normally expressed at various levels of the basement membrane zone, such as bullous pemphigoid antigen-1, laminin-111 (laminin-1) and type IV collagen. In the case of EBS Dowling–Meara, electron microscopy demonstrates characteristic tonofilament clumping, and in JEB and DEB abnormalities of the hemidesmosomes and anchoring fibrils, respectively, are present. Immunohistochemistry with a panel of antibodies to basement membrane proteins involved in the pathogenesis of EB may reveal reduced or absent staining, thereby indicating the causative molecular pathology. Two commercially available antibodies, GB3 (specific for laminin 332) and LH7:2 (specific for type VII collagen), can be used to rapidly confirm or exclude JEB-Herlitz and severe generalized RDEB, respectively. Patients with JEB-Herlitz will show complete 78. Chino T, Tamai K, Yamazaki T, et al. Bone marrow cell transfer into fetal circulation can ameliorate genetic skin diseases by providing fibroblasts to the skin and inducing immune tolerance. Am J Pathol. 2008;173:803–814. 79. Tolar J, Ishida-Yamamoto A, Riddle M, et al. Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells. Blood. 2008;113(5):1167–1174.

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absence of staining with GB3, and severe generalized RDEB is characterized by totally absent expression of type VII collagen. This type of analysis may be less helpful in milder forms of JEB and DEB where immunohistochemistry with additional antibodies against basement membrane components and electron microscopy may be required. Gene mutation analysis can now be undertaken for all types of EB, but may be costly in view of the genetic heterogeneity of some forms (e.g. laminin 332-deficient JEB) and the size and complexity of some of the responsible genes (e.g. PLEC1 and COL7A1). Genetic screening is not indicated in all cases of EB as it often does not affect management of the affected individual. However, it may be useful in determining inheritance patterns in a family, in particular whether an individual with DEB and no other affected family members has mild RDEB or DDEB arising from a new mutation. This information has implications for counseling the parents as to their recurrence risk in subsequent pregnancies, as well as for the individual themselves. A major reason for undertaking genetic analysis for EB, particularly severe forms, is to be able to offer earlier prenatal testing in families requesting this. Prenatal diagnosis of severe forms of EB by intrauterine skin biopsy has been available for more than a quarter of a century,80 but it can only be undertaken in the second trimester and is a highly specialized technique. If mutations or informative markers are identified in a family with EB, however, first trimester testing from chorionic villi or amniocentesis is now possible and well established.81 Very recently, techniques of in vitro fertilization and DNA analysis from single embryonic cells have made pre-implantation diagnosis feasible, avoiding the need to terminate an established pregnancy since only unaffected embryos are selected for implantation.81

KINDLER SYNDROME Introduction Kindler syndrome is a rare autosomal recessive genetic disorder characterized by poikiloderma, photosensitivity and skin fragility.82 In the most recent consensus classification it has been included within the spectrum of EB, forming a fourth major subtype of mixed EB, reflecting the variable cleavage plane observed at the dermal–epidermal junction.1

Clinical features Infants often present in the neonatal period with acral blistering although more extensive blistering has been reported. The tendency to develop blisters and photosensitivity improves with maturity, but generalized atrophic scarring and poikiloderma are progressive. Poikiloderma often begins on sun-exposed surfaces and extends to covered areas. Fusion of the digits that resembles recessive dystrophic EB is a feature of this disorder (Fig. 16.18). Other less commonly reported findings include palmoplantar hyperkeratosis, colitis, esophageal, urethral and anal stenosis, 80. Rodeck CH, Eady RA, Gosden CM. Prenatal diagnosis of epidermolysis bullosa letalis. Lancet. 1980;1(8175):949–952. 81. Fassihi H, Eady RA, Mellerio JE, et al. Prenatal diagnosis for severe inherited skin disorders: 25 years’ experience. Br J Dermatol. 2006;154:106–113. 82. Kindler T. Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy. Br J Dermatol. 1954;66:104–111.

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It may be difficult to distinguish Kindler syndrome from EB in the immediate newborn period; however, the development of poikiloderma with age helps to establish the diagnosis. More­ over, a history of blistering and scarring helps to distinguish it from other disorders such as Bloom syndrome and Rothmund– Thomson syndrome that are also characterized by poikiloderma and photosensitivity.

Management and prognosis

Figure 16.18  Kindler syndrome (Courtesy Dr A. Torrelo). and nail dystrophy. Squamous cell carcinoma of the lip and hard palate and transitional cell carcinoma of the bladder have been reported in Kindler syndrome.83–85 There is a progressive gingivitis and many patients lose some teeth by adulthood.

Laboratory findings and pathophysiology Kindler syndrome is a distinct disorder that should be distinguished from DEB. Light microscopy is not specific and shows features of poikiloderma (epidermal atrophy, vacuolization of the basal layer, capillary dilatation and dermal edema).85 Electron microscopy of skin biopsy specimens shows duplication of the lamina densa. Cleft formation may occur low within basal keratinocytes, within the lamina lucida or beneath the lamina densa, hence its new designation as mixed EB. The anchoring fibrils and hemidesmosomes are normal. Immunohistochemical analysis demonstrates normal staining with antibodies against hemidesmosomal and anchoring filament proteins but reduced or absent staining against fermitin family homolog 1 (FFH1) (formerly known as kindlin-1). This protein is expressed in focal adhesions where it is involved in linking the actin cytoskeleton to the underlying extracellular matrix via integrin complexes. Mutations in the FFH1 gene have been identified in many families with Kindler syndrome.86,87 Whilst mucocutaneous fragility results from disruption of focal contact-actin adhesion, the mechanisms of poikiloderma and photosensitivity are less well understood.

Physician support Many countries have networks of specialist services for patients and families with EB, that also provide information and support to physicians caring for them. A number of registries also exist and can provide useful help and support, e.g. the NEBR in the USA, and similar registries in Scotland, England, Wales and Italy. In addition, the Dystrophic Epidermolysis Bullosa Research Association (DEBRA), with branches in many countries throughout the world, provides valuable support and medical infor­ mation to physicians, patients and their families. DEBRA International and the EB Medical Research Foundation also provide funding for significant basic science and clinical EB research. Useful websites and details of networks and registries are available in Fine et al. (2008).1

BULLOUS ICHTHYOSIS (CONGENITAL BULLOUS ICHTHYOSIS OF BROCQ) Introduction Bullous ichthyosis (BI), also known as bullous congenital ichthyosiform erythroderma of Brocq, or epidermolytic hyperkeratosis, is a rare inherited mechanobullous eruption, first described by Brocq in 1902.88 It is characterized by blistering and variable erythroderma in early life and the subsequent development of ichthyosis.

Genetics

The differential diagnosis of Kindler syndrome includes other inherited blistering diseases and the congenital poikilodermas.

BI is an autosomal dominant condition with many similarities to epidermolysis bullosa simplex (EBS), but whereas the latter condition results from mutations in the genes for the basal keratins 5 and 14, BI results from mutations in the genes for the

83. Haber RM, Hanna WM. Kindler syndrome clinical and ultrastructural findings. Arch Dermatol. 1996;132:1487–1490. 84. Patrizi A, Pauluzzi P, Neri I, et al. Kindler syndrome: report of a case with ultrastructural study and review of the literature. Pediatr Dermatol. 1996; 13:397–402. 85. Lotem M, Raben M, Zeltser R, et al. Kindler syndrome complicated by squamous cell carcinoma of the hard palate: successful treatment with high dose radiation therapy and granulocyte–macrophage colonystimulating factor. Br J Dermatol. 2001;144:1284–1286.

86. Jobard F, Bouadjar B, Caux F, et al. Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Hum Mol Genet. 2003;12:925–935. 87. Ashton GH, McLean WH, South AP, et al. Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome. J Invest Dermatol. 2004;122:78–83. 88. Brocq L. Erythrodermie congénitale ichthyoseforme avec hyperépidermotrophie. Ann Derm Syph. 1902;3:1–31.

Differential diagnosis

INHERITED VESICULOBULLOUS DISEASE

Individuals with Kindler syndrome usually demonstrate improvement of blistering with aging; however, the poikiloderma and atrophy are progressive. Management is supportive and the use of sun protection is advocated.

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Figure 16.19  Bullous ichthyosis: blistering in a premature infant.

Figure 16.20  Bullous ichthyosis (same patient as Fig. 16.19, aged 3 years): corrugated hyperkeratosis.

suprabasal keratins 1 and 10 (KRT1 and KRT10, respectively).89 A number of mutational ‘hot spots’ have been found, and it is likely that the position and nature of the mutation affects the clinical severity of the condition. Approximately half of all cases are the result of de novo mutations. In an affected parent, the condition may be subtle and localized to the flexures, or rarely the affected parent may have an epidermolytic epidermal nevus representing mosaicism for the mutation. Gonadal mosaicism may explain the occurrence of BI in more than one child of unaffected parents.90

Clinical features BI may show pronounced phenotypic variability within a family.91 Blistering and erythroderma are usually present at birth (Fig. 16.19), and the extent of the blistering may resemble the severe forms of EBS or staphylococcal scalded skin syndrome. Mild trauma during normal handling of a baby may induce bullae and erosions. This blistering tendency and the erythema usually subside during the first year, although the skin fragility may persist into adult life. Gradually, the skin becomes thickened and hyperkeratotic, and these changes may be widespread or, in mild cases, the hyperkeratosis may be confined to the flexures, producing a characteristic corrugated configuration of thickening (Fig. 16.20). The face is normally not significantly involved. There may be severe palmoplantar involvement, associated with flexion contractures of the digits, and such patients usually have mutations of the gene for keratin 1.92 Severe involvement of the palms and soles may be very disabling and interfere with mobility. The blisters of BI do not leave scarring or atrophy. Widespread hyperkeratosis is sometimes associated with a rather typical musty smell, which is probably the result of overgrowth of yeasts or bacteria within the stratum corneum.

89. Ishida-Yamamota A, McGrath JA, Judge MR, et al. Selective involvement of keratins K1 and K10 in the cytoskeletal abnormality of epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma). J Invest Dermatol. 1992;99:19–26. 90. Paller AS, Syder AJ, Chan YM, et al. Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med. 1994;331:1408–1415.

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Pathophysiology Keratins 1 and 10 are expressed by suprabasal epidermal cells, and the lower cell layers of the epidermis are unaffected. The keratinocytes within the upper spinous and granular layers show cytolytic degeneration with cytoplasmic edema and perinuclear vacuolization, clumping of the keratin intermediate filaments and coarse keratohyalin granules. The stratum corneum becomes thick and eukeratotic. These histological features comprise epidermolytic hyperkeratosis, and are similar to the histological and ultrastructural changes seen in Dowling–Meara EBS.

Differential diagnosis In the early stages, BI should be differentiated from severe forms of EB and from staphylococcal scalded skin syndrome. As the ichthyotic changes develop, differentiation from other autosomal dominant ichthyoses, such as ichthyosis vulgaris, is necessary.

Management and prognosis In the neonatal period the therapeutic considerations are the same as for the severe forms of EB, and comprise careful handling and management of blisters. The erythrodermic skin requires careful attention due to increased transepidermal water and heat loss. With the onset of ichthyosis, standard emollient therapy is required, and keratolytics may be helpful. However, caution should be used in small children with significant erythema since systemic absorption of agents such as salicylic acid can lead to

91. Nomura K, Umeki K, Hatayama I, et al. Phenotypic heterogeneity in bullous congenital ichthyosiform erythroderma. Arch Dermatol. 2001;137:1192–1195. 92. Virtanen M, Gedde-Dahl T, Mörk N-J, et al. Phenotypic/genotypic correlations in patients with epidermolytic hyperkeratosis and the effects of retinoid therapy on keratin expression. Acta Derm Venerol. 2001;81:163–170.

Vesiculobullous disease

The clinical features that distinguish ichthyosis bullosa of Seimens from BI are the lack of erythroderma, the typical mauserung phenomenon, the confinement of epidermolytic changes to the superficial epidermal layers and the presence of intra­ corneal blistering. The differential diagnosis of ichthyosis bullosa of Siemens includes epidermolysis bullosa simplex and other autosomal dominant types of ichthyosis, including ichthyosis vulgaris and BI.

Management Treatment consists of the liberal and frequent application of an emollient, but in troublesome cases the use of an oral retinoid such as acitretin in low dose can be very effective.99 The maintenance dose of retinoid is lower than that for BI and retinoidinduced blistering is not a problem.

HAILEY–HAILEY DISEASE

ICHTHYOSIS BULLOSA OF SIEMENS

Introduction

Introduction

Hailey–Hailey disease, also known as benign familial pemphigus, is a rare autosomal dominant mechanobullous disease characterized by recurrent blisters and erosions, typically involving the intertriginous sites.

Ichthyosis bullosa of Siemens (IBS) has a number of similarities to BI; however, there are clinical distinctions, and the demonstration that is caused by mutations in the gene encoding keratin 298 further distinguishes it from BI.

Clinical features Like BI, IBS is an autosomal dominant mechanobullous disorder with blisters and erosions caused by minor trauma, although it is a milder condition. It may be present at birth or develop later in infancy; it is characterized by an absence of erythroderma. Dark hyperkeratotic skin develops mainly on the limbs, with a tendency to spare the trunk except for the periumbilical region. The knees, elbows, dorsa of the hands and feet and the limb flexures are predilection sites. The palms and soles are usually spared. The condition is frequently uncomfortable as a result of skin cracking, causing a degree of immobility. Blistering may worsen during the summer, and is exacerbated by sweating. The hyperkeratotic element may improve during the summer months. Like BI, blistering does not result in scarring or atrophy. A particularly distinctive clinical feature is the development of superficially denuded, peeling areas – the so-called ‘mauserung phenomenon’ (molting). Histological examination reveals a more subtle degree of epidermolytic hyperkeratosis than BI, confined to the granular layer; this is compatible with keratin 2 being expressed only in the upper part of the stratum granulosum. 93. Chiaretti A, Schembri Wismayer D, Tortorolo L, et al. Salicylate intoxication using a skin ointment. Acta Pediatr. 1997;86:330–331. 94. Lacour M, Mehta-Nikhar B, Atherton DJ, et al. An appraisal of acitretin therapy in children with inherited disorders of keratinization. Br J Dermatol. 1996;134:1023–1029. 95. Golbus MS, Sagebiel RW, Filly RA, et al. Prenatal diagnosis of congenital bullous ichthyosiform erythroderma (epidermolytic hyperkeratosis) by fetal skin biopsy. N Engl J Med. 1980;302:93–95. 96. Rothnagel JA, Longley MA, Holder RA, et al. Prenatal diagnosis of epidermolytic hyperkeratosis by direct gene sequencing. J Invest Dermatol. 1994;102:13–16.

INHERITED VESICULOBULLOUS DISEASE

toxicity.93 In severe cases, systemic acitretin therapy appears to be safe and effective.94 A standard starting dose of acitretin is 0.5 mg/kg per day, and the subsequent dose titrated to the response. In BI retinoids can be very effective in treating the hyperkeratosis, but an exacerbation of the blistering tendency may limit the dose. Retinoid therapy is thought to be particularly effective in patients with keratin 10 mutations, and less so in those with keratin 1 mutations.92 Topical antimicrobials or topical and systemic antibiotics may be necessary if blisters become infected. The yeasty odor often associated with this condition may be helped by 2% ketoconazole shampoo used regularly as a body wash. Prenatal diagnosis of BI is possible. Initially, this required fetal skin biopsy,95 but can now be undertaken by direct gene sequencing96 once the mutation has been identified in the proband. This technique can be done early in pregnancy. The presence of the characteristic tonofilament clumps of BI within amniotic fluid cells raises the possibility of a diagnosis being made by amniocentesis,97 although there is potential for a false-negative result.

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Clinical features These have been systematically described by Burge.100 The onset of Hailey–Hailey disease is rare in the first decade of life; it usually presents in the second to fourth decades. It involves intertriginous sites, particularly the axillae, inguinal and submammary regions, and neck. It occasionally involves the antecubital and popliteal fossae and the scalp may also rarely be involved. Minor trauma results in blisters and erosions, which fluctuate in severity. The condition tends to be worse during the summer from heat and sweating, and friction of clothing such as collars and underwear. Pruritus and pain are common and the latter can be disabling and limit physical activities, especially when the groin is involved. The morphology of the lesions is variable. They often take the form of expanding plaques with a peripheral scaly border. Superimposed on the plaques there may be crusts, erosions, vesicles or pustules. Flexural lesions may become hypertrophic. Sometimes the erosions are aligned to resemble the furrows of a ploughed field. The lesions of Hailey–Hailey disease are often malodorous and may become secondarily infected with bacteria, dermatophytes, candida, and herpes simplex virus. Nikolski’s sign is often positive. The mucous membranes are usually not involved. Lesions heal without scarring.

97. Eady RAJ, Gunner DB, Carbone LD, et al. Prenatal diagnosis of bullous ichthyosiform erythroderma: detection of tonofilament clumps in fetal epidermal and amniotic fluid cells. J Med Genet. 1986;23:46–51. 98. McLean WHI, Morley SM, Lane EB, et al. Ichthyosis bullosa of Siemens – a disease involving keratin 2e. J Invest Dermatol. 1994;103:277–281. 99. Steijlen PM, van Dooren-Greebe RJ, Happle R, et al. Ichthyosis bullosa of Siemens responds well to low-dosage oral retinoids. Br J Dermatol. 1991;125:469–471. 100. Burge SM. Hailey–Hailey disease: the clinical features, response to treatment and prognosis. Br J Dermatol. 1992;126:275–282.

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Asymptomatic longitudinal white bands on the nails are a common feature of Hailey–Hailey disease.

tacalcitol; these are usually employed in adult cases and reports have been anecdotal.

Pathophysiology and genetics

CONGENITAL EROSIVE AND VESICULAR DERMATOSIS HEALING WITH RETICULATED SUPPLE SCARRING

Hailey–Hailey disease is caused by mutations in ATP2C1, the gene encoding a novel calcium pump.101 Intracellular calcium stores seem to be important in regulating epidermal cell–cell adhesion and differentiation, although the precise mechanism whereby defects in the calcium pump cause the clinical phenotype of Hailey–Hailey disease is not clear.

Histology INHERITED VESICULOBULLOUS DISEASE

Hailey–Hailey disease is characterized by suprabasal acantholysis, associated with mild dyskeratosis. Acanthosis and a mild dermal perivascular infiltrate may be present. Direct and indirect immunofluorescence are negative. Ultrastructural examination demonstrates breakdown of desmosome–keratin filament complexes.

Differential diagnosis Hailey–Hailey disease is often subtle and may be misdiagnosed as flexural eczema, fungal infection, impetigo, candidal intertrigo, seborrheic dermatitis or contact dermatitis. It may also be confused with Darier’s disease.

Management and prognosis Hailey–Hailey disease may become less troublesome with age and prolonged remissions may occur. There is a small risk of superimposed squamous cell carcinoma.102,103 Secondary infection with the herpes simplex virus must be considered in cases of severe exacerbation,104 and there is an increased likelihood of allergic contact dermatitis to medicaments.105 Both topical corticosteroids and topical antibiotics may be effective treatments. A combination of a medium potency or potent topical corticosteroid with an antibiotic preparation for a limited time period is a reasonable initial therapeutic option. Oral antibiotics may be helpful and some patients may require oral antibiotics on a long-term, low-dose basis.100 Topical antiseptic preparations may help to control malodor, and emollients are usually helpful. In recalcitrant cases, a variety of treatments have been used, including Grenz rays, full-thickness excision of affected skin, carbon dioxide laser vaporization, dermabrasion, cryosurgery, dapsone, vitamin E, PUVA, photodynamic therapy, pulsed dye laser, methotrexate, thalidomide, cyclosporin, oral retinoids and

101. Hu Z, Bonifas JM, Beech J, et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey–Hailey disease. Nat Genet. 2000;24:61–65. 102. Holst VA, Fair KP, Wilson BB, et al. Squamous cell carcinoma arising in Hailey–Hailey disease. J Am Acad Dermatol. 2000;43:368–371. 103. Cockayne SE, Rassl DM, Thomas SE. Squamous cell carcinoma arising in Hailey–Hailey disease of the vulva. Br J Dermatol. 2000;142:540–542. 104. Flint ID, Spencer DM, Wilkin JK. Eczema herpeticum in association with familial benign chronic pemphigus. J Am Acad Dermatol. 1993;28: 257–259. 105. Reitamo S, Remitz A, Lauerma AI, et al. Contact allergies in patients with familial benign chronic pemphigus (Hailey–Hailey disease). J Am Acad Dermatol. 1989;21:506–510.

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Introduction Congenital erosive and vesicular dermatosis with reticulated supple scarring is a very rare disorder106 that may be confused with epidermolysis bullosa in the newborn period. Affected individuals present with crusted erosions and vesicles that heal relatively rapidly leaving reticulate scarring. The etiology is unknown but intrauterine infection, trauma, vasospastic phenomena and immune complex disease have been postulated.106–108

Clinical features Infants with congenital erosive and vesicular dermatosis are usually premature and lesions present at birth. Erosions, crusts and vesicles appear on the scalp, trunk and extremities with relative sparing of the palms and soles. Facial involvement is less frequently reported. Lesions heal within the first several weeks to months of life with reticulate or ‘cobblestoned’ scarring. Skin fragility usually resolves relatively soon after the newborn period, although ongoing mild blistering has been reported.107 Heat intolerance is believed to be secondary to lack of eccrine structures in the areas of scarring.108 Nail dystrophy, loss of tongue papillae and sparse hair have been seen in some cases.106–108 Chronic recurrent conjunctivitis and nasolacrimal duct scarring were observed in one patient.107 Neurologic impairment has been reported in some patients but it is unclear whether it is related to the cutaneous disorder or the underlying prematurity.106

Laboratory findings Laboratory findings are non-specific. In cases in which tests were performed, there was no evidence of intrauterine infection. Skin biopsy specimens obtained in the newborn period revealed epidermal erosions with fibrin and neutrophils and a neutrophilic dermal infiltrate. Immunofluorescence and electron microscopy are not diagnostic.107,108

Differential diagnosis The differential diagnosis for this rare disorder includes infectious diseases that may present in the immediate newborn period and other disorders characterized by neonatal blistering

106. Cohen BA, Esterly NB, Nelson PF. Congenital erosive and vesicular dermatosis healing with reticulated supple scarring. Arch Dermatol. 1985;121:361–367. 107. Stein S, Stone S, Paller AS. Ongoing blistering in a boy with congenital erosive and vesicular dermatosis healing with reticulated supple scarring. J Am Acad Dermatol. 2001;45:946–948. 108. Sidhu-Malik NK, Resnick SD, Braunstein-Wilson B. Congenital erosive and vesicular dermatosis healing with reticulated supple scarring: report of three new cases and review of the literature. Pediatr Dermatol. 1998;15: 214–218.

Figure 16.21  Incontinentia pigmenti bullae on upper limb (Courtesy Dr

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INHERITED VESICULOBULLOUS DISEASE

Vesiculobullous disease

Figure 16.22  Pachyonychia congenita: tented thickening of fingernails.

A. Torrelo).

and erosions. The clinical course and scarring are characteristic and establish the diagnosis.

PACHYONYCHIA CONGENITA

Management and prognosis

Pachyonychia congenita (PC) is a rare genodermatosis in which combinations of ectodermal defects serve to distinguish two major forms: type 1 (PC-1, Jadassohn–Lewandowsky)111 and type 2 (PC-2, Jackson–Lawler).112

The treatment of this condition is supportive. Local wound care includes application of topical antibiotics and dressings until the erosions heal. There is a potential for future sweating abnormalities.106–108

INCONTINENTIA PIGMENTI Incontinentia pigmenti (IP), or Bloch–Sulzberger syndrome, is a rare multisystem ectodermal disorder characterized by cutaneous, ocular, dental, and neurological features. It is inherited as an X-linked dominant trait due to mutations or rearrangements in the gene encoding NF-kappa B essential modulator (NEMO)/I kappa B kinase-gamma (IKK gamma).109 The first stage of IP is characterized by small blisters that demonstrate eosinophils on Tzanck smear, arise in crops, and usually develop within the first postnatal week, but may take several weeks to develop (Fig. 16.21). Bullae may occur anywhere on the body, often orientated along Blaschko’s lines; they are frequently seen on the legs in a linear distribution, and usually spare the face. Each crop of blisters settles within about a week, and the vesicular phase does not normally exceed 6 months, although there are case reports of repeated blistering with infection, even up to 7 years.110 There are three other phases of IP: verrucous plaques mainly on the extremities; a distinctive pattern of hyperpigmentation lasting through to adolescence; and lastly dermal hypopigmented atrophy often oriented along Blaschko’s lines; they are frequently seen on the legs. It is not necessary that all these stages occur, and they may overlap.

109. Smahi A, Courtois G, Vabres P, et al. Genomic rearrangement in NEMO impairs NF-kappa B activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000;405:466–472. 110. Bodak N, Hadj-Rabia S, Hamel-Teillac D, et al. Late recurrence of inflammatory first-stage lesions in incontinentia pigmenti: an unusual phenomenon and a fascinating pathologic mechanism. Arch Dermatol. 2003;139:201–204.

Introduction

Clinical features Patients usually present in infancy or early childhood with specific nail changes characterized by subungual hyperkeratosis leading to wedge-shaped nails (Fig. 16.22). Palmoplantar bullae in PC, although not a constant or necessarily prominent feature, can be incapacitating (Fig. 16.23). They begin in childhood or in adults, and are more pronounced in PC-1. Hyperhidrosis, which is a common feature of PC, increases the blistering tendency which tends to be worse during the summer months. A progressive focal palmoplantar keratoderma over pressure points and sites of blistering may be incapacitating, particularly in PC-1. Oral leukokeratosis and follicular keratoses over extensor aspects of the limbs and buttocks are commonly observed in PC-1. Laryngeal involvement due to mucosal changes is also sometimes observed as hoarseness. In PC-2, oral changes are not generally seen, but affected individuals may have natal teeth. Patients with type 2 disease also often have short, sparse hair and develop steatocystoma multiplex (see Ch. 12).

Pathophysiology PC-1 results from mutations in the genes encoding keratin 16 and 6a (KRT16 and KRT6a, respectively),112,113 whereas PC-2 is the result of mutations in the keratin 17 or 6b genes (KRT17 and

111. Jadassohn J, Lewandowsky F. Pachyonychia congenita. In: Ikonographia dermatologica. Berlin: Urban & Schwarzenberg; 1906:29. 112. Jackson ADM, Lawler SD. Pachyonychia congenita: report of 6 cases in one family, with note on linkage data. Ann Eugenics. 1951;16:142–146. 113. McLean WHI, Rugg EL, Lunny DP, et al. Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet. 1995;9:273–276.

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Figure 16.23  Pachyonychia congenita: plantar bullae.

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KRT6b, respectively).112,114 Keratin intermediate filaments constitute the principal stress-bearing cytoskeletal framework within epithelial cells, and mutations within the keratin genes may be disruptive to normal filament assembly, which may lead to a weakened keratin molecule, less able to withstand stress and strain and thus predisposing to cytolysis. The bullae in PC arise within the stratum spinosum and are histologically indistinguishable from friction bullae.

Differential diagnosis The principal differential diagnosis is epidermolysis bullosa simplex, but the wide spectrum of clinical features associated with PC normally allows ready distinction.

Management and prognosis The application of 20% aluminum chloride hexahydrate in an alcoholic solution twice daily to the areas of blistering has been shown to reduce the tendency to form bullae.115 Topical keratolytics and emollients may improve the focal palmoplantar keratoderma, especially when combined with regular paring of very thickened areas. Some patients may also benefit from systemic retinoid therapy, although the dose may need careful titration to minimize skin fragility. A fine nail drill is useful to keep thickened nails flatter so that they are cosmetically more acceptable and cause less discomfort with footwear.

THE PORPHYRIAS Several of the porphyrias may present in childhood as a bullous eruption including congenital erythropoietic porphyria, por­ phyria cutanea tarda and variegate porphyria.116,117 Congenital erythropoietic porphyria (Gunther disease) is a rare, severe form of porphyria in which the clinical symptoms

114. Bowden PE, Haley JL, Kansky A, et al. Mutation of a type II keratin gene (K6a) in pachyonychia congenita. Nat Genet. 1995;10:363–365. 115. Smith FJ, Jonkman MF, van Goor H, et al. A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. Hum Mol Genet. 1998;7:1143–1148. 116. Tidman MJ, Wells RS. Control of plantar blisters in pachyonychia congenita with topical aluminium chloride. Br J Dermatol. 1988;118:451–452.

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are initially similar to PCT, with cutaneous hyperfragility, marked photosensitivity and hypertrichosis. Bullae heal with severe scarring which leads to mutilation and scleroderma-like changes. The teeth fluoresce under ultraviolet light. Erythropoietic protoporphyria usually presents at about 2 years of age. Patients develop a severe erythema in a photosensitive distribution which is extremely painful and may result in bullae. Porphyria cutanea tarda (PCT) may present in childhood. This is a mechanobullous disorder manifesting as hyperfragility of the skin, in which minor trauma results in erosions or blisters that are often hemorrhagic. The dorsa of the hands are usually affected, as is the face and occasionally elsewhere on the limbs. The blisters heal with scarring and milia formation. Hypertrichosis, especially on the forehead, is a feature of familial PCT, occurring in 50% of patients. Analysis of plasma, urinary and faecal porphyrins establishes the diagnosis. However, a bedside test is the fluorescence of a urine specimen under ultraviolet light. Similar cutaneous manifestations occur in variegate porphyria and hereditary coproporphyria (see Ch. 7). Pseudoporphyria is characterized by similar clinical features to PCT, including blistering, skin fragility, scarring, milia and photosensitivity, although without porphyrin abnormalities.118 In children, it is most commonly triggered by ingestion of nonsteroidal anti-inflammatory drugs, although chronic renal failure, dialysis and UV irradiation may also cause pseudoporphyria.119

AUTOIMMUNE VESICULOBULLOUS DISEASE All the autoimmune blistering disorders seen in adults also occur in children, but are much rarer. Accurate incidence and prevalence data are not available. The genetic basis for the majority of these conditions has yet to be established. In children, most of the autoimmune blistering disorders have certain specific features, but nonetheless, it is frequently difficult to accurately distinguish between the subepidermal autoimmune blistering conditions on the basis of their clinical, histological, and immunopathological features. While the application of sophisticated laboratory techniques such as immunoblotting and immunoelectron microscopy in the subepidermal blistering disorders has enabled characterization of the targeted autoantigens, it has also demonstrated great antigenic heterogeneity in what were previously considered to be clearly defined conditions. The boundaries between these diseases are becoming more blurred as knowledge about the target antigens increases. Immunoblotting and immunoelectron microscopy are not widely available as routine procedures. However, information about the plane of blistering can be obtained using salt-split normal human skin as the substrate in the indirect immunofluo-

117. Meola T, Lim HW. The porphyrias. Dermatol Clin. 1993;11:583–596. 118. Bickers DR, Pathak MA, Lim HW. The porphyrias. In: Freedberg IM, Eisen AZ, Wolff K, et al, eds. Dermatology in general medicine, ed 5. New York: McGraw-Hill; 1999:1766–1803. 119. Green JJ, Manders SM. Pseudoporphyria. J Am Acad Dermatol. 2001;44:100–108.

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CHRONIC BULLOUS DISEASE OF CHILDHOOD Introduction Chronic bullous disease of childhood (CBDC) is also known as linear IgA disease of childhood: early synonyms included juvenile dermatitis herpetiformis and juvenile pemphigoid. CBDC is an acquired autoimmune subepidermal blistering disorder characterized by the deposition of a linear band of IgA along the 120. Lacour JP, Bernard P, Rostain G, et al. Childhood acquired epidermolysis bullosa. Pediatr Dermatol. 1995;12:16–20. 121. Wakelin SH, Allen J, Wojnarowska F. Childhood bullous pemphigoid – report of a case with dermal fluorescence on salt-split skin. Br J Dermatol. 1995;133:615–618. 122. Nemeth AJ, Klein AD, Gould EW, et al. Childhood bullous pemphigoid. Clinical and immunologic features, treatment and prognosis. Arch Dermatol. 1991;127:378–386. 123. Coleman H, Shrubb VA. Chronic bullous disease of childhood – another cause for potential misdiagnosis of sexual abuse? Br J Gen Pract. 1997;47:507–508. 124. Collier PM, Wojnarowska F, Welsh K, et al. Adult linear IgA disease and chronic bullous disease of childhood: the association with human lymphocyte antigens Cw7, B8, DR3 and tumour necrosis factor influences disease expression. Br J Dermatol. 1999;141:867–875. 125. Bowen J. Five cases of bullous dermatitis in children following vaccination. Br J Dermatol. 1901;8:392–394. 126. Jablonska S, Chorzelski T, Beutner E, et al. Juvenile dermatitis herpetiformis in the light of immunofluorescence studies. Br J Dermatol. 1971;85:307–313.

dermal–epidermal junction: it involves both skin and, less commonly, mucous membranes. The molecular basis of CBDC has not been clearly defined and it may well represent a heterogeneous disorder. Historically, linear IgA disease (of adults) has been differentiated from CBDC although they probably represent the same entity.124 Bowen125 (1901) is generally credited with reporting the first cases of CBDC but it was not until immunohistochemistry became a routine diagnostic procedure that CBDC became defined by the presence of a strong linear band of IgA at the epidermal basement membrane, distinguishing it from dermatitis herpetiformis and bullous pemphigoid in childhood.125–129 CBDC occurs in all ethnic groups and may be more common in developing countries. The annual incidence in the UK has been estimated at 1 in 500 000 children.130 AUTOIMMUNE VESICULOBULLOUS DISEASE

rescence examination of a patient’s serum. Normal skin is cleaved within the lamina lucida of the epidermal basement membrane by 1 molar sodium chloride solution, and thus if the circulating antibody is found on the epidermal side (roof) of salt-split skin it suggests that the target antigen is either within the upper part of the lamina lucida or associated with the cell membrane or intracytoplasmic structures of the basal keratinocyte. If the circulating antibody localizes to the dermal side (floor) of the salt-split skin, the target antigen is beneath the lamina lucida, either within the lamina densa or in the sub-lamina densa zone. As an example, this simple technique can usually distinguish bullous pemphigoid from epidermolysis bullosa acquisita,120 although dermal binding of circulating antibody does occasionally occur in bullous pemphigoid.121 Suction-induced blisters are also characterized by a cleavage plane within the lamina lucida and can be used as the substrate in the same way as salt-split skin. Another simple technique to establish the cleavage plane in a blistering disorder is to map the dermo–epidermal junction with an antibody to type IV collagen (which is located in the lamina densa of the epidermal basement membrane). In bullous pemphigoid, the blister forms in the lamina lucida and thus type IV collagen will localize to the base of a natural blister, whereas in epidermolysis bullosa acquisita, where the natural blister arises within the sublamina densa zone, type IV collagen antibody will be visualized in the blister roof.122 Type IV collagen staining can be done on wax-embedded material using a commercially available antibody. All entities discussed under this heading can be confused in the early stages of the disease with more common conditions such as herpes simplex or bullous impetigo. Generalized blistering may mimic erythema multiforme or Stevens–Johnson syndrome. Perianal blistering and erosions should be differentiated from sexual abuse,123 bullous lichen sclerosus and bullous fixed drug eruption.

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Clinical features CBDC usually presents in children less than 5 years of age, although it can occur at any time during childhood. There may be a preceding prodromal illness such as an upper respiratory tract, urinary tract or viral infection. Rarely, a history of preceding vaccination or treatment with antibiotics or nonsteroidal antiinflammatory agents may be elicited. The relevance of such putative triggers remains to be established. CBDC presents abruptly with tense vesicles or bullae, occasionally with constitutional symptoms such as fever or anorexia. The lesions often arise on normal-looking skin, but occasionally occur on urticated plaques. The severity of CBDC is variable, and the bullae may be localized or widespread. They can occur on any body region, although the most common locations are the face (particularly the perioral regions), extremities, genital area and trunk.131 In the early stages of the condition, new lesions may arise around the margins of older ones, giving an appearance that has been described as the ‘string of pearls’ rosettes or ‘cluster of jewels’ sign (Fig. 16.24). The central clearing and peripheral blistering may give rise to polycyclic lesions. Pruritus when present is usually not intense, unlike that associated with dermatitis herpetiformis. Resolved bullae generally do not leave scars but may cause hyper- or hypopigmentation, especially in dark-skinned individuals. Occasionally, the lesions are large and hemorrhagic. Mucous membrane involvement is a common feature affecting up to 76% of patients,132 and may lead to scarring. The oral 127. Prystowsky S, Gilliam J. Benign chronic bullous disease of childhood. Arch Dermatol. 1976;112:837–838. 128. Esterly N, Furey N, Kirschner B, et al. Chronic bullous dermatosis of childhood. Arch Dermatol. 1977;113:42–46. 129. Van der Meer JB, Remme JJ, Nefkens MJ, et al. IgA antibasement membrane antibodies in a boy with pemphigoid. Arch Dermatol. 1977;113:1462. 130. Collier PM, Wojnarowska F. Chronic bullous disease of childhood. In: Harper J, Oranje A, Prose N, eds. Textbook of pediatric dermatology. Oxford: Blackwell Scientific; 2000:711–723. 131. Kanwar AJ, Sandhu K, Handa S. Chronic bullous dermatosis of childhood in north India. Pediatr Dermatol. 2004;21:610–612. 132. Marsden RA, McKee PH, Bhogal B, et al. A study of benign chronic bullous dermatosis of childhood and comparison with dermatitis herpetiformis and bullous pemphigoid occurring in childhood. Clin Exp Dermatol. 1980;5:159–176.

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A

B

Figure 16.24  (A,B) Chronic bullous disease of childhood (Courtesy Dr A. Torrelo).

mucous membranes are most commonly involved with erosions rather than bullae. Conjunctival involvement affects approximately 65% of children,129 causing redness and a gritty discomfort of the eyes, and subsequent conjunctival scarring that may lead to entropion and corneal damage. The genital and nasal mucous membranes may also rarely be involved.

Pathophysiology and histology CBDC is the result of a humoral response to a normal constituent of the epidermal basement membrane zone. Although the target antigen is known to be present in all human stratified squamous epithelia, it has not yet been defined with certainty. Salt-split skin studies of antibody distribution have been inconclusive and suggest that the ultrastructural localization of the target antigen may be in both the lamina lucida and sub-lamina

133. Wojnarowska F, Whitehead P, Leigh IM, et al. Identification of the target antigen in chronic bullous disease of childhood and linear IgA disease of adults. Br J Dermatol. 1991;124:157–162. 134. Zone J, Taylor T, Kadunce D, Meyer L. Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest. 1990;85:812–820.

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densa zones. Immunoelectron microscopy also suggests binding sites for the IgA antibody within the lamina lucida and beneath the lamina densa. Immunoblotting studies suggest that the IgA autoantibodies appear to recognize different target antigens, most frequently proteins with molecular weights of 97 kDa133 and 285 kDa,134 which are present on the epidermal side of salt-split skin. The 97 kDa protein most likely represents a processed form of a recently described 120 kDa anchoring filament-associated protein which may correspond to a portion of the extracellular domain of BP180 or LAD1. Some patients have had antibodies against a 290 kDa protein corresponding to type VII collagen. These studies show that CBDC is heterogeneous. Histological examination of fresh lesions is not diagnostic and does not distinguish CBDC from pemphigoid, dermatitis herpetiformis or EB acquisita. The bullae are subepidermal and associated with a neutrophil or eosinophil-rich inflammatory infiltrate. The diagnosis of CBDC relies on the immunohistochemical demonstration of a linear band of IgA along the dermal– epidermal junction. This may or may not be associated with weaker bands of IgG, IgM or C3. In the very early stages of the disease, false-negative immunohistochemical results can be obtained and the test may need to be repeated. Immunohistochemical examination requires only a small biopsy of uninvolved, preferably perilesional, skin. There may be a regional variation in the intensity of antibody deposition at the dermal– epidermal junction and the forearm is best avoided.135 A circulating IgA antibody is present in approximately 80% of children with CBDC, but is often of low titer and not sufficiently sensitive to be useful in monitoring disease activity. In contrast to dermatitis herpetiformis, CBDC is not associated with gluten-sensitive enteropathy: although there are anecdotal reports of CBDC and celiac disease coexisting, large series have not confirmed an association.130 There may be a genetic susceptibility to CBDC with an increased incidence of HLA-B8, HLA-DR3 and HLA-DQW2.

Therapy and prognosis The treatment options for CBDC include dapsone, prednisolone, sulfamethoxypyridazine, and sulfapyridine. All treatment modalities potentially have significant side-effects, that need to be weighed against the clinical severity of the condition and the fact that natural remission can be expected in the majority of patients within 5 years of onset. Mild blistering may not require systemic treatment, and the judicious short-term application of a moderately-potent or super potent topical corticosteroid may suffice. If systemic therapy proves necessary, it may be required for only a brief period, although protracted treatment may be required. A gluten-free diet confers no clinical benefit in CBDC. Dapsone is the most commonly used systemic medication in view of its neutrophilic pathology, either as a single agent or, if

135. Collier PM, Wojnarowska F, Millard PR. Variation in the deposition of the antibodies at different anatomical sites in linear IgA disease of adults and chronic bullous disease of childhood. Br J Dermatol. 1992;127:482–484.

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136. Alajlan A, Al-Khawajah M, Al-Sheikh O, et al. Treatment of linear IgA bullous dermatosis of childhood with flucloxacillin. J Am Acad Dermatol. 2006;54:652–656. 137. Siegfried EC, Sirawan S. Chronic bullous disease of childhood: successful treatment with dicloxacillin. J Am Acad Dermatol. 1998;39:797–800. 138. Skinner RB, Rotondo CK, Schneider MA, et al. Treatment of chronic bullous dermatosis of childhood with oral dicloxacillin. Pediatr Dermatol. 1995;12:65–66. 139. Powell J, Kirtschig G, Allen J, et al. Mixed immunobullous disease of childhood: a good response to antimicrobials. Br J Dermatol. 2001;144:769–774. 140. Young HS, Coulson IH. Linear Ig A: successful treatment with cyclosporin. Br J Dermatol. 2000;143(1):204–205. 141. Ang P, Tay YK. Treatment of linear IgA bullous dermatosis of childhood with colchicine. Pediatr Dermatol. 1999;16(1):50–52. 142. Wojnarowska F. Linear IgA disease of adults. In: Wojnarowska F, Briggaman RA, eds. Management of blistering diseases. London: Chapman & Hall; 1990:105–118.

allele is associated with longer disease duration124 but other major histocompatibility complex associations do not appear to affect the prognosis.

BULLOUS PEMPHIGOID Introduction Bullous pemphigoid (BP) is usually a condition of the elderly, rarely presenting in children. To date, less than 100 cases have been reported. The major clinical, histopathologic and immunologic features of childhood BP are the same as in adulthood. The autoantibodies that occur in childhood BP target the same antigenic epitopes as in the adult condition.143 BP has been recorded as early as the first few months of postnatal life, but transplacental transmission has not been recorded. The gender incidence is equal. In an effort to differentiate childhood BP from other conditions, Nemeth et al.122 proposed the following diagnostic criteria: (1) age 18 years and younger; (2) clinical appearance of tense blisters; (3) subepidermal blisters with eosinophilia; (4) linear deposits of IgG or C3 at the epidermal basement membrane zone (BMZ) on direct immunofluorescence of perilesional skin, or circulating IgG anti-BMZ autoantibodies on indirect immunofluorescence using patient serum. There have been no clearly identified triggers for childhood BP; temporal associations with vaccinations,144–146 second organ transplantation,147 hyperIgE syndrome148 and chronic renal allograft rejection149 have been reported.

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there is a large eosinophilic component, in combination with prednisolone. An appropriate starting dose for dapsone is 1 mg/ kg body weight per day, and this can be increased depending on the response. Dapsone is usually well tolerated. It is necessary to screen for glucose-6-phosphate dehydrogenase deficiency before treatment is started, especially in those racial groups particularly at risk. The full blood count, reticulocytes and liver function should be monitored for hemolysis, agranulocytosis and changes in liver function on a weekly basis for at least 1 month. Thereafter, the frequency of blood tests can gradually be reduced once the condition has been stabilized. Dapsone can also cause methemoglobinemia, detectable clinically by blue discoloration of the lips and tongue, and the introduction of cimetidine, an inhibitor of the cytochrome P450 family of enzymes, may minimize this adverse reaction. Once blistering is in remission, the dosage of dapsone can gradually be reduced; a convenient way of doing this is to give it on alternate days and continue to slowly reduce the dose. If dapsone in acceptable dosage does not control the blistering in CBDC, or if the disease continues to progress in the first few weeks after dapsone treatment has been initiated, prednisolone should be introduced, provided there are no contraindications, in a dose of 1 mg/kg body weight per day, with the dosage adjusted depending on clinical response. Once blistering is controlled, it is usually possible to taper the dosage of prednisolone and to stop it relatively quickly. Systemic antibiotics, including flucoxacillin,136 dicloxacillin137,138 and erythromycin,139 can be effective for control and may be considered as first line agents in some cases. In difficult cases, it is reasonable to consider alternative treatments, such as sulfapyridine or sulfamethoxypyridazine. These drugs are associated with potentially serious side-effects including bone marrow suppression and, in some countries, are only available on a restricted basis. There have been anecdotal reports of successful treatment of CBDC with colchicine, azathioprine and cyclosporin.140,141 Although the majority of cases of CBDC go into natural remission within 5 years of onset, the condition may progress through puberty and into adulthood. There does not appear to be a correlation between the severity of blistering and chronicity, and there are no usefully predictive clinical parameters. HLA-B8 positivity may be associated with a more favorable outcome and less risk of ocular disease.142 Ophthalmic monitoring throughout childhood and beyond is advisable. Possession of the TNF-2

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Clinical features The clinical features of childhood BP are characterized by tense, sometimes hemorrhagic bullae, arising either on normalappearing or inflamed skin. Urticarial plaques are common, and the inflammation may be in annular or polycyclic patterns. (Fig. 16.25A). The sites of blister predilection are the flexural areas, including the inner thighs, the flexural aspects of the forearms, axillae, the lower abdomen, and groin. Pruritus is variable and lesions tend to heal without scarring or milia formation. The major distinguishing features between adult and childhood disease are the more frequent involvement of the mucous membranes, acral involvement and no malignant association in childhood BP. The marked involvement of the palmar and plantar surfaces is a very striking feature of infantile-onset BP

143. Chimanovitch I, Hamm H, Georgi M, et al. Bullous pemphigoid of childhood: autoantibodies target the same epitopes within the NC16A domain of BP 180 as autoantibodies in bullous pemphigoid of adulthood. Arch Dermatol. 2000;136:527–532. 144. Cambazard F, Thivolet J, Mironneau P. Bullous pemphigoid in a 4-month-old boy. Br J Dermatol. 1994;131:449–451. 145. Oranje AP, Vuzevski VD, van Joost T, et al. Bullous pemphigoid in children. Report of three cases with special emphasis on therapy. Int J Dermatol. 1991;30:339–342. 146. Baykal C, Okan G, Sarica R. Childhood bullous pemphigoid developed after the first vaccination. J Am Acad Dermatol. 2001;44:348–350. 147. Morelli JG, Weston WL. Childhood immunobullous disease following a second organ transplant. Pediatr Dermatol. 1999;16:205–207. 148. Erbagci Z. Childhood bullous pemphigoid in association with hyperimmunoglobulin E syndrome. Pediatr Dermatol. 2008;25:28–33. 149. Yamazaki S, Yokozeki H, Katayama I, et al. Childhood bullous pemphigoid associated with chronic renal allograft rejection. Br J Dermatol. 1998;138:547–548.

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C

Figure 16.25  Bullous pemphigoid. (A) Polycyclic plaques (Courtesy Dr A. Torrelo). (B) Plantar bullae in an infant (Courtesy Dr A. Torrelo). (C) Mouth and lip involvement with BP.

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(Fig. 16.25B), and is seen in 79% of affected infants versus 17% of older children.150,151 Facial involvement is more common in childhood BP, and can sometimes be mistaken for impetigo. Involvement of the mucous membranes occurs more frequently in children than in adults, particularly the oral (Fig. 16.25C) and ocular mucous membranes. Localized vulval pemphigoid is a morphological variant of bullous pemphigoid152–154 with the target antigens being either BP180 or BP230. It is characterized by localization to the vulval region with recurrent, often hemorrhagic, bullae and painful erosions. Pruritus may be a feature. Painful micturition is usual. Lesions heal without scarring or milia formation, and no other

mucous membranes are involved. Genital involvement is rarely seen in childhood BP occurring in infancy.151

150. Trueb RM, Didierjean L, Fellas A, et al. Childhood bullous pemphigoid: report of a case with characterization of the targeted antigens. J Am Acad Dermatol. 1999;40:338–344. 151. Waisbourd-Zinman O, Ben-Amitai D, Cohen AD, et al. Bullous pemphigoid in infancy: clinical and epidemiologic characteristics. J Am Acad Dermatol. 2008;58:41–48. 152. Schumann H, Amann U, Tasanen K, et al. A child with localized vulval pemphigoid and IgG autoantibodies targeting the C-terminus of collagen XVII/BP 180. Br J Dermatol. 1999;140:1133–1138.

153. Saad RW, Domloge-Hultsch N, Yancey KB, et al. Childhood localized vulvar pemphigoid is a true variant of bullous pemphigoid. Arch Dermatol. 1992;128:807–810. 154. Farrell AM, Kirtschig G, Dalziel KL, et al. Childhood vulval pemphigoid: a clinical and immunopathological study of five patients. Br J Dermatol. 1999;140:308–312.

Pathophysiology and histology The targets of the autoantibodies in BP are two hemidesmosomeassociated proteins, BP230 and/or BP180. BP230 (bullous pemphigoid antigen 1) is an intracellular protein associated with the hemidesmosome attachment plaques. BP180 (bullous pemphigoid antigen 2, Type XVII collagen) is a transmembrane glycoprotein extending from the hemidesmosome into the lamina lucida in association with anchoring filaments.

Vesiculobullous disease

Therapy and prognosis The prognosis of childhood BP is good, and most reported cases have had a disease duration of 1 year or less, although the course may occasionally be more protracted. The initial treatment of choice has traditionally been systemic corticosteroids, starting with a dose of prednisolone of 1–2 mg/kg per day.146 Dapsone or sulfapyridine may be used as adjunctive therapy, and a combination of erythromycin and nicotinamide has been suggested as a safe alternative to oral steroids.156 Increasingly, potent topical corticosteroids are being used in the treatment of adult bullous pemphigoid,157 but it is unknown whether this is as effective in childhood BP. Systemic therapy for localized vulval pemphigoid, with prednisolone or sulfapyridine, may be required, but topical corticosteroid therapy may suffice.158

hood. Clinically, histologically and immunopathologically, there is an overlap with other autoimmune subepidermal blistering disorders, such as epidermolysis bullosa acquisita and chronic bullous disease of childhood: it has been suggested that cicatricial pemphigoid in childhood may be an unusual and more severe variant of chronic bullous disease of childhood.159

Clinical features CP can occur at any time in childhood and it may be associated with a generalized eruption involving the face, trunk and limbs, characterized by urticarial, annular, polycyclic or target-like lesions. The dominant clinical feature is the involvement of mucous membranes. Involvement of the conjunctival mucous membranes may proceed to symblepharon, entropion and corneal scarring, which may result in blindness. The oral, laryngeal, nasal, and genital mucous membranes may also be involved, and scarring is an important feature. CP may be confined to the oral cavity (oral pemphigoid). It may present in children as a desquamative gingivitis.160,161 Because of its rarity in childhood, diagnosis may be delayed.162

Pathophysiology and histology

Cicatricial pemphigoid (CP), also known as benign mucous membrane pemphigoid, is an extremely rare condition in child-

CP is heterogeneous with respect to its target antigens: it is most commonly associated with autoantibodies to BP180,163 and less frequently to laminin 5 or type VII collagen. A few patients have been described with autoantibodies to the beta 4 subunit of the α6β4 integrin.164 The usual target antigen in CP, BP180, is a transmembrane hemidesmosomal glycoprotein: epitopes on both the extra- and intracellular domains of BP180 are targeted by either IgG or IgA antibodies. Direct immunofluorescence examination usually reveals IgA and/or IgG deposited in a linear fashion at the dermal–epidermal junction. Circulating antibodies against epithelial basement membrane constituents are detected in approximately 50% of CP sera by indirect immunofluorescence. Immunoelectron microscopy reveals immunoreactants over the lower part of the lamina lucida or on the lamina densa.

155. Arechalde A, Braun RP, Calza AM, et al. Childhood bullous pemphigoid associated with IgA antibodies against BP180 or BP230 antigens. Br J Dermatol. 1999;140:112–118. 156. Wakelin SH, Allen J, Wojnarowska F. Childhood bullous pemphigoid – report of a case with dermal fluorescence on salt-split skin. Br J Dermatol. 1995;133:615–618. 157. Joly P, Roujeau J-C, Benichou J, et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med. 2002;346:321–327. 158. Guenther LC, Shum D. Localized childhood vulval pemphigoid. J Am Acad Dermatol. 1990;22:762–764. 159. Wojnarowska F, Marsden RA, Bhogal B, et al. Chronic bullous disease of childhood, childhood cicatricial pemphigoid, and linear IgA disease of adults. A comparative study demonstrating clinical and immunopathologic overlap. J Am Acad Dermatol. 1988;19:792–805.

160. Roche C, Field EA. Benign mucous membrane pemphigoid presenting as desquamative gingivitis in a 14-year-old child. Int J Paediatr Dent. 1997;7:31–34. 161. Sklavounou A, Laskaris G. Childhood cicatricial pemphigoid with exclusive gingival involvement. Int J Oral Maxillofac Surg. 1990;19:197–199. 162. Cheng YS, Rees TD, Wright JM, et al. Childhood oral pemphigoid: a case report and review of the literature. J Oral Pathol Med. 2001;30:372–377. 163. Schmidt E, Skrobek C, Kromminga A, et al. Cicatricial pemphigoid: IgA and IgG autoantibodies target epitopes on both intra- and extracellular domains of bullous pemphigoid antigen 180. Br J Dermatol. 2001;145:778–783. 164. Leverkus M, Bhol K, Hirako Y, et al. Cicatricial pemphigoid with circulating autoantibodies to beta 4 integrin, bullous pemphigoid 180 and bullous pemphigoid 230. Br J Dermatol. 2001;145:998–1004.

CICATRICIAL PEMPHIGOID Introduction

AUTOIMMUNE VESICULOBULLOUS DISEASE

The histology of bullous pemphigoid is that of a subepidermal blister with an intact overlying epidermis and no necrosis. The inflammatory infiltrate is comprised mainly of eosinophils, with some neutrophils and lymphocytes. Direct immunofluorescence examination usually reveals a linear deposition of IgG and C3, and less frequently IgM and IgA155 may be found. Indirect immunofluorescence usually, but not always, demonstrates a circulating antibody which is directed against the epidermal side of salt-split normal human skin. However, occasionally dermal binding may be observed, despite Western immunoblotting revealing an epidermal location for the target antigens.156 The titer of circulating antibody in bullous pemphigoid does not necessarily reflect the disease activity. Antigen mapping with Type IV collagen stains the base of natural blisters, confirming a cleavage plane within the lamina lucida. Immunoblotting in bullous pemphigoid shows autoantibodies directed against BP230 and/or BP180. Immunoelectron microscopy reveals deposition of autoantibody in the upper portion of the lamina lucida, closely related to the intracellular attachment plaques of the hemidesmosomes.

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Therapy and prognosis CP in childhood can clear completely, but both the cutaneous and mucous membrane involvement may persist and extend into adulthood. For those rare cases recorded, the usual treatment has consisted of systemic corticosteroids, dapsone or sulfapyridine.159 Topical corticosteroids may give symptomatic relief. Ophthalmological monitoring is mandatory when the conjunctival mucous membranes are involved.

HERPES (PEMPHIGOID) GESTATIONIS Introduction AUTOIMMUNE VESICULOBULLOUS DISEASE

Herpes (pemphigoid) gestationis (HG) is a rare autoimmune disease that develops during pregnancy or in the immediate postpartum period. Its incidence has been estimated at 1 : 50 000 pregnancies, and cutaneous involvement of the baby on delivery is uncommon, with a reported incidence of 2–10% of neonates at risk.163,165,166 The characteristic blistering of HG in the neonate is related to a peak in the transplacental transfer of anti-BP180 antibodies just before delivery.167

Clinical features Most of the reported babies with HG have had limited cutaneous involvement, but occasionally the eruption may be widespread. It is characterized by intensely pruritic urticarial plaques with tense bullae. The eruption in the neonate is self-limited and usually resolves spontaneously during the first 2 weeks after birth, rarely being evident after 3 months. The gender incidence is equal.

Therapy and prognosis Specific treatment is not normally necessary, although a moderately potent topical corticosteroid may be useful for those infants in whom there is a significant inflammatory element. The prognosis for infants with cutaneous involvement is not different from that for children without cutaneous lesions born to mothers with HG; they may be small for their gestational age, and there may be a tendency to prematurity. Lesions usually disappear spontaneously in a matter of days. The possibility of adrenal insufficiency should be considered in neonates born to mothers affected with HG who have received systemic corticosteroids for a prolonged period.

EPIDERMOLYSIS BULLOSA ACQUISITA Introduction Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal immunobullous disorder that is rare in adults and extremely rare in childhood. There is no gender or racial predilection for childhood EBA but, like most of the immunobullous disorders, there is probably a genetic susceptibility. An increased incidence of HLA-DR2 has been noted in some patients with EBA. The clinical features are variable,169 and clinical distinction from bullous pemphigoid and chronic bullous disease of childhood is not usually possible.

Clinical features

HG is the consequence of the formation of an avidly complementbinding autoantibody that usually targets BP180, and occasionally BP230.168 This IgG-class antibody readily crosses the placenta, and the development of HG in the neonate is due to passive transplacental transfer of antibody. Monitoring the circulating maternal levels of anti BP180 antibodies can assist in treatment planning, particularly for the mother.167 The histological features of the eruption are those of subepidermal edema and blistering, associated with a moderate dermal infiltrate, composed largely of eosinophils. Direct immunofluorescence examination of perilesional skin usually demonstrates a linear deposition of C3 along the epidermal basement membrane, with a linear deposition of IgG in 75% of cases. Indirect

EBA may present at any age in childhood, from 3 months onwards, and it can be very variable in its presentation.170 There are three clinical phenotypes. The first is the classic noninflammatory mechanobullous type presenting with skin fragility, blisters and erosions at sites of trauma, particularly over acral bony prominences; these heal to leave milia and atrophic scars which, especially in dark-skinned individuals, may be hypo- or hyperpigmented (Fig. 16.26). Occasionally, the nails are damaged and may become dystrophic or are shed. The second pattern is an inflammatory type of EBA which mimics other inflammatory bullous disorders, such as bullous pemphigoid and chronic bullous disease of childhood. Pruritic tense bullae, which may become hemorrhagic, arise on normal, erythematous or urticarial skin. These lesions form erosions and crusts, sometimes leaving pigmentary change, but usually without scarring. Involvement of the mucous membranes is frequent and at times may

165. Chen SH, Chopra K, Evans TY, et al. Herpes gestationis in a mother and child. J Am Acad Dermatol. 1999;40:847–849. 166. Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol. 1999;24: 255–259. 167. Aoyama Y, Asai K, Hioki K, et al. Herpes gestationis in a mother and newborn: immunoclinical perspectives based on a weekly follow-up of the enzyme-linked immunosorbent assay index of a bullous pemphigoid antigen noncollagenous domain. Arch Dermatol. 2007;143:1168–1172.

168. Ghohestani R, Nicolas JF, Kanitakis J, et al. Pemphigoid gestationis with autoantibodies exclusively directed to the 230-kDa bullous pemphigoid antigen (BP230Ag). Br J Dermatol. 1996;134:603–604. 169. Arpey CJ, Elewski BE, Moritz DK, et al. Childhood epidermolysis bullosa acquisita. Report of three cases and review of the literature. J Am Acad Dermatol. 1991;24:706–714. 170. Edwards S, Wakelin SH, Wojnarowska F, et al. Bullous pemphigoid and epidermolysis bullosa acquisita: presentation, prognosis, and immunopathology in 11 children. Pediatr Dermatol. 1998;15:184–190.

Pathophysiology and histology

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immunofluorescence examination may reveal a circulating IgG antibody which localizes to the epidermal side of salt-split skin.

Vesiculobullous disease

subsequent milia and scarring.

be severe. The oral, genital, conjunctival and urethral mucous membranes may all be involved. This type may closely mimic chronic bullous disease of childhood when the perioral, periorbital and genital regions develop an annular eruption.171,172 The third clinical variant is a type resembling cicatricial pemphigoid, defined by predominantly mucous membrane involvement and a pronounced tendency to scarring. The involvement of oral, conjunctival, nasal, esophageal, laryngeal and genital mucous membranes in children may lead to a variety of complications including malnutrition, symblepharon of the conjunctivae which may progress to blindness,173 and stenosis of the esophagus, urethra or genital tract. In its clinical course, EBA may progress from a noninflammatory mechanobullous to an inflammatory pattern. Childhood onset EBA differs from the adult condition in that it tends to be more commonly inflammatory in presentation, to have an almost universal mucosal involvement and to respond more quickly to systemic therapy.174 In adults, EBA is associated with a variety of internal disorders, including inflammatory bowel disease, diabetes mellitus, lymphomas and autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus and thyroiditis. In children such associations have not been recorded.

Pathophysiology and histology EBA is characterized by the formation of autoantibodies to type VII collagen; the morphological expression is of anchoring fibrils in the sub-lamina densa region of the epidermal basement membrane. Tissue-bound antibody is assumed to activate the complement system which results in the recruitment of inflammatory cells and subsequent separation of the epidermis from the dermis, with the cleavage plane immediately beneath the

171. Inauen P, Hunziker T, Gerber H, et al. Childhood epidermolysis bullosa acquisita. Br J Dermatol. 1994;131:898–900. 172. Park SB, Cho KH, Youn JL, et al. Epidermolysis bullosa acquisita in childhood – a case mimicking chronic bullous dermatosis of childhood. Clin Exp Dermatol. 1997;22:220–222. 173. Caux F, Kirtschig G, Lemarchand-Venencie F, et al. IgA-epidermolysis bullosa acquisita in a child resulting in blindness. Br J Dermatol. 1997;137:270–275. 174. Mayuzumi M, Akiyama M, Nishie W, et al. Childhood epidermolysis bullosa acquisita with autoantibodies against the noncollagenous 1 and 2

lamina densa of the dermal–epidermal junction. Western immunoblotting of sera from patients with EBA shows the circulating antibody to react with a 290 kDa protein (the ‘EBA antigen’) and its breakdown product of 145 kDa in a dermal extract of normal human skin. Histological examination of a fresh lesion reveals a subepi­ dermal bulla with a predominantly neutrophilic inflammatory infiltrate, admixed with eosinophils. Direct immunofluorescence examination of perilesional skin typically reveals a linear deposition of IgG and C3 along the basement membrane zone, and occasionally there is also weak staining for IgA and IgM. Very occasionally, IgA may be the predominant immunoreactant.173 Indirect immunofluorescence examination is usually positive in EBA and the circulating antibody labels the dermal side of the bulla in salt-split normal human skin.120 Direct immunoelectron microscopy reveals IgG deposits under the lamina densa, within the region normally occupied by anchoring fibrils.

AUTOIMMUNE VESICULOBULLOUS DISEASE

Figure 16.26  EBA in an adolescent: skin fragility involving knuckles, with

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Differential diagnosis The differential diagnosis of EBA is wide and includes other autoimmune blistering disorders including bullous pemphigoid, chronic bullous disease of childhood, cicatricial pemphigoid, pemphigus vulgaris and dermatitis herpetiformis. Bullous systemic lupus erythematosus can also present with a similar clinical picture; the presence of antinuclear antibody will distinguish between the two. Stevens–Johnson syndrome and inherited forms of porphyria should also be considered, as well as infectious disorders such as herpes simplex and bullous impetigo. EBA may develop during infancy175 and must then be distinguished from dystrophic epidermolysis bullosa.

Therapy and prognosis The long-term prognosis for EBA in children is much better than in adults, with childhood EBA usually undergoing remission within 1–4 years, although occasionally its course can be more protracted. While EBA in adults tends to be resistant to treatment, the childhood form of EBA is much more responsive. A combination of prednisolone and dapsone is the best form of therapy for childhood EBA.176 A reasonable commencing dose of prednisolone is 1 mg/kg per day, and for dapsone 2 mg/kg per day. Remission is usually quick, within a matter of weeks and, once this is attained, it is standard practice to gradually taper off prednisolone therapy and then to gradually taper the dose of dapsone. Resistant cases may require larger doses of pred­ nisolone and dapsone. Alternative therapies include the use of sulfapyridine, a combination of nicotinamide and erythromycin,

domains of type VII collagen: case report and review of the literature. Br J Dermatol. 2006;155:1048–1052. 175. McCuaig CC, Chan LS, Woodley DT, et al. Epidermolysis bullosa acquisita in childhood. Differentiation from hereditary epidermolysis bullosa. Arch Dermatol. 1989;125:944–949. 176. Callot-Mellot C, Bodemer C, Caux F, et al. Epidermolysis bullosa acquisita in childhood. Arch Dermatol. 1997;133:1122–1126.

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Pathophysiology and histogenesis

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Figure 16.27  Bullous systemic lupus erythematosus. and for localized disease a superpotent topical steroid may suffice.

The target antigen in BSLE has been shown in a number of cases to be type VII collagen, with Western immunoblotting studies against extracts of human dermis showing that the circulating antibodies bind to the 290 kDa and 145 kDa dermal proteins that represent the EBA antigens. Antibodies to type VII collagen are not always present in BSLE patients and it is possible in some cases that autoantibodies are produced to a variety of other molecules that may be involved in dermal–epidermal adhesion, such as bullous pemphigoid antigen 1 (BP230), laminin 5 and laminin 6.180 When type VII collagen is the target antigen, the circulating antibody may recognize various epitopes on the noncollagenous domain. BSLE is characterized by a subepidermal blister with a neutrophil-predominant inflammatory infiltrate within the upper dermis. Direct immunofluorescence examination of lesional skin shows IgG and complement deposition along the epidermal basement membrane, with occasional weaker staining with IgA and/or IgM. The immunoreactants along the basement membrane zone may have a granular or linear pattern. Indirect immunofluorescence examination on salt-split skin usually shows antibody localization to the dermal side. Ultrastructural examination shows immune deposits on or beneath the lamina densa of the dermal–epidermal junction.

BULLOUS SYSTEMIC LUPUS ERYTHEMATOSUS Introduction

Therapy and prognosis

Systemic lupus erythematosus has been reported in association with pemphigus vulgaris, bullous pemphigoid, dermatitis herpetiformis and epidermolysis bullosa acquisita. However, the term bullous systemic lupus erythematosus (BSLE) is used to describe an acquired autoimmune subepidermal blistering disorder in an individual fulfilling the criteria of the American Rheumatism Association for systemic lupus erythematosus. BSLE is likely to be a heterogeneous group of diseases, and it may be that in SLE there is a genetic predisposition to form antibodies to constituents of the dermal–epidermal junction that are critical for maintaining epidermal–dermal adhesion.177 It can manifest during the course of, or as the initial presentation of SLE. BSLE is an unusual condition, and it has only rarely been reported in children.178,179

The treatment of choice for BSLE is dapsone, and the blistering tendency usually responds quickly. The prognosis is good, and remission the norm. However, the ultimate prognosis depends on the degree of internal organ involvement by the underlying systemic lupus erythematosus.

Clinical features BSLE usually presents as a chronic, widespread, itchy, nonscarring bullous eruption, with tense blisters arising on normal or urticated skin (Fig. 16.27). The distribution normally includes sun-exposed areas, but non-exposed sites can also be involved. Milia and pigmentary change may or may not be seen, but there is no skin fragility. Mucous membrane involvement, including the oral, nasal and genital mucous membranes, may occur.

177. Yell JA, Allen J, Wojnarowska F, et al. Bullous systemic lupus erythematosus: revised criteria for diagnosis. Br J Dermatol. 1995;132:921–928. 178. Kettler AH, Bean SF, Duffy JO, et al. Systemic lupus erythematosus presenting as a bullous eruption in a child. Arch Dermatol. 1988;124:1083–1087. 179. Shirahama S, Furukawa F, Yagi H, et al. Bullous systemic lupus erythematosus: detection of antibodies against noncollagenous domain of type VII collagen. J Am Acad Dermatol. 1998;38:844–848.

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PEMPHIGUS Introduction Pemphigus is a group of autoimmune intraepidermal vesiculo­ bullous diseases, characterized by loss of contact between keratinocytes (acantholysis) as the result of formation of autoantibodies to desmosomal proteins. There are two main forms of pemphigus: the suprabasal type, which includes pemphigus vulgaris (PV) and pemphigus vegetans which are usually associated with mucous membrane involvement, and a superficial type, which includes pemphigus foliaceus (PF) and pemphigus erythematosus, in which mucous membrane involvement is not a prominent feature. Pemphigus is rare in childhood: the commonest form is PV, followed by PF, with pemphigus vegetans181 and erythematosus182 both being very rare. All the clinical variants that occur in adulthood have been recorded in children, including the para-

180. Chan LS, Lapiere JC, Chen M, et al. Bullous systemic lupus erythematosus with autoantibodies recognizing multiple basement membrane components, bullous pemphigoid antigen I, laminin-5, laminin-6, and type VII collagen. Arch Dermatol. 1999;135:569–573. 181. Wananukul S, Pongprasit P. Childhood pemphigus. Int J Dermatol. 1999;38:29–35. 182. Lyde CB, Cox SE, Cruz PD. Pemphigus erythematosus in a five-year-old child. J Am Acad Dermatol. 1994;31:906–909.

Vesiculobullous disease

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the differential diagnosis of mucosal blistering in both adults and children (Fig. 16.29).

Pathophysiology and histology

neoplastic form. The sex incidence is equal, and the mean age of onset of pemphigus in childhood is 12 years.183 There appears to be a genetic susceptibility, and a number of environmental factors which cause the disease to develop. Certain drugs, such as penicillamine, captopril, enalapril and rifampicin, may precipitate pemphigus,184 and there is a possibility that a number of acantholytic substances, such as thiolcontaining molecules, phenols and tannins in plant foods, may play a role in the initiation and maintenance of the disease.185 In addition, there is a form of superficial pemphigus, fogo selvagem, that is endemic in certain rural and developing regions of Brazil. Fogo selvagem occurs mainly in children who live in close proximity to rivers and the distribution of this condition coincides approximately with the habitat of the blackfly, Simulium nigrimanum,185,186 which may be a vector in disease transmission.

Pemphigus vulgaris Clinical features The clinical presentation of PV in children is similar to that in adults. The disintegrating epidermis that characterizes pemphigus cannot withstand hydrostatic pressure, and the blisters in PV are usually flaccid and quickly rupture, leaving painful and persistent erosions and crusts (Fig. 16.28). Nikolski’s sign is positive. Because of the superficial nature of the pathological process, scarring is not usually a feature of PV, but it may occur secondary to infection or excoriation. In PV, involvement of the mucous membranes, particularly those of the mouth, is common and may be the presenting feature. Genital and ocular mucous membrane involvement occurs less frequently than oral involvement. PV should be in

183. Bjarnason B, Flosadottir E. Childhood, neonatal and stillborn pemphigus vulgaris. Int J Dermatol. 1999;38:680–688. 184. Thami GP, Kaur S, Kanwar AJ. Severe childhood pemphigus vulgaris aggravated by enalapril. Dermatology. 2001;202:341. 185. Tur E, Brenner S. Diet and pemphigus. In pursuit of exogenous factors in pemphigus and fogo selvagem. Arch Dermatol. 1998;134:1406–1410. 186. Santi CG, Sotto MN. Immunopathologic characterization of the tissue response in endemic pemphigus foliaceus (fogo selvagem). J Am Acad Dermatol. 2001;44:446–450.

AUTOIMMUNE VESICULOBULLOUS DISEASE

Figure 16.28  Pemphigus vulgaris: flaccid bullae.

There is still controversy surrounding the nature of the target antigens in pemphigus, although the evidence points to antidesmoglein antibodies as having a central role in the pathogenesis of both the superficial and suprabasal forms.187 Desmogleins are structural components of desmosomes, and in PV the humoral response is to desmogleins 1 and 3; antibodies to both of these desmosomal constituents seem to be necessary to induce suprabasal acantholysis. However, there may be other autoantibodies, perhaps acting in concert with anti-desmoglein anti­ bodies, such as anti-acetylcholine receptor antibodies, that are also important.188 In PV, the histological changes are those of acantholysis, with individual keratinocytes often seen floating in the suprabasal cleavage plane, and the basal keratinocytes remaining attached to the epidermal basement membrane, resembling a ‘row of tombstones.’ There is usually a dermal infiltrate consisting of lymphocytes, neutrophils and eosinophils. Direct immunofluorescence examination of involved or peri­ lesional skin, in both suprabasal and superficial forms of pemphigus, reveals deposition of IgG around keratinocytes, giving a characteristic ‘chicken wire’ or ‘crazy paving’ pattern. C3 may also be present in a pericellular distribution. More than one biopsy may occasionally be necessary to demonstrate the characteristic histology and immunofluorescence.187 Indirect immunofluorescence examination of serum from affected individuals usually confirms the presence of circulating antibody, and the titer correlates with clinical severity and can be used to monitor progress during treatment.

Treatment and prognosis The prognosis for PV in childhood may be better than for the adult disease. The mortality is less and it is rarely fatal.183 The side-effects from systemic corticosteroid therapy contribute to morbidity, especially the possibility of infections such as pneumonia and septicemia. The mainstay of treatment for PV in childhood is systemic corticosteroid therapy, given either orally or as intravenous pulses. A commencing dose of prednisolone between 1 and 2 mg/kg per day is standard, although this may need to be increased depending on response. As the condition comes under control, the dose of prednisolone should be tapered as quickly as possible, and consideration given to an alternating day regimen. The use of potent topical or intralesional corticosteroid preparations should be considered for isolated recalcitrant foci of persistent blistering. Topical corticosteroid therapy may enable reduced systemic doses of corticosteroids. Dapsone has been advocated as a steroid-sparing measure,189 and other steroid-sparing drugs that have been used in the treat-

187. Stanley JR, Nishikawa T, Diaz LA, et al. Pemphigus, is there another half of the story? J Invest Dermatol. 2001;116:489–490. 188. Grando SA, Pittelkow MR, Shultz LD, et al. Pemphigus: an unfolding story. J Invest Dermatol. 2001;117:990–994. 189. Bjarnason B, Skoglund C, Flosadottir E. Childhood pemphigus vulgaris treated with dapsone: a case report. Pediatr Dermatol. 1998;15:381–383.

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A

B

AUTOIMMUNE VESICULOBULLOUS DISEASE

C

Figure 16.29  (A) Oral lesions of pemphigus vulgaris. (B,C) Pemphigus vulgaris on the back of a child.

ment of childhood pemphigus include azathioprine,181 metho­ trexate,181 cyclophosphamide,183 hydroxychloroquine190 and intramuscular gold.183 In cases that are particularly resistant to therapy, the possibility of pulsed intravenous corticosteroid therapy, with or without plasmapheresis, should be considered.183 It remains to be seen whether dietary manipulation, excluding foods with potentially acantholytic constituents, has a role to play in the control of PV.

Pemphigus foliaceus (PF) PF, also known as superficial pemphigus, is rarely seen in children. The recognized target antigen is desmoglein-1, a transmembrane desmosomal protein. There are two major categories of PF: the endemic form, fogo selvagem; and a non-endemic form, which is rarely seen in children. The average age of presentation of the non-endemic form is 7.7 years.190 The scalp and face are the most common sites of involvement. The etiology of the non-endemic form is unknown but certain drugs have been implicated in the adult form of the disease.

190. Metry D, Hebert AA, Jordon RE. Nonendemic pemphigus foliaceus in children. J Am Acad Dermatol. 2002;46:419–422.

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Clinical features The blister roof in the superficial forms of pemphigus is too thin to allow significant fluid accumulation within the cleavage plane so the lesions are usually an erythematosquamous with perhaps very superficial erosions sometimes resembling an exfoliative dermatitis (Fig. 16.30).181 Arcuate, circinate or polycyclic lesions, commonly on the head and neck, may be seen,190 and may easily be mistaken for impetigo. Scarring is not a feature.

Pathophysiology and histology In PF and fogo selvagem the antibody response is to desmoglein 1, a 160 kDa constituent of desmosomes at the level of the stratum granulosum, and desmoglein inactivation at this level is considered to be responsible for the subcorneal cleavage plane. In superficial forms of pemphigus, the degree of acantholysis may be subtle. Direct immunofluorescence shows deposition of IgG around keratinocytes. Additionally, in pemphigus erythema-

Vesiculobullous disease

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Paraneoplastic pemphigus Paraneoplastic pemphigus associated with Castleman’s tumor has been recorded in a child.192,193 This case mimicked Stevens– Johnson syndrome and responded to tumor resection and immunosuppressive therapy. Indirect immunofluorescence using rodent bladder epithelium was positive and immunoblotting studies showed the presence of antibodies to epidermal antigens with molecular weights of 190, 210, 230 and 250 kDa. Prognosis is guarded.

DERMATITIS HERPETIFORMIS Introduction and historical note

tosus, there is usually a linear deposition of IgG or IgM at the epidermal basement membrane zone.

Differential diagnosis PF may present as an exfoliative dermatitis, and impetigo, seborrheic dermatitis, psoriasis and staphylococcal scalded skin syndrome may also be mistaken for PF. It is most commonly mistaken for impetigo.

Clinical features

In women with active PV183 and PF,192 the possibility of the fetus developing the disease as the result of transplacental passage of circulating maternal antibodies must be considered. Maternal PV is sometimes associated with stillbirth, but the prognosis is excellent for both neonatal PV and PF, the bullae resolving spontaneously in neonates within a week or two. A high titer of circulating pemphigus antibody in the maternal circulation prior to delivery may forewarn of neonatal involvement.

The cutaneous lesions of DH in childhood resemble those in the adult condition, with intensely pruritic vesicles and erythematous papules, sometimes associated with urticarial plaques. Symmetrical involvement of the extensor surfaces of the limbs, buttocks, shoulders, nape of neck and scalp is characteristic. Vesicles are often excoriated as soon as they develop and blistering may therefore not be evident. Scarring of the skin is not a particular feature, but may occur as a result of excoriation or secondary infection. Mucous membrane involvement is not a feature of DH. Childhood DH may present with other clinical signs such as the presence of non-pruritic inflammatory papules197 or the development of pruritic palmar purpuric macules and papules.198 The latter presentation is associated with extravasated red blood cells, but with the typical histologic and immunofluorescence characteristics of DH. Gluten-sensitive enteropathy (subclinical or clinical) is present in almost all children with DH.199 If investigated, most of these children will have a degree of villous atrophy of the small intestine, either partial or subtotal. In most instances, the gluten-

191. Connelly EA, Aber C, Kleiner G, et al. Generalized erythrodermic pemphigus foliaceous in a child successful response to Rituximab treatment. Pediatr Dermatol. 2007;24(2):172–176. 192. Avalos-Diaz E, Olague-Marchan M, Lopez-Swiderski A, et al. Transplacental passage of maternal pemphigus foliaceus autoantibodies induces neonatal pemphigus. J Am Acad Dermatol. 2000;43:1130–1134. 193. Lemon MA, Weston WL, Huff JC. Childhood paraneoplastic pemphigus associated with Castleman’s tumour. Br J Dermatol. 1997;136:115–117. 194. Duhring LA. Dermatitis herpetiformis. JAMA. 1884;3:225. 195. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North

American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2005;40:1–19. 196. Weston WL, Morelli JG, Huff JC. Misdiagnosis, treatments and outcomes in the immunobullous diseases in children. Pediatr Dermatol. 1997;14: 264–272. 197. Woollons A, Darley CR, Bhogal BS, et al. Childhood dermatitis herpetiformis: an unusual presentation. Clin Exp Dermatol. 1999;24:283–285. 198. McGovern TW, Bennion SD. Palmar purpura: an atypical presentation of childhood dermatitis herpetiformis. Pediatr Dermatol. 1994;11:319–322. 199. Reunala TL. Dermatitis herpetiformis Clin Dermatol. 2001;19:728–736.

Treatment and prognosis The prognosis for PF is good. Treatment is the same as for PV, but PF is a milder condition and topical corticosteroid therapy may suffice. There has been a report of the use of Rituximab in a child with severe PF.191

Neonatal pemphigus

AUTOIMMUNE VESICULOBULLOUS DISEASE

Figure 16.30  Pemphigus foliaceous in a girl (Courtesy Dr A. Torrelo).

Dermatitis herpetiformis (DH) is a chronic autoimmune blistering disorder, the clinical features of which were defined in a seminal description by Duhring in 1884.194 While its exact prevalence is unknown, DH represents one of the most common autoimmune blistering disorders in childhood.195,196 In children, the sex incidence appears equal, whereas in adults it is more common in males. It may be more common in Europe (particularly in Spain) than in North America and it is unusual in children of African and Asian descent. It has been reported as occurring in a child as young as 10 months, but it can present at any time during childhood, with some sources indicating that its most common presentation is between 2 and 7 years,181 and others that the mean age is 14 years.196

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sensitive enteropathy is asymptomatic at the time of presentation, and, generally, clinical symptoms are relatively mild. Approximately 40% of children with DH have a history of chronic or relapsing diarrhea before a diagnosis of DH is made,200 and in only 10% is there a diagnosis of celiac disease at presentation.

Pathophysiology and histology

INFECTIONS

Although DH is a rare condition in childhood, it may be overdiagnosed if only the clinical features are considered;196 therefore, pathological confirmation is mandatory. The classic histologic picture is that of a subepidermal blister with neutrophilic (and occasionally eosinophilic) microabscesses within the dermal papillae. Fibrin deposition is common. The pathognomonic diagnostic feature is the presence, on direct immunofluorescence examination of perilesional skin, of a granular deposition of IgA within the dermal papillae, occasionally accompanied by C3. The principal target antigen is epidermal transglutaminase.201 False-negative results can occur if skin at distant sites from the blistering, rather than perilesional skin is taken for direct immunofluorescence.196 Clinical suspicion of DH should prompt measurement of the circulating IgA autoantibody to tissue transglutaminase (TTG): this is the target antigen in celiac disease and the titer reflects the degree of abnormality in the jejunal mucosa,195 and can be used to monitor the response to treatment or recurrence of the disease. False negative testing can occur in IgA-deficient individuals, and thus requests for celiac serology should be accompanied by measurement of the IgA levels: in these cases negative testing should be followed by an intestinal biopsy.

Differential diagnosis DH may be mistaken for a variety of pruritic conditions, including acute or subacute eczema, insect bite reactions, scabies, pityriasis lichenoides et varioliformis acuta and polymorphic light eruption and neurotic excoriations.

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mated.200 The main side-effects of dapsone are agranulocytosis and hemolysis, and it is recommended that the full blood count and reticulocyte count be checked weekly for 4 weeks after commencing dapsone, and then monthly for the next 5 months. Thereafter, the frequency can be reduced to 3-monthly. Methemoglobinemia may occur with higher dapsone doses, but this rarely requires treatment in childhood. Cimetidine may offer protection. As in the adult disease, the response to dapsone is very quick, but relapse is rapid if the dapsone is stopped. Once control of the disease has been obtained, the dosage of dapsone should be tapered either by reducing the daily dose, perhaps down to 0.125–0.5 mg/kg per day, or increasing the time between doses; control may be possible with as little as a single weekly dosage. If the child is on a gluten-free diet, it may be possible to stop dapsone completely and quickly. If there are unacceptable side-effects with dapsone, sulfa­ pyridine and sulfamethoxypyridazine are possible alternatives, although these may not be available in every country: furthermore, there may be some cross-reaction with dapsone regarding side-effects. The use of superpotent topical corticosteroids for short periods may be considered as a dapsone-sparing measure. The prognosis for childhood DH is unclear. Short and long remissions are possible, but remission in childhood may be followed by recurrence in adolescence or young adulthood. Until the ideal duration of a gluten-free diet has been established, it should be considered indefinite. Untreated celiac disease and DH have been associated with an increased risk of lymphoma. Although not as high as previously reported, the current standardized incidence ratio for cancer is 1.2.202

INFECTIONS A number of cutaneous infections can present with blistering and should be considered in the differential diagnosis of vesiculo-bullous disorders.

Therapy and prognosis

HERPES SIMPLEX VIRUS (HSV) INFECTION

The mainstays of treatment are dapsone and a gluten-free diet. A gluten-free diet alone causes reversal of the intestinal abnormality in 100% of cases and the disappearance of cutaneous lesions in 82%.200 It should be anticipated that skin lesions may take up to 1–3 months of gluten-free diet before complete resolution. Even occasional episodes of small amounts of gluten in the diet might cause a flare-up of the cutaneous disease. Dapsone alone is an effective treatment for the eruption, but does not affect the gastrointestinal abnormality. The standard initial dose of dapsone in childhood is 0.5–2 mg/kg per day.197 The sideeffects of dapsone have been discussed above (see ‘Chronic bullous disease of childhood’). In order to minimize the risk of hemolysis at the onset of therapy, it is recommended that the circulating level of glucose-6-phosphate dehydrogenase be esti-

Primary HSV infection usually presents in childhood as a gin­ givostomatitis, with vesicles occurring in the mouth and on the perioral region, sometimes associated with malaise and fever. Vesicles on the mucous membranes progress to painful ulcers, usually with regional lymphadenopathy, halitosis and excessive drooling. Autoinoculation may result in short- and long-term blistering of the hands and genital regions. Recrudescent HSV infection occurs on the lips and adjacent face, although other body regions may be involved. Progression through vesicular, pustular and crusted phases is the rule and healing takes place within 2 weeks. HSV infection in neonates carries with it the risk of herpes encephalitis, and appropriate early antiviral treatment greatly reduces morbidity and mortality.

200. Ermacora E, Prampolini L, Tribbia G, et al. Long-term follow-up of dermatitis herpetiformis in children. J Am Acad Dermatol. 1986;15:24–30. 201. Sardy M, Karpati S, Merkl B, et al. Epidermal transglutaminase (Tgase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med. 2002;195: 747–757.

202. Askling J, Linet M, Gridley G, et al. Cancer incidence in a populationbased cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology. 2002;123:1428–1435.

Vesiculobullous disease

Chickenpox is caused by the varicella zoster virus and is a very common childhood exanthem. It is associated with a prodrome of variable severity and characterized by pruritic vesicles, occurring in crops over approximately 1 week, which progress to pustules and then crusts. Secondary bacterial infection is a common complication. Herpes zoster can occur in both immunocompetent and immunocompromised children. If chickenpox is acquired by the mother after the 20th week of pregnancy, there is a risk to the infant of acquiring herpes zoster in the first year of life.203 If a child develops varicella in the first year of life they have a good chance of acquiring herpes zoster by ten years.

STAPHYLOCOCCAL SCALDED SKIN SYNDROME AND BULLOUS IMPETIGO Introduction and historical note Staphylococcal scalded skin syndrome (SSSS) was described more than a century ago by von Rittershain207 and is sometimes known as Ritter’s disease. It is only very recently that a firm understanding of the pathogenesis has developed. SSSS is a toxin-mediated epidermolytic bullous disease caused by Staphylococcus infection, which usually affects infants and young children. SSSS can also occur, much less commonly, in adults who frequently have a predisposing condition such as immunosuppression, renal impairment or overwhelming sepsis, although SSSS has been described in healthy immunocompetent adults.

HAND, FOOT AND MOUTH DISEASE

Clinical features

Hand, foot and mouth disease is caused by Coxsackie virus A16 and tends to occur in epidemics. Flaccid vesiculopustules arise in the mouth and on the palms and soles, progressing to erosions and ulcers, sometimes associated with a mild prodrome of fever and anorexia. Healing occurs uneventfully. An epidemic of hand, foot, and mouth disease caused by entero­ virus 71 resulted in many fatalities from neurological com­ plications and severely handicapped survivors.204 Enterovirus 71 has also been associated with an outbreak of hand, foot and mouth disease with severe pulmonary edema and a high mortality.205

The severity of SSSS varies from localized blistering to erythroderma and generalized desquamation. The localized form of SSSS (bullous impetigo) is characterized by the development of fragile flaccid blisters, as the thin roof, comprised only of the stratum corneum and a few cells of the stratum granulosum, cannot withstand significant hydrostatic pressure. The bullae contain clear, cloudy or frankly purulent fluid, with normal surrounding skin and the child is systemically well. Generalized SSSS presents in young children mainly under 5 years, with mild systemic symptoms that include rhinitis, conjunctivitis, fever, irritability, malaise and appetite suppression. This is followed by the development of erythema, which can affect all body regions but has a predilection for the flexures. The skin is extremely tender and the child is very irritable. The next phase of the disease is the development of extensive superficial bullae which rapidly become deroofed revealing large areas of raw, red, moist skin, with an appearance similar to a hot water scald. Nikolski’s sign is positive. The mucous membranes are not usually involved. The primary focus of staphylococcal infection is often not apparent in SSSS, but the umbilical, perianal and nasal area usually harbor the Staphylococcus. With appropriate treatment, the fever usually subsides rapidly, bullae formation ceases and the erythema gradually subsides. In the majority of cases, complete recovery occurs within 2 weeks, leaving no permanent sequelae.

CELLULITIS Bullous change superimposed on cellulitis is usually associated with Streptococcus pyogenes or Staphylococcus aureus infection.

BLISTERING DACTYLITIS Blistering dactylitis is caused by infection with a β hemolytic streptococcus and is characterized by a distinctive blistering of the volar aspects of the fingers and palms. Incision and drainage of tense bullae and a course of oral phenoxymethyl penicillin or erythromycin is the treatment of choice.

SCABIES Scabies infestation in young children may be associated with vesiculopustules, chiefly of the hands and feet. Rarely, scabies may mimic bullous pemphigoid.206

203. Kurlan JG, Connelly BL, Lucky AW. Herpes zoster in the first year of life following postnatal exposure to varicella-zoster virus: four case reports and a review of infantile herpes zoster. Arch Dermatol. 2004;140(10):1268– 1272. 204. Huang CC, Lin CC, Chang YC, et al. Neurologic complications in children with enterovirus 71 infection. N Engl J Med. 1999;341:936–942. 205. Wang SM, Liu CC. Enterovirus 71: epidemiology, pathogenesis and management. Expert Rev Anti Infect Ther. 2009;7(6):735–742. 206. Shahab RK, Loo DS. Bullous scabies. J Am Acad Dermatol. 2003;49:346–350.

INFECTIONS

CHICKENPOX (VARICELLA)

16

Pathophysiology and histogenesis SSSS is the result of the action of staphylococcal exfoliative toxins208,209 produced by infection with certain strains of Staphylococcus aureus. The toxins are serine proteases, and their specific substrate is desmoglein 1, a desmosomal intercellular adhesion

207. Ritter von Rittershain G. Die exfoliativa Dermatitis jungerer Sauglinge. Zentralzeit Kinderheilkd. 1878;2:3–23. 208. Ladhani S, Joannou CL, Lochrie DP, et al. Clinical, microbial, and biochemical aspects of the exfoliative toxins causing staphylococcal scalded-skin syndrome. Clin Microbiol Rev. 1999;12:224–242. 209. Nishifuji K, Sugai M, Amagai M. Staphylococcal exfoliative toxins: ‘molecular scissors’ of bacteria that attack the cutaneous defense barrier in mammals. J Dermatol Sci. 2008;49:21–31.

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REACTIVE BLISTERING DISORDERS

molecule that is located in the epidermis, in the region of the stratum granulosum. The impaired intercellular adhesion and consequent blister formation that characterizes SSSS is the result of a very specific proteolytic cleavage of desmoglein 1 by the staphylococcal exfoliative toxins, which reach the skin via the bloodstream.210–212 Desmoglein 1 is also the target antigen of the autoantibody produced in pemphigus foliaceus in which blisters occur at exactly the same level as in SSSS. The epidemiology and clinical features of SSSS may be, at least partially, explained by the serotypes of the exfoliative toxins and the presence of neutralizing antibodies to them.208,213 Breastfeeding may confer protection against SSSS in neonates as a result of transfer of antibodies in breastmilk.208 The presence of antibodies may also determine the pattern of infection and may explain why the bullae of bullous impetigo contain staphyloco­ ccal organisms whereas the contents of the blisters of widespread SSSS are usually sterile. The diagnosis of SSSS is supported by the characteristic clinical picture, the demonstration of an exfoliative toxin-producing strain of S. aureus and the confirmation of a histological cleavage plane at the level of the stratum granulosum. In practice, the staphylococcal infection may be covert. Swabs should be taken for bacteriological culture from the nostrils, nasopharynx, conjunctivae, umbilical area and the anus. In generalized SSSS the skin is usually sterile but, if there is clinical suspicion of secondary infection, swabs for culture from the skin should be taken. Phage typing of the staphylococcus is not considered sufficiently sensitive or specific to be a diagnostic criterion for SSSS.208 At present the reliable, convenient and rapid detection of exfoliative toxins is not available. The diagnosis is usually based on the characteristic clinical picture; biopsy is not necessary. If there is diagnostic doubt, a simple procedure involves obtaining a tissue sample by removing a small piece of the sloughed skin with scissors, snap-freezing it in liquid nitrogen and cutting frozen sections. It is painless, does not require local anesthetic and provides a rapid result, usually within 1 h, effectively distinguishing SSSS from toxic epidermal necrolysis. In SSSS the exfoliating skin consists of stratum corneum and a few cell layers of the stratum granulosum, whereas in toxic epidermal necrolysis the roof of the blister is formed by the entire thickness of a necrotic epidermis (Fig. 16.31).

Differential diagnosis The most important differential diagnosis of SSSS is toxic epidermal necrolysis. The clinical picture of a scalded appearance can be very similar, although mucosal involvement is always present in toxic epidermal necrolysis. The scalded appearance may also raise the possibility of child abuse.214

210. Amagai M, Matsuyoshi N, Wang ZH, et al. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein I. Nat Med. 2000;6:1275–1277. 211. Amagai M, Yamaguchi T, Hanakawa Y, et al. Staphylococcal exfoliative toxin B specifically cleaves desmoglein I. J Invest Dermatol. 2002;118: 845–850. 212. Hanakawa Y, Schechter NM, Lin C, et al. Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome. J Clin Invest. 2002;110:53–60.

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Figure 16.31  Stevens–Johnson syndrome/toxic epidermal necrolysis: histology showing full thickness necrosis of the epidermis, with a tongue of viable epidermis encroaching on to the blistered area.

Therapy and prognosis Fluid loss, fluid overload,215 temperature dysregulation and secondary cutaneous infection are all potential complications that require monitoring. With appropriate antibiotic treatment the overall prognosis is excellent. SSSS in adulthood carries a higher mortality rate than in childhood as these patients are usually immunocompromised.208 Mild forms of SSSS, including bullous impetigo, are managed with appropriate oral antibiotics. As desquamation occurs within a few days into the illness, an emollient should be applied regularly. In generalized SSSS, children are usually hospitalized and intravenous antibiotics are given. Methicillin antibiotics are usually administered. Analgesia may be required.

REACTIVE BLISTERING DISORDERS ERYTHEMA MULTIFORME (See also Chs 19 and 30.)

Introduction and historical note Erythema multiforme (EM) is an acute self-limited vesiculobullous disorder characterized by the development of erythematous macules and papules, which evolve into ‘target’ lesions; it was first described by von Hebra in 1860.216 Stevens and Johnson

213. Yamasaki O, Yamaguchi T, Sugai M, et al. Clinical manifestations of staphylococcal scalded-skin syndrome depend on serotypes of exfoliative toxins. J Clin Microbiol. 2005;43:1890–1893. 214. Porzionato A, Aprile A. Staphylococcal scalded skin syndrome mimicking child abuse by burning. Forensic Sci Int. 2007;168:1–4. 215. Blyth M, Estela C, Young AE. Severe staphylococcal scalded skin syndrome in children. Burns. 2008;34:98–103. 216. Von Hebra F. Acute exantheme und hautkrankheiten. Handbuch der Speciellen Pathologie und Therapie. Erlangen: Verlag von Ferdinand von Enke; 1860:198–200.

Vesiculobullous disease

Clinical features

Pathophysiology and histogenesis The pathogenesis of EM is unknown. It is considered to be a reaction pattern to a herpetic infection. It is probably a delayed hypersensitivity immune response, with a cytotoxic immunological attack on keratinocytes expressing foreign antigens of the herpes virus. Herpes simplex virus DNA can frequently be demonstrated by polymerase chain reaction amplification of material obtained from the epidermis of EM lesions, whether or not the attack has been preceded by a cold sore.221 Histological examination shows a lymphohistiocytic perivascular infiltrate with vacuolar degeneration of the lower epidermis and individual necrotic keratinocytes. In more severe cases, there is necrosis of the entire thickness of the epidermis, and dermal– epidermal separation occurs close to the epidermal basement membrane which lies in the floor of the lesion. There are no specific immunohistochemical changes.

Prodromal symptoms are either absent or mild, consisting of a low-grade fever, cough and a reluctance to eat. Constitutional symptoms during the course of the eruption are usually absent or moderate in degree. Crops of lesions develop over a few days in acral regions, particularly the palms and dorsa of the hands, wrists, feet, extensor aspects of the elbow and knees, and occasionally the face. A seasonal clustering in the spring months, presumably the result of sun exposure, is well documented. Individual lesions usually start as dull red macules or maculopapules, which may increase in size up to approximately 3  cm. The lesions are usually asymptomatic with occasional itch or tenderness. They usually develop into target (or iris) lesions, which are a diagnostic feature of EM. The target lesions consist of two or three concentric rings. The central zone represents acute epidermal injury, usually commencing as a dusky erythematous or purpuric macule before developing into a tense bulla, which often has a lackluster sheen as the result of epidermal damage. The bulla contents may be clear or hemorrhagic. There is usually a middle pale zone of edematous skin and finally an outer halo of well-demarcated erythema. As its name suggests, there may be a variable pattern ranging from necrotic macules to an exclusively blistering disorder with the lesions monomorphous in each individual patient. They fade over a period of 2–4 weeks, without specific treatment. One mucous membrane is frequently involved in EM; this is usually the oral mucosa. Initially it tends to be relatively mildly affected, but quickly becomes denuded, giving rise to painful erosions which may make eating and drinking difficult. On the lips, identifiable target lesions may form.220 Rarely, the ocular, genital, pharyngeal, laryngeal and esophageal mucous membranes may be affected. Cutaneous and mucous membrane lesions heal without scarring, usually with no complications. There is no internal organ involvement.

There is consensus that Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), also known as Lyell’s syndrome, are part of a single spectrum, differing only in severity. EM is another entity with acral, target lesions and an excellent prognosis217 SJS-TEN are serious conditions, with TEN at the severest end of the spectrum. Lesions are flat atypical target lesions or purpuric macules and bullae in SJS-TEN. The mucous membrane involvement is severe and extensive in SJS-TEN.224

217. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child. 1922;24:526–527. 218. Schalock PC, Dinulos JG, Pace N, et al. Erythema multiforme due to Mycoplasma pneumoniae infection in two children. Pediatr Dermatol. 2006;23:546–555. 219. Lam NS, Yang YH, Wang LC, et al. Clinical characteristics of childhood erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in Taiwanese children. J Microbiol Immunol Infect. 2004;37: 366–370. 220. Weston WL, Morelli JG, Rogers M. Target lesions on the lips: childhood herpes simplex associated with erythema multiforme mimics Stevens– Johnson syndrome. J Am Acad Dermatol. 1997;37:848–850.

221. Weston WL, Brice SL, Jester JD, et al. Herpes simplex virus in childhood erythema multiforme. Pediatrics. 1992;89:32–34. 222. Leaute-Labreze C, Lamireau T, Chawki D, et al. Diagnosis, classification and management of erythema multiforme and Stevens–Johnson syndrome. Arch Dis Child. 2000;83:347–352. 223. Weston WL, Morelli JG. Herpes simplex virus-associated erythema multiforme in prepubertal children. Arch Pediatr Adolesc Med. 1997;151:1014–1016. 224. Assier H, Bastuji-Garin S, Revuz J, et al. Erythema multiforme with mucous membrane involvement and Stevens–Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol. 1995;131:539–543.

REACTIVE BLISTERING DISORDERS

described a more severe condition in 1922,217 subsequently known as Stevens–Johnson syndrome (SJS); it is characterized by severe mucosal, as well as cutaneous disease and, like EM, is also associated with epidermal necrosis. For many years, EM was classified into minor and major forms, the major variant being synonymous with SJS. EM and SJS are now regarded as distinct entities.216 Some authorities define SJS as a variant of toxic epidermal necrolysis with less skin involvement and others as a distinct entity usually as a result of infection with Mycoplasma pneumoniae.218,219

16

Differential diagnosis EM in childhood is frequently misdiagnosed222 and may be mistaken for urticaria, drug reactions, pemphigoid, chronic bullous disease of childhood and, occasionally, polymorphic light eruption when limited to sun-exposed skin.

Treatment and prognosis EM is usually mild and attacks subside within 2–4 weeks, usually without sequelae, apart from occasional pigmentary change. Treatment is symptomatic.219 Herpes simplex virus-associated EM in childhood does not progress to SJS/TEN.220 Prophylactic oral acyclovir, if given early enough, may prevent the occurrence of EM.223

STEVENS–JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS (See also Chs 19 and 30.)

Introduction

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The etiology is principally infectious for EM and drug-induced for SJS-TEN.221,222,224 SJS-TEN usually occurs as a single event and recurrences are unusual, in contrast to EM where recurrences are common. Drugs are the primary causative factor for SJS-TEN in adults and one cause in children,225 although this has been challenged.222 Antibiotics (especially sulfonamides and penicillins226), anticonvulsants (especially carbamazepine), and non-steroidal anti-inflammatory agents are the classes of drug usually incriminated. A variety of infections precipitate SJS, particularly Mycoplasma pneumoniae.227 At times, the trigger factor cannot be established.

Clinical features REACTIVE BLISTERING DISORDERS

In SJS-TEN there is often a prodromal illness consisting of symptoms such as fever, cough, headache, malaise, arthralgia, myalgia and gastrointestinal upset or the symptoms and signs may start abruptly with fever. The onset of the eruption is sudden and initially takes the form of a macular or morbilliform, tender, dusky erythematous eruption involving the face, trunk and limbs, with at times a suggestion of target lesions. Nikolski’s sign is usually positive. The eruption gradually worsens over several days as lesions coalesce and develop flaccid and occasionally hemorrhagic bullae. Depending on the severity of the condition, the epidermis detaches as a result of very minor frictional forces, and large flaccid bullae, resembling scalds, develop and rupture leaving sheets of necrotic epidermis with a moist erythematous base (Fig. 16.32). In severe cases the nails may be shed. Unusually, SJS-TEN may be associated with subcorneal pustules.228 Mucous membrane lesions are common and cause considerable pain. Bullae are associated with edema and erythema that break down to form painful erosions. The oral cavity and the vermilion border of the lips are almost invariably affected, and the discomfort causes difficulties with eating. The lips are covered with hemorrhagic crusts. The conjunctival and genital mucous membranes may be involved, particularly the glans penis in boys and the vulva and vagina in girls, which may lead to dysuria and urinary retention. TEN may affect the respiratory and gastrointestinal tracts. Involvement of the respiratory mucosa may lead to respiratory failure229 and patchy pulmonary disease may occur. Involvement of the esophagus may cause dysphagia and malnutrition but strictures are unusual.230 Ileal involvement may lead to abdominal pain and diarrhea, and the colon can also be involved. Fluid loss, dehydration and electrolyte imbalance can cause the development of hemodynamic shock, coma and seizures, and septicemia and septic shock are potential dangers.

225. Sheridan RL, Weber JM, Schultz JT, et al. Management of severe toxic epidermal necrolysis in children. J Burn Care Rehabil. 1999;20:497–500. 226. Ball R, Ball LK, Wise RP, et al. Stevens–Johnson syndrome and toxic epidermal necrolysis after vaccination: reports to the vaccine adverse event reporting system. Pediatr Infect Dis J. 2001;20:219–223. 227. Tay YK, Huff JC, Weston WL. Mycoplasma pneumoniae infection is associated with Stevens–Johnson syndrome, not erythema multiforme (von Hebra). J Am Acad Dermatol. 1996;35:757–760. 228. Reichert-Penetrat S, Barband A, Antunes A, et al. An unusual form of Stevens–Johnson syndrome with subcorneal pustules associated with Mycoplasma pneumoniae infection. Pediatr Dermatol. 2000;17:202–204.

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Figure 16.32  Lamotrigin induced toxic epidermal necrolysis extensive blistering (Courtesy Dr A. Torrelo).

Pathophysiology and histogenesis Like EM, SJS-TEN is probably a cytotoxic immune reaction directed against keratinocytes expressing foreign antigens. However, unlike EM, there is a great over-expression of tumor necrosis factor-alpha (TNF-α) in the epidermis,231,232 which is thought to play an important role in keratinocyte death, and possibly explains the much greater degree of epidermal necrosis in SJS-TEN than in EM. Histological examination (Fig. 16.31) of SJS and TEN shows a prominent degree of epidermal necrosis occurring on a background of relatively little inflammatory infiltrate. Sub­ epidermal cleavage is usually present. In TEN, there is fullthickness epidermal necrosis and widespread dermal–epidermal separation.

Differential diagnosis Viral exanthems can resemble milder forms of SJS, and burns or scalds have to be considered for the more severe forms of the condition. Staphylococcal scalded skin syndrome can be difficult to distinguish from TEN, but histological examination of frozen sections of the bulla roof rapidly establishes the diagnosis (see Staphylococcal Scalded Skin Syndrome, SSSS, above). TEN can also be confused with pemphigus of all types, particularly the paraneoplastic variant.

229. Schamberger MS, Goel J, Braddock SR, et al. Stevens–Johnson syndrome and respiratory failure in a nine-year-old boy. South Med J. 1997;90: 755–757. 230. Lamireau T, Leaute-Labreze C, Le Bail B, et al. Esophageal involvement in Stevens–Johnson syndrome. Endoscopy. 2001;33:550–553. 231. Paquet P, Nikkels A, Arrese JE, et al. Macrophages and tumour necrosis factor alpha in toxic epidermal necrolysis. Arch Dermatol. 1994;130: 605–608. 232. Paquet P, Pierard GE. Erythema multiforme and toxic epidermal necrolysis: a comparative study. Am J Dermatopathol. 1997;19:127–132.

Vesiculobullous disease

The prognosis of SJS-TEN depends on the severity of the condition and the surface area involved. With appropriate medical treatment, the prognosis in children is good, with a lower mortality than in adults.220,225 Milder cases can be nursed on a dermatology ward, but more severe cases are best managed in a specialized burn unit.225,233 The offending drug should be withdrawn as soon as possible. Treatment of any underlying infection, and rectifying any electrolyte and fluid imbalance, is important. In severe cases, a central venous line and urinary catheter may be required.225 Wound desiccation and superinfection should be avoided, by using a suitable emollient. Regular swabs of the skin should be taken to anticipate secondary infection which should then be treated with appropriate antibiotics. Biological wound dressings are beneficial. General supportive measures include a high-calorie and high-protein diet: the energy requirement of children with SJS/TEN can be readily calculated.234 Oral intake is usually not possible and parenteral feeding should be considered. Close ophthalmic supervision is important. If severe oropharyngeal involvement prevents a child from guarding the airway, prophylactic intubation should be considered.225 The role of systemic corticosteroid therapy is controversial and is considered beneficial by some235 and detrimental by others.236 Systemic corticosteroids do increase the risk of infection, but their advocates suggest tapering the dose quickly once disease progression has ceased, and perhaps combining their use with a prophylactic antibiotic. Intravenous immunoglobulin (IVIG) has become the standard treatment for TEN in children,237–240 although randomized trials are required to fully evaluate the efficacy of IVIG. The standard dose is 3 g/kg divided over 2–3 days. Late complications of SJS-TEN include pigmentary change, especially in dark-skinned children, and fingernail loss or deformity.225,241 Cutaneous scarring is not usual except when there has been secondary infection, but the mucous membranes,

233. Ringheanu M, Laude TA. Toxic epidermal necrolysis in children – an update. Clin Pediatr (Phila). 2000;39:687–694. 234. Mayes T, Gottschlich M, Khoury J, et al. Energy requirements of pediatric patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Nutr Clin Pract. 2008;23:547–550. 235. Kakourou T, Klontza D, Soteropoulou F, et al. Corticosteroid treatment of erythema multiforme major (Stevens–Johnson syndrome) in children. Eur J Pediatr. 1997;156:90–93. 236. Prendiville JS, Hebert AA, Greenwald MJ, et al. Management of Stevens– Johnson syndrome and toxic epidermal necrolysis in children. J Pediatr. 1989;115:881–887. 237. Morici MV, Galen WK, Shetty AK, et al. Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome. J Rheumatol. 2000;27:2494–2497. 238. Tristani-Firouzi P, Petersen MJ, Saffle JR, et al. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol. 2002;47:548–552.

particularly the genital mucous membranes, may be scarred and severe phimosis may result.241 The eyes are specially prone to scarring with keratitis sicca being a common cause of long-term morbidity.225,241,242 If bronchiolitis obliterans develops the prognosis is poor.

MISCELLANEOUS BLISTERING DISORDERS BLISTERING PHOTODERMATOSES Photosensitivity in childhood may be associated with blister formation. Actinic prurigo is an inflammatory photodermatosis characterized by a pruritic vesiculopustular eruption developing several hours after exposure to sunlight. Hydroa vacciniforme is typified by tender vesicles developing on sun-exposed sites, mainly in boys, that heal with scarring. The distribution of blistering and the temporal relationship to sun exposure usually suggest a photosensitive etiology.

MISCELLANEOUS BLISTERING DISORDERS

Treatment and prognosis

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COMA BLISTERS Blistering in comatose subjects (coma blisters) has been associated with carbon monoxide exposure, drug overdose, neurological damage, hypoglycemia and diabetic ketoacidosis.243 Coma blisters usually arise within 24 h of the onset of coma and resolve in 10–14 days; they are often associated with ecchymoses. Coma bullae are associated with a rather typical histology, consisting of epidermal necrosis with intraepidermal and subepidermal cleavage and necrosis of the eccrine glands and ducts. There is usually an associated deposition of immunoglobulins or complement, especially around the eccrine apparatus, which is thought to be related non-specifically to tissue injury. The cause of coma blisters remains unclear, but it is assumed that local hypoxia associated with pressure often plays a part, although coma blisters do not necessarily occur at pressure sites.

239. Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with Stevens-Johnson syndrome and toxic epidermal necrolysis: seven cases and review of the literature. Pediatrics. 2003;112:1430–1436. 240. Mangla K, Rastogi S, Goyal P, et al. Efficacy of low dose intravenous immunoglobulins in children with toxic epidermal necrolysis: an open uncontrolled study. Indian J Dermatol Venereol Leprol. 2005;71:398–400. 241. Sheridan RL, Schulz JT, Ryan CM, et al. Long-term consequences of toxic epidermal necrolysis in children. Pediatrics. 2002;109:74–78. 242. Chang YS, Huang FC, Tseng SH, et al. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: acute ocular manifestations, causes, and management. Cornea. 2007;26:123–129. 243. Mehregan DR, Daoud M, Rogers RS. Coma blisters in a patient with diabetic ketoacidosis. J Am Acad Dermatol. 1992;27:269–270.

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Diseases of the dermis and subcutaneous tissues Julie S. Prendiville and Alfons L. Krol SKIN-COLORED CYSTS AND NODULES

NODULAR DISEASES

EPIDERMOID CYSTS Julie S. Prendiville

Swelling or distortion of the skin contours, due to infiltration or expansion of the dermis or the underlying subcutaneous tissues, often presents as a diagnostic problem in infants and children. Cysts and nodules are circumscribed swellings in the skin, whereas infiltrative diseases result in diffuse thickening and swelling of the skin. A diverse group of disorders may present with skin nodules. Most of these conditions are rare; a few are common. To provide the clinician with an organized approach to nodular skin lesions, the first part of the chapter is divided into two sections: (1) skincolored cysts and nodules; (2) skin nodules with color change of the overlying skin. Some skin conditions of children that may be included within this classification are discussed in detail in other chapters. The infiltrative diseases of the skin, with the exception of granuloma annulare, are uncommon in children. They are characterized by thickening, swelling, and a firm quality to the dermal tissue on palpation. As in approaching any clinical problem, the clue to the etiology will depend on whether the process is localized or systemic, its degree of infiltration, presence of inflammation, and color changes. Reviewing the various components of the dermis (cellular and supporting structures) allows one to arrive at a correct diagnosis, often aided by histopathological confirmation.



Epidermoid cysts (also known as epidermal cysts, epithelial inclusion cysts, sebaceous cysts, and wens) are dermal or subcutaneous nodules in which a keratin-filled cyst is lined by epithelium. Unna credits Schweninger in 1886 with understanding the experimental production of epidermal inclusion cysts after skin trauma and inversion of the epithelium.1 Unna recognized that the so-called sebaceous cyst was not lined with sebaceous glands but only with epithelium.

Epidemiology Epidermoid cysts are rare in childhood and occur predominantly in young and middle-aged adults.2 Epidermoid inclusion cysts on the hands or feet may be induced by trauma; in Gardner syndrome they are inherited in an autosomal dominant pattern and may be present at birth or appear as late as the fourth decade of life.3 There has been no reported racial or sexual predilection.

Presenting history Parents will bring a child for medical care because of a lump in the skin. There is sometimes an underlying concern about skin cancer.4 The cyst may become inflamed, which prompts the parent to seek medical advice. In the circumstance of a sudden appearance of an epidermoid cyst, there may be a history of a preceding puncture wound or other penetrating skin injury.

SKIN-COLORED CYSTS AND NODULES

Physical examination

Raised lesions with indistinct borders and a palpable deep portion on which the overlying skin is usually of normal color are considered in this category. These include epidermoid cysts, dermoid cysts, bronchogenic cysts and pilomatricomas.

Epidermoid cysts are firm, spherical nodules that vary in size up to 1–2 cm in their greatest diameter. An inflamed cyst is tender on palpation, and the overlying skin is red. Multiple epidermoid cysts in a child should cause one to suspect Gardner syndrome.3,5

1.

4.

2. 3.

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Crissey JT, Parish LC. The dermatology and syphilology of the nineteenth century. New York: Praeger Scientific; 1981. Golitz LE, Poomeechaiwong S. Cysts. In: Farmer ER, Hood AF, eds. Pathology of the Skin. Norwalk, CT: Appleton and Lange; 1990. Cooper PH, Fechner RE. Pilomatricoma-like changes in the epidermal cells of Gardner’s syndrome. J Am Acad Dermatol. 1983;8:639–644.

5.

Knight PJ, Reiner CB. Superficial lumps in children. What, when, and why. Pediatrics. 1983;72:147–153. Gardner EJ, Richards RC. Multiple cutaneous and subcutaneous lesions occurring simultaneously with hereditary polyposis and osteomatosis. Am J Hum Genet. 1953;5:139–147.

Diseases of the dermis and subcutaneous tissues

In Gardner syndrome, epidermoid cysts are irregularly distributed over the face, scalp, trunk, and extremities. In solitary epidermoid cysts, the remainder of the physical examination is normal. In Gardner syndrome, other clinical manifestations are usually found.5 Thick, irregular, firm masses may be observed on the abdominal wall or proximal extremities, which represent a desmoid tumor, a locally invasive fibrous tumor observed in Gardner syndrome. Cutaneous lipomas may also be found. Hard, bony masses on the jaw represent mandibular osteomas.

Laboratory findings Multiple intestinal polyps may be visualized on barium studies or endoscopic examination in Gardner syndrome.5

17

Therapy and prognosis For solitary epidermoid cysts, no therapy is necessary. Parents may wish to have the cyst removed for cosmetic purposes. For red, tender cysts, drainage and oral antibiotics may be required to treat secondary infection. In Gardner syndrome, large intestinal polyps can occur during adolescence but are more likely to appear during the third decade of life.5 In at least 50% of patients, colonic cancer develops in the intestinal polyps, and predictive studies estimate that all affected family members are at risk.5,9 Careful follow-up by a pediatric gastroenterologist or pediatrician is recommended because malignant transformation has been documented in the first decade of life.9

Pathophysiology and histogenesis Epidermoid cysts have a wall of true epidermis and contain laminated layers of horny material.6 The wall and contents of the epidermoid cyst are identical to that of the infundibulum of the pilosebaceous unit, but lack the deeper sebaceous duct and gland. The cyst does not contain sebum. In experimental wounds that invert the epidermis into the skin, epidermoid cysts can be induced. The epidermoid cysts of Gardner syndrome are considered to be developmental and perhaps represent defects in assembly of the skin.5,6 Inflamed cysts may rupture their keratinous contents through the thin epithelial wall into the dermis, inciting a foreign body immune reaction. Secondary bacterial infection sometimes occurs. Pilomatricoma-like changes, including shadow cells and calcification, have been observed in epidermoid cysts, particularly in cases of Gardner syndrome.3,6,7

Differential diagnosis

Dermoid cysts are epithelium-lined cysts that contain epidermal appendages, including hair follicles, and may contain hair, sebum, keratin, and sometimes associated apocrine glands.10 They are developmental in origin and are believed to arise as a consequence of displacement of dermal and epidermal cells into and along embryonic lines of fusion.10 They are usually noted at birth, in infancy, or in early childhood. Sites of predilection are the periorbital region, midline of the nose, scalp, and anterior neck.11 There is no known racial or sexual predilection, although a slight preponderance of female patients was noted in one study.10 The exact prevalence of dermoid cysts is not known.

Presenting history Dermoid cysts present as a nodule on the face, head or neck. They are usually asymptomatic unless there is infection of the cyst or underlying tissues. An associated sinus tract with intra­ cranial extension may result in recurrent meningitis.12

Superficial lymph nodes may be mistaken for epidermoid cysts because they are also round, firm, skin-colored nodules, which may have a smooth feel on palpation. Superficial lymph nodes in children are frequently found near the skin surface of the neck and groin. Pilomatricomas may be confused with epidermoid cysts, but are attached to the overlying epidermis, have a hard, irregular feel, and lack the smooth configuration of epidermoid cysts. Lipomas may also be confused, although they are subcutaneous in location and are softer than true epidermoid cysts. Dermoid cysts may mimic epidermoid cysts, but occur over lines of fusion, and histopathologic differentiation may be required. They must also be distinguished from congenital developmental cysts on the neck.8 Thyroglossal cysts occur on the midline of the neck and branchial cleft cysts occur on the lateral neck and overlying the medial end of the clavicle.

Physical examination

6.

9.

7. 8.

Benharroch D, Sachs MI. Pilomatricoma associated with epidermoid cyst. J Cutan Pathol. 1988;16:40–43. Pujol RM, Casanova JM, Egido R, et al. Multiple familial pilomatricomas: a cutaneous marker for Gardner syndrome? Pediatr Dermatol. 1995;12:331–335. Howard R. Congenital midline lesions: pits and protuberances. Pediatr Ann. 1998;27:150–160.

SKIN-COLORED CYSTS AND NODULES

DERMOID CYSTS

Dermoid cysts appear as round, firm, often slightly compressible, skin-colored nodules on the face or scalp. They are often observed around the eyes (Fig. 17.1), particularly the lateral eyebrow or within the orbit. Lesions in the nasoglabellar region, and occasionally elsewhere, may have an overlying punctum or sinus opening that contains fine hairs. Extrusion of sebaceous material is sometimes seen.11 Lesions on the eyelid, although seldom associated with a sinus, may erode underlying bone.

Pathophysiology and histogenesis Dermoid cysts are the result of sequestration of skin at lines of embryonic closure during skin development.11 They are

Naylor EW, Lebenthal E. Early detection of adenomatosis polyposis coli in the Gardner’s syndrome. Pediatrics. 1979;63:222–227. 10. Pollard ZF, Robison HD, Calhoun J. Dermoid cysts in children. Pediatrics. 1976;57:379–382. 11. Bartlett SP, Lin KY, Grossman R, et al. The surgical management of orbitofacial dermoids in the pediatric patient. Plast Reconstr Surg. 1993;91:1208–1215. 12. Pensler JM. Craniofacial dermoids. Plast Reconstr Surg. 1988;82:953–958.

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obtained before surgery for all midline lesions, lesions with a punctum or sinus opening, and lesions in the orbit with indistinct margins.11 If present, CT imaging should be followed by magnetic resonance imaging (MRI) to determine whether the sinus tract communicates with the meninges. If there is a connection the sinus tract should be excised at the same time as the dermoid cyst.11,12 Ophthalmologic evaluation is indicated for lesions within the orbital rim because of possible pressure effects on the globe.11

PILOMATRICOMA

SKIN-COLORED CYSTS AND NODULES

Figure 17.1  A dermoid cyst over the eyebrow. (Courtesy of Dr A. Torrelo.)

differentiated from epidermoid cysts by the presence of hair and sebum within the cystic contents and the presence of sebaceous glands, hair follicle structures, and/or apocrine glands in the epithelial lining of the cyst.10,11 Dermoid cysts are usually subcutaneous in location. There should be some concern about midline lesions, especially on the nose, because these may have an accompanying sinus tract, sometimes with intracranial extension.11,12

Differential diagnosis The differential diagnosis of a dermoid cyst includes nasal glioma, encephalocele, meningocele, ectopic meningeal tissue, epidermoid cyst, and hemangioma. The distinction between epidermoid and dermoid cysts may be difficult clinically. However, except for traumatic epidermoid cysts, which are usually located on the hands and feet, and cysts associated with Gardner syndrome, dermoid cysts are more common than epidermoid cysts in infants and young children.

Therapy and prognosis Simple excision is the treatment of choice for lesions on the eyebrow.11 Midline dermoid cysts may be superficial, may have an accompanying sinus tract that adheres to the underlying periosteum or nasal septum, or may sometimes extend intracranially.12 A detailed computed tomographic (CT) image should be

13. Moehlenbeck FW. Pilomatricoma (calcifying epithelioma): a statistical study. Arch Dermatol. 1973;108:532–534. 14. Demircan M, Balik E. Pilomatricoma in children: a prospective study. Pediatr Dermatol. 1997;14:430–432. 15. Pirouzmanesh ABS, Reinisch JF, Gonzalez-Gomez I, et al. Pilomatrixoma: a review of 346 cases. Plast Reconstruct Surg. 2003;112:1784–1789. 16. Geh JL, Moss Al. Multiple pilomatrixomata and myotonic dystrophy: a familial association. Br J Dermatol. 1999;52:143–145. 17. Cambiaghi S, Ermacora E, Brusasco A, et al. Multiple pilomatricomas in Rubenstein-Taybi syndrome: a case report. Pediatr Dermatol. 1994;11:21–25. 18. Blaya B, Gonzalez-Hermosa R, Gardeazabal J, et al. Multiple pilomatricomas in association with trisomy 9. Pediatr Dermatol. 2009;26:482–484.

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Pilomatricoma (also known as calcifying epithelioma of Malherbe) is a benign adnexal tumor derived from hair matrix cells. It commonly appears in the first or second decade of life and has a slight female preponderance.13 Familial occurrence is well documented.7,14 Pilomatricomas have a predilection for the head and neck.15 They may also occur on the arms and, less commonly, on the trunk and lower extremities. Most are solitary nodules, but multiple and eruptive lesions may occur. Multiple pilomatricomas can be associated with myotonic dystrophy.16 They have also been described in Gardner syndrome, Rubenstein–Taybi syndrome, Turner syndrome, Soto’s syndrome and in association with trisomy 9.7,17–20

Clinical features The pilomatricoma presents as a slowly growing, firm to hard, lobulated nodule that is fixed to the epidermis but is freely mobile over underlying structures (Fig. 17.2). The overlying skin is typically skin-colored or white but may show a blue-red discoloration. It can vary in size from 0.5 to 5 cm in diameter, and rarely, larger lesions may occur.6 Anetoderma-like changes of the overlying skin have been described.21 Rapid enlargement by bleeding into a lesion may occur.22

Pathophysiology and histogenesis Pilomatricomas have been shown to arise from genetic alterations that influence β-catenin stabilization.23 A similar genetic defect is found in patients with colon cancer. Ultrastructural and histochemical studies show a keratinization pattern resembling that seen in normal hair cortex. Histopathologically, the pilomatricoma is composed of irregularly shaped islands of epithelial cells located in the deep dermis or subcutaneous fat and surrounded by a capsule of connective tissue. Pilomatricomas

19. Wood S, Nguyen D, Hutton K, Dickson W. Pilomatricomas in Turner syndrome. Pediatr Dermatol. 2008;25:449–451. 20. Gilaberte Y, Ferrer-Lozano M, Olivan MJ, et al. Multiple giant pilomatricoma in familial Sotos syndrome. Pediatr Dermatol. 2008;25: 122–124. 21. Jones CC, Tschen JA. Anetodermic cutaneous changes overlying pilomatricomas. J Am Acad Dermatol. 1991;25:1072–1076. 22. Julian CG, Bowers PW. A clinical review of 209 pilomatricomas. J Am Acad Dermatol. 1998;39:191–195. 23. Chan EF, Gat U, McNiff JM, et al. A common skin tumour is caused by activating mutations in beta-catenin. Nature Genet. 1999;21:410– 413.

Diseases of the dermis and subcutaneous tissues

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showing a mass with an echogenic center and hypoechoic rim at the junction of the dermis and subcutaneous fat.24

Therapy and prognosis Surgical excision though a small skin incision is the treatment of choice. Others advocate incision and curettage.22 It has been suggested that some pilomatricomas regress spontaneously.25 Malignant pilomatricoma is very rare, particularly in childhood.26

SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

A

KELOIDS AND HYPERTROPHIC SCARS (These conditions are discussed in Ch. 19.)

DERMATOFIBROMAS

B

Figure 17.2  (A) Pilomatricoma on the neck. (B) Pilomatricoma on the ear. (B, Courtesy of Dr A. Torrelo.)

A dermatofibroma (also known historically as fibrous histiocytoma, histiocytoma cutis, and sclerosing hemangioma) is a small, benign circumscribed fibrous growth limited to the skin.27 Unna was credited with first describing dermatofibromas as benign fibrous skin growths.1 The term dermatofibroma was introduced in 1930. Other authorities, believing these growths were histiocytic in nature, designated them as histiocytomas or fibrous histiocytomas. In 1943, the term sclerosing hemangioma was introduced to describe this tumor. Most authorities prefer the term dermatofibroma.

Epidemiology are composed of two types of cell: basophilic and shadow. Basophilic cells are seen at the periphery or side of the lesion and have darkly staining round or elongated nuclei and scanty cytoplasm. Shadow cells have a well-defined border and a central unstained area where the nucleus has been lost. Cells in transition between basophilic and shadow cells are also seen. In older lesions, basophilic cells may be few or absent. Areas of keratinization are frequently observed within the tumor, with melanin, melanocytes, and foreign body giant cells. Calcification is a common finding, and ossification occasionally occurs. Pilomatricoma-like histopathologic changes have been described in epidermoid cysts, particularly in patients with Gardner syndrome.3

Differential diagnosis The differential diagnosis of pilomatricoma includes cysts, calcified nodule, and other cutaneous adnexal tumors. Ultrasonography has been found to be a useful diagnostic tool, typically

24. Hughes J, Lam A, Rogers M. Use of ultrasonography in the diagnosis of childhood pilomatrixoma. Pediatr Dermatol. 1999;16:341–344. 25. Headington JT. Tumors of hair follicle differentiation. In: Farmer ER, Hood AF, eds. Pathology of the skin. Norwalk, CT: Appleton and Lange; 1990.

The precise prevalence of dermatofibromas is unknown. They are commonly seen in adults. They are not common in young children but may be seen in adolescence.

Presenting history A dermatofibroma presents as a slowly growing nodule. There are usually no associated symptoms. There may be concern about skin cancer or cosmesis.

Physical examination Dermatofibromas are small (1–5 mm in diameter), firm, erythematous or pigmented nodules (Fig. 17.3), usually found on the leg or trunk. Occasionally, they may reach 15 mm in diameter but rarely exceed 20 mm in size.27 Multiple lesions may be present. Lateral pressure on the lesion produces dimpling of its surface known as the ‘dimple sign’. The remainder of the physical examination is normal.

26. Joshi A, Sah SP, Agrawal CS, et al. Pilomatrix carcinoma in a child. Acta Derm Venereol. 1999;79:476–477. 27. Sanchez RL. The elusive dermatofibromas. Arch Dermatol. 1990;126:522–523.

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matomyofibroma is a larger plaque-like dermal tumor with distinctive immunohistochemical features.28 Dermatofibro­ sarcoma protuberans is also usually larger in size (>2 cm), more cellular, has a monomorphous infiltrate, and extends deeper into the subcutaneous tissues than the benign dermatofibroma.27

Therapy and prognosis Dermatofibromas tend to persist. They may rarely grow up to 15 mm in their maximal diameter. Usually, no treatment is required. If there is concern about the clinical diagnosis or cosmesis, then excisional biopsy is preferred, with complete removal of the lesion. SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

INFANTILE DIGITAL FIBROMA

Figure 17.3  Firm, pigmented dermatofibroma on the leg of an adolescent.

Infantile digital fibroma is a benign growth of fibrous tissue found about the distal portion of the fingers or toes.29 Reye29 is credited with first describing this growth in 1965 and emphasizing its distinction from fibrosarcoma. Synonyms include digital fibrous tumor of Reye and recurrent digital fibrous tumor of childhood.29,30

Pathophysiology and histogenesis Dermatofibromas contain numerous fibroblasts with increased deposition of collagen in the dermis accompanied by a proliferation of the overlying epidermis.27 Often, the acanthotic epidermis has increased melanin present. Histopathologic variants include hemosiderotic dermatofibromas and dermatofibromas with lipidization.27 The histogenesis of dermatofibromas has not been clearly established; the cell of origin may be the histiocyte, the fibro­ blast, or both.27 Many authorities believe that they represent reactive proliferation of fibroblasts and the overlying epithelium as a result of minor trauma.27 Because they do not spontaneously regress, some authorities consider them to be neoplasms.27

Differential diagnosis Dermatofibromas are pigmented and may be confused with melanoma but, unlike melanomas, dermatofibromas are firm and demonstrate dimpling, ‘the dimple sign,’ when the surface of the lesion is pinched or squeezed. The growth rate is slow in dermatofibromas and rapid in melanoma. The overlying epidermis in a dermatofibroma is thickened and firm in contrast to that of a melanoma. Other pigmented nodules, such as intradermal nevi, may be confused with dermatofibromas and mastocytomas, which may have overlying pigmentation of the skin. Juvenile xanthogranulomas are usually yellow or orange-brown in color. Pilomatricomas with discoloration of the overlying skin may also be confused. A biopsy may be necessary to distinguish these lesions. It is also important to distinguish dermatofibromas from other fibrous proliferations of childhood. A dermatofibroma may clinically resemble a keloid scar, a dermatomyofibroma, or dermatofibrosarcoma protuberans. Der-

28. Rose C, Brocker E-B. Dermatomyofibroma: case report and review. Pediatr Dermatol. 1999;16:456–459. 29. Reye RDK. Recurring digital fibrous tumor of children. Arch Pathol. 1965;80:228–231.

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Epidemiology Infantile digital fibroma is not inherited and affects infants younger than 1 year of age.29,30 Lesions may be present at birth or develop up to 12 months of age. There is no significant sexual or racial predilection.

Presenting history A history of a rapidly growing lump about the nail is often given.29,30 Because these lesions grow rapidly, cancer is often suspected. The lesions are usually asymptomatic but may interfere with nail growth, and a deformed nail is often a secondary component.29,30 The child may have had a previous biopsy or attempted excision of the lesion followed by rapid regrowth of the fibrous tumor.

Physical examination A firm nodule occurring around the fingernail or toenail is observed (Fig. 17.4). The nodule is usually asymptomatic, involving one lateral side of the digit, and may be the cause of a deformity within the nail plate. The overlying skin may be red or have a normal color. The lesion is usually limited to a single digit, but a few infants have had two lesions. The remainder of the physical examination is normal.

Laboratory findings There are no associated laboratory abnormalities with infantile digital fibroma.

30. Beckett JH, Jacobs AH. Recurring digital fibromas of childhood: a review. Pediatrics. 1977;59:401–406.

Diseases of the dermis and subcutaneous tissues

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Therapy and prognosis Infantile digital fibroma often involutes spontaneously within a few years. For small lesions without functional impairment, it is recommended to wait for spontaneous resolution.32 For larger lesions, surgery may be necessary. Incomplete surgical excision is associated with a high rate of local recurrence. There is no influence on the overall growth or development of the child but larger lesions may cause functional impairment or difficulty fitting shoes.

PANNICULITIS

Pathophysiology and histogenesis Reye first observed prominent cytoplasmic inclusions that were not detectable on ordinary histologic stains but were prominently observed on iron hematoxylin stains of the tissue.29 Initially, it was thought that it was a virus-induced, benign fibroblastic tumor.30 This idea was based on eosinophilic inclusions observed within the cytoplasm of proliferating fibroblasts that were accentuated by phosphotungstic acid stains of excised tumors. Electron microscopic studies, however, show that the cytoplasmic inclusions represent degenerated organelles without any evidence of viral particles. Ultrastructural studies have shown the tumor cells to be myofibroblasts.31 Nodules of dense proliferating fibroblasts in a collagenous stroma are observed within the dermis and replace most of the normal dermal components. Eosinophilic perinuclear cytoplasmic inclusions surrounded by a clear halo stain pink with trichrome stain. Immunostaining is positive for desmin, actin, vimentin, and keratin.

Differential diagnosis The fibrous thickening overlying a subungual exostosis may exactly mimic an infantile digital fibroma. A radiograph of the digit should be obtained before attempting a biopsy to rule out a bony exostosis. Thickening of the epidermis, such as in a callus or a corn, can also sometimes be confused with the deeper swelling of infantile digital fibroma. A calloused pad resulting from vigorous finger sucking by a baby can be occasionally confused. Because of the abrupt onset and rapid growth, a biopsy may be necessary to rule out a malignant tumor such as fibrosarcoma.

31. Yun K. Infantile digital fibromatosis. Immunohistocytochemical and ultrastructural observations of cytoplasmic inclusions. Cancer. 1988;61:500–507. 32. Ishii N, Matsui K, Ichiyama S, et al. A case of infantile digital fibromatosis showing spontaneous regression. Br J Dermatol. 1989;121:129–133. 33. Peters MS, Su WPD. Panniculitis. Dermatol Clin. 1992;10:37–57. 34. White JW, Winklemann RK. Weber-Christian panniculitis: a review of 30 cases with this diagnosis. J Am Acad Dermatol. 1998;39:56–62.

SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

Figure 17.4  Infantile digital fibromatosis (courtesy of Dr A. Torrelo).

Panniculitis refers to inflammation of the subcutaneous fat. It may arise as a primary idiopathic process or in association with a variety of systemic or cutaneous disorders. Some diseases primarily involve the fat lobules (e.g., cold panniculitis or pancreatic panniculitis), whereas others involve the fibrous septa with extension to adjacent fat lobules, with or without vasculitis (e.g., erythema nodosum and polyarteritis nodosa). However, there is considerable histologic overlap, and a simple classification of septal versus lobular panniculitis can be misleading.33 No current clinical or histologic classification of panniculitis is entirely satisfactory. The literature is further confused by varied and imprecise terminology. Eponymous terms such as Weber–Christian disease and Rothman–Makai syndrome are no longer considered useful; in the past, these have included cases that would now be classified as lupus panniculitis, erythema nodosum, α1antitrypsin deficiency, or factitial panniculitis.34 To arrive at a satisfactory diagnosis, the clinical history, anatomic location and number of lesions, presence or absence of ulceration or lipoatrophy, and associated systemic disease or symptoms should be evaluated in conjunction with histopathologic examination of an adequate deep skin biopsy.33 A classification of panniculitis in childhood is presented in Box 17.1. Erythema nodosum is by far the most common condition in this category.35

ERYTHEMA NODOSUM Erythema nodosum (EN) is characterized by the sudden onset of tender erythematous subcutaneous nodules on the extensor surfaces of the legs. Willan is credited with the introduction of the term erythema nodosum in 1798 and he recognized its association with tuberculosis.1 After the incidence of tuber­ culosis waned, other infectious agents such as Streptococcus, Coccidioides, and Histoplasma became more important in their association with erythema nodosum.35–37 Recently, with a resurgence of Mycobacterium tuberculosis infection, clinicians may once again be confronted with tuberculosis manifesting with panniculitis, including both EN and erythema induratum of Bazin.

35. Torrelo A, Hernandez A. Panniculitis in children. Dermatol Clin. 2008;26:491–500. 36. Ozols II, Wheat LJ. Erythema nodosum in an epidemic of histoplasmosis in Indianapolis. Arch Dermatol. 1981;117:709–712. 37. Labbe L, Perel Y, Maleville J, et al. Erythema nodosum in children: a study of 27 patients. Pediatr Dermatol. 1996;136:447–450.

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BOX 17.1 CLASSIFICATION OF PANNICULITIS Erythema nodosum Erythema induratum of Bazin

>> Nodular vasculitis Neonatal

>> Subcutaneous fat necrosis of the newborn >> Sclerema neonatorum Physical agents

>> Cold, popsicle, or equestrian >> Injections, iatrogenic or factitial >> Blunt trauma Connective tissue disease SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

>> Lupus panniculitis >> Scleroderma, eosinophilic fasciitis, or morphea profunda >> Dermatomyositis >> Polyarteritis nodosa Drug-induced

>> Poststeroid >> Others Enzymatic

>> α1-antitrypsin deficiency >> Pancreatic disease38 Infections and Infestations

>> Bacterial, fungal, or mycobacterial38,39 >> Eosinophilic panniculitis40 Subcutaneous noninfectious granulomas

>> Subcutaneous granuloma annulare >> Sarcoidosis Cytophagic histiocytes

>> Histiocytic cytophagic panniculitis >> Subcutaneous panniculitis-like T-cell lymphoma Idiopathic and lipoatrophic panniculitis Lipoatrophy may also occur in association with lupus panniculitis, dermatomyositis, morphea, juvenile rheumatoid arthritis, injections, and traumatic fat necrosis.

Epidemiology

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Presenting history Erythema nodosum presents with an abrupt onset of tender red lesions on the anterior lower legs. Lesions often arise symmetrically, but occasionally, one leg is involved unilaterally for up to 7 days before the other.35 Very painful lesions may cause the child to limp. About 25% of children have a prodrome of sore throat and fever.35 Lymphadenitis occurs in 3% of children, but in contrast to adult cases, joint symptoms are uncommon.35 Cough or other respiratory symptoms may be present in children with associated tuberculosis, coccidioidomycosis, or histoplasmosis.35,36 Co-existing chronic inflammatory bowel disease may cause bloody diarrhea and weight loss, although EN may be the first manifestation of inflammatory bowel disease. In 4% of children, a history of a similar previous episode of EN is obtained.35 Tuberculosis was the infectious agent most commonly associated with EN until the mid-20th century, but it is now a far less common cause than Group A streptococcus.36,41 Erythema nodosum is also associated with coccidioidomycosis and histoplasmosis, particularly in endemic areas. Other infectious agents such as mumps and Yersinia have been associated.35,41 Sulfonamides and oral contraceptives are the only drugs convincingly associated with the occurrence of EN.35 An association with chronic inflammatory bowel disease is well recognized (Fig. 17.5). Erythema nodosum in adults has been associated with pregnancy,42 sarcoidosis, blastomycosis, cat-scratch disease, and lymphoreticular malignancies, but such associations in children are not well documented. Many cases of erythema nodosum are idiopathic.

Physical examination Erythema nodosum typically presents as a number of erythematous nodules with irregular or indistinct borders on the extensor surfaces of the lower legs (Fig. 17.5).35 Lesions present for more than 4 days, appear dull red, and those more than 10 days old have a brown or bruised character.35 The evolution of lesions is much like that of a bruise. They heal without ulceration or scarring. Lesions have been well described on the trunk, the upper extremities, and the head and neck in adults, and this distribution may occasionally be seen in infancy and childhood. Careful attention should be paid to examination of the respiratory system because of the association of EN with infectious agents of the upper and lower respiratory tract.

Erythema nodosum in children has an equal sex ratio, whereas in adults there is a female predominance.35,37,41 The eruption is rare before 2 years of age, but a child aged 7 months with EN has been well documented.36 The peak age in childhood is during adolescence for females and ages 10–14 for males.35 Convincing evidence for a hereditary predisposition is lacking and there is no racial predilection.36,37

Laboratory findings

38. Requena L, Sanchez E. Panniculitis. J Am Acad Dermatol. 2001;45:163–183. 39. Pao W, Duncan KO, Bolognia JL, et al. Numerous eruptive lesions of panniculitis associated with group A streptococcus bacteremia in an immunocompetent child. Clin Infect Dis. 1998;27:430–433. 40. Adame J, Cohen JA. Eosinophilic panniculitis: diagnostic considerations and evaluation. J Am Acad Dermatol. 1996;34:229–234.

41. Kakourou T, Drosatou P, Psychou F, et al. Erythema nodosum in children: a prospective study. J Am Acad Dermatol. 2001;44:17–21. 42. Salvatore MA, Lynch PJ. Erythema nodosum, estrogens, and pregnancy. Arch Dermatol. 1980;116:557–558.

The erythrocyte sedimentation rate is virtually always elevated in children with EN.39 A few children have leukocytosis. A throat culture and serologic tests for the presence of streptococcal infection are useful. A chest radiograph should be obtained to rule out pulmonary disease, including sarcoidosis, tuberculosis,

coccidioidomycosis, and histoplasmosis. A stool culture and serology for Yersinia infection are warranted if bowel symptoms exist.41 Other laboratory investigations and investigational procedures, such as endoscopy, may be indicated by the history and physical examination.

helpful differentiating sign. Early lesions of necrobiosis lipoidica diabeticorum are not tender and have a slow rather than an abrupt onset. Skin lesions of polyarteritis nodosa are associated with a mottled livedo pattern of the surrounding skin and discontinuous livedo in non-lesional sites elsewhere. Factitial panniculitis may also produce red nodules in the skin. Careful inspection for a puncture wound and a period of observation may help establish this diagnosis. Psychogenic purpura (Gardner–Diamond syndrome) should be considered but this is an unusual location and lesions are not tender. Lupus panniculitis (profundus) can mimic EN, although lesions rarely involve the lower legs. Pancreatic fat necrosis, including lupus erythematosus (LE)-induced pancreatic fat necrosis, can also mimic EN. Hypersensitivity to biting and stinging insects may produce giant insect bite reactions on the lower legs. The clinical history, presence of pruritus, and observation of a central punctum are helpful in differentiating this condition. Bacterial cellulitis may be confused with EN if lesions are unilateral. Lesions on the soles of the feet that resemble EN are seen in palmar plantar hidradenitis of childhood.43 The cutaneous nodules seen in Behçet syndrome represent a panniculitis that is histologically different from EN and are associated with mucosal ulcerations.38 In atypical cases associated with fever, a skin biopsy is indicated to distinguish EN from subcutaneous panniculitis-like T-cell lymphoma.

Pathophysiology and histogenesis

Therapy and prognosis

Figure 17.5  Erythema nodosum: tender, dusky red nodules over the anterior surface of the lower legs.

38

Erythema nodosum is a septal panniculitis without vasculitis. In early lesions, neutrophils and lymphocytes are observed in the fibrous septa, periseptal fat lobules, and around subcutaneous vessels. The overlying dermis often shows a mild, lymphocytic perivascular infiltrate. Abscess formation and fat necrosis are not observed. In lesions more than 4 days old, neutrophils are absent from the infiltrate, and a lymphocytic infiltrate predominates; this eventually evolves into granulomatous infiltration with the presence of giant cells. Miescher’s radial granulomas are considered a histopathologic hallmark of EN and may be present in evolving or fully developed lesions.38 It is believed that EN is a cutaneous reactive response to a variety of possible antigenic stimuli.38 During epidemics of coccidioidomycosis or histoplasmosis, about 5% of infected children develop EN.34,36 In addition, the timing of the lesions corresponds to the time it might require to develop a host response to the infectious organism. There is no good explanation for localization of the lesions to the anterior lower legs, but thermal and mechanical factors have been hypothesized.35

Erythema nodosum in children is a self-limited disease, usually resolving after 2–4 weeks.35,36,41 Rarely, it may have a chronic or recurrent course. When an associated infectious agent is identified, appropriate antimicrobial therapy should be instituted. If sulfonamides or birth control pills are suspected as precipitating factors, they should be discontinued. A nonsteroidal anti-inflammatory drug such as indomethacin or naproxen may be indicated for analgesia and to reduce inflammation.44 A short, 24- to 48-hour, period of bed rest may be most useful. Supportive bandaging may also serve to reduce edema and give symptomatic relief. For chronic, recurrent EN, supersaturated potassium iodide 2–10 drops tid is reported to be effective.45 Systemic corticosteroids are rarely indicated in children with EN unless required for treatment of underlying inflammatory bowel disease. School or physical activities may need to be restricted for up to 10–14 days. The impact of EN is usually limited to this 2-week period unless the disorder is recurrent, in which case it can cause more long-term disability. Restrictions imposed by an associated infectious process or inflammatory bowel disease may be limiting.

Differential diagnosis

ERYTHEMA INDURATUM OF BAZIN

Erythema nodosum may be confused with other processes involving the subcutaneous fat. The location of thrombophlebitis on the flexor rather than the extensor aspect of the leg is a

Erythema induratum is a lobular granulomatous panniculitis associated with vasculitis. It was first described in association with tuberculosis and is still considered a tuberculid.46 It presents

43. Naimer SA, Zvulunov A, Ben-Amitai D, et al. Plantar hidradenitis in children induced by exposure to wet footwear. Pediatr Emerg Care. 2000;16:182–183. 44. Ubogy Z, Persellin RH. Suppression of erythema nodosum by indomethacin. Acta Derm Venereol (Stockh). 1983;62:265–267.

45. Sterling JB, Heymann WR. Potassium iodide in dermatology: a 19th century drug for the 21st century – uses, pharmacology, adverse effects, and contraindications. J Am Acad Dermatol. 2000;43:691–697. 46. Chang MW, Lawrence R, Orlow SL. Erythema induratum of Bazin in an infant. Pediatrics. 1999;103:498–500.

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as nodular lesions, predominantly on the lower legs, that are indistinguishable from idiopathic nodular vasculitis.

Epidemiology Erythema induratum is most commonly seen on the lower legs of adult women. It is reported rarely in children.46,47

Presenting history

SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

The recurrent tender nodules have a predilection for the posterior lower legs but may occur on the upper limbs and buttocks. There may rarely be an associated fever and/or symptoms of Mycobacterium tuberculosis infection. Many patients otherwise appear healthy and have no clinical symptoms of tuberculosis. There may be a history of travel or contact with an individual with active tuberculosis.

Physical examination Erythematous to violaceous papules and nodules are seen mostly on the calves but occasionally on the upper extremities, face, feet, thighs and buttocks. The lesions frequently ulcerate. Nodules and ulceration persist for weeks or months before healing and continue to recur unless treated. The physical examination is often otherwise normal. An intradermal tuberculin test is typically positive.

Laboratory examination Chest radiography is indicated to look for pulmonary infiltrates or hilar adenopathy. Gastric aspirates and sputum cultures are less helpful in the diagnosis of tuberculosis in children than in adults.46

Pathophysiology and histogenesis Histopathologic examination of a nodule shows a lobular granulomatous panniculitis with fat necrosis. There is also septal panniculitis and vasculitis with chronic inflammation and fibrosis. Tubercle bacilli are rarely found in the skin lesions either by special stains or tissue culture. In some cases M. tuberculosis DNA may be detected by polymerase chain reaction. A tuberculid is believed to result from a hypersensitivity reaction to antigenic particles of tubercle bacilli that arrive in the skin by hematogenous spread. This theory is supported by the finding of M. tuberculosis DNA in skin specimens.46

Differential diagnosis Erythema induratum must be distinguished from EN and other forms of panniculitis. Erythema nodosum typically involves the

47. Lighter J, Tse DB, Li Y, et al. Erythema induratum in a child: evidence for a cell-mediated hyper-response to Mycobacterium tuberculosis. Pediatr Infect Dis J. 2009;28:326–328. 48. Ter Poorten JC, Hebert AA, Ilkiw R. Cold panniculitis in a neonate. J Am Acad Dermatol. 1995;33:383–385. 49. Day S, Klein BL. Popsicle panniculitis. Pediatr Emerg Care. 1992;8:91–93.

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anterior, rather than posterior, lower legs and does not ulcerate. The absence of vasculitis in EN is a further distinguishing feature. Erythema induratum of Bazin may be considered a subset of nodular vasculitis, of which many cases are idiopathic.

Therapy and prognosis A standard course of antituberculous therapy is curative in patients with clinical evidence of tuberculosis, a strongly positive intradermal tuberculin test, or when M. tuberculosis DNA is detected in the skin. The rarity of erythema induratum and nodular vasculitis in childhood may cause it to be underrecognized.46 A high index of suspicion and careful evaluation for underlying disease is essential.

COLD PANNICULITIS Cold panniculitis (also known as popsicle panniculitis and equestrian panniculitis) is a condition in which cold injury causes erythematous plaques and subcutaneous nodules. It occurs most often in infants and children. It may be more common in black infants.48 Exposure to frigid air, contact with cold objects such as popsicles, and use of ice packs and cooling blankets before cardiac surgery, or to treat cardiac arrhythmia, have all been implicated as precipitating agents.48–50 It may also be seen on the thighs and buttocks of young women who ride horseback,51 or on the thighs of hikers wearing light clothing in cold weather.

Presenting history The characteristic lesion is a persistent, nontender erythematous nodule. Lesions associated with popsicle injury occur on one or both cheeks. A history of popsicle ingestion, application of cold objects to the skin, or exposure to frigid air should be sought. In young horseback riders, similar lesions may appear on the buttocks or thighs.51 A recent history of hypothermia induction before cardiac surgery is relevant if subcutaneous fat necrosis develops on the trunk or upper limbs.50

Physical examination The red-purple, indurated nodules on the cheeks of infants and toddlers with popsicle panniculitis have a firm, rubbery consistency and are usually nontender. They may be unilateral or bilateral. The overlying skin is intact, and there is no epidermal change. The child is usually otherwise healthy. In panniculitis associated with hypothermia related to cardiac surgery, the clinical picture is indistinguishable from that of subcutaneous fat necrosis of the newborn with generalized lesions on the dorsal trunk and limbs.50

50. Silverman AK, Michels EH, Rasmussen JE. Subcutaneous fat necrosis in an infant, occurring after hypothermic cardiac surgery. Case report and analysis of etiologic factors. J Am Acad Dermatol. 1986;15:331–336. 51. Beacham BE, Cooper PH, Buchanan CS, et al. Equestrian cold panniculitis in women. Arch Dermatol. 1980;116:1025–1027.

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Laboratory findings No pathologic cold agglutins, cold hemolysins, cryoglobulins, or other laboratory abnormalities are detected in infants or children with localized cold panniculitis.49

Increased sensitivity of the subcutaneous fat of young infants to cold injury is believed to be due to a higher concentration of saturated fatty acids than is found in later childhood and adult life.52 Saturated fats have a propensity to solidify at higher temperatures and briefer exposure to cold than unsaturated fats. Application of ice or popsicles may reproduce the lesions.49 Histopathologically, cold panniculitis is characterized by fat necrosis; thickening of septa with plump fibroblasts; and a few foam cells, neutrophils, and eosinophils.36

SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

Pathophysiology and histogenesis

Figure 17.6  Subcutaneous fat necrosis of the newborn.

Differential diagnosis Localized fat necrosis, such as popsicle panniculitis, must be distinguished from bacterial cellulitis, trauma, and frostbite.49 All of these conditions are associated with pain or tenderness. Facial cellulitis is usually accompanied by fever and systemic symptoms. Epidermal changes, sometimes with vesiculation, are seen in cases of frostbite. Hypothermia-induced lesions that are clinically indistinguishable from subcutaneous fat necrosis may lack the characteristic histopathologic findings of fat crystals and calcium deposition.50,53

Therapy and prognosis Cold panniculitis resolves without sequelae in a few weeks to a few months.49 No intervention is recommended. Avoiding popsicles and general cold avoidance strategies should be effective.

SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN Fat necrosis of the subcutaneous tissues during the first few weeks of life is a disorder of unknown cause.53 It occurs in fullterm or postmature neonates. There is often a history of a difficult delivery or induced hypothermia. The usual age of onset is 1–6 weeks but it may be seen in the first week of life.

Presenting history Firm, red to violaceous, asymptomatic nodules occur in an otherwise healthy newborn. They are not usually present at birth. Sites of predilection are the cheeks, shoulders, back, buttocks, thighs, and legs. There is no limitation of movement even in cases with extensive involvement.

52. Chuang S-D, Chiu H-C, Chang C-C. Subcutaneous fat necrosis of the newborn complicating hypothermic cardiac surgery. Br J Dermatol. 1995;132:805–810. 53. Fretzin DF, Arias AM. Sclerema neonatorum and subcutaneous fat necrosis of the newborn. Pediatr Dermatol. 1987;4:112–122. 54. Burden AD, Krafchik BR. Subcutaneous fat necrosis of the newborn: a review of 11 cases. Pediatr Dermatol. 1999;16:384–387.

Physical examination The lesions are often symmetrical, variably circumscribed, nodules with a red to violaceous color (Fig. 17.6). Some lesions have a woody hard induration and may develop calcification. The affected areas are freely mobile over the underlying tissues.53 Larger nodules may become fluctuant and occasionally ulcerate, discharging an oleaginous material through the skin. Some depression or atrophy of the affected areas may develop, and a brownish discoloration may replace the original inflammatory appearance. Infants with subcutaneous fat necrosis should be observed for signs and symptoms of hypercalcemia, which can take up to 5 months to develop.54,55

Laboratory investigations Fat necrosis of the newborn has been associated with hypercalcemia.54–56 This was fatal in three cases. Serum calcium levels should therefore be monitored in these infants up to 5 months of age. Radiographic studies may show evidence of calcification in the subcutis.53 Elevated serum ferritin levels were detected in association with hypercalcemia in a single case; the hyperferritinemia subsided as the skin lesions resolved.57

Pathophysiology and histogenesis The subcutaneous tissues show a lobular panniculitis with crystallization of fat.36,53 Needle-like clefts are surrounded by a granulomatous inflammatory cell infiltrate that extends into the fibrous septa. Deposits of calcium may be seen. The cause and pathogenesis of the subcutaneous fat necrosis are unknown. Obstetric trauma, hypothermia, maternal diabetes mellitus, perinatal respiratory distress or asphyxia, and pre-eclamptic

55. Norwood-Galloway A, Lebwohl M, Phelps RG, et al. Subcutaneous fat necrosis of the newborn with hypercalcemia. J Am Acad Dermatol. 1987;16:435–439. 56. Fernandez-Lopez E, Garcia-Dorado J, de Unamuno P, et al. Subcutaneous fat necrosis of the newborn and idiopathic hypercalcemia. Dermatologica. 1990;180:250. 57. Zaulyanov LL, Jacob SE, Elgart GW, et al. Subcutaneous fat necrosis of the newborn and hyperferritinemia. Pediatr Dermatol. 2007;24:93.

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toxemia of pregnancy have been implicated as associated factors.54 In a study of 11 patients, 10 had been delivered by cesarean section.54 Differences in the composition of neonatal adipose tissue resulting in abnormal adaptation to cold exposure have been considered to be a significant predisposing factor. Similar lesions may be induced by hypothermia, although these do not show the characteristic crystallization of fat.50,52 The association between fat necrosis and hypercalcemia is not well understood.54

Differential diagnosis

SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

Subcutaneous fat necrosis of the newborn must be distinguished from sclerema neonatorum and other forms of panniculitis. Sclerema neonatorum is associated with diffuse hardening of the skin in an infant who is premature, debilitated, and often moribund. Although needle-like clefts may be seen histologically, sclerema lacks the associated inflammatory response seen in subcutaneous fat necrosis of the newborn.53 Some authors believe them to be variants of the same disease.54 Traumatic panniculitis induced by forceps delivery might also be confused.

Therapy and prognosis Treatment of subcutaneous fat necrosis is usually unnecessary. Most infants have an excellent prognosis with complete resolution of lesions within the first few months of life. Liquefaction and dystrophic calcification of larger lesions may result in more persistent nodules. Subcutaneous atrophy occasionally occurs. Hypercalcemia, if present, may result in a fatal outcome and should be actively treated.52,54,56 Current treatment includes hydration, furosemide, and corticosteroids.58 The use of bisphosphonates to treat hypercalcemia associated with subcutaneous fat necrosis of the newborn is controversial.58

shoulders, and buttocks. It is associated with severe illness including congenital heart disease, or gastroenteritis (e.g., necrotizing enterocolitis). The appearance of sclerema is a poor prognostic sign, and most affected infants die.53

Physical examination In sclerema, there is diffuse induration and immobility of the entire skin of the back, shoulders, and buttocks of the newborn. It spares the palms, soles, and scrotum.53 The infant is usually premature, hypothermic, acidotic, and acutely ill. Mottling of the vessels of the skin may be exaggerated over the affected area. Associated disorders, such as congenital heart disease or other congenital anomalies, may be present.

Laboratory findings Severe acid–base disturbances, electrolyte disturbances, hypoxia, and laboratory findings of infection may be found.

Pathophysiology and histogenesis Adipose cells containing needle-shaped clefts in radial array are distributed throughout the fat lobules.53 The clefts represent the sites of fat crystals removed during processing of the tissue. Fat necrosis itself does not occur. There may be a sparse infiltrate of acute and chronic inflammatory cells, and the fibrous septa between the fat lobules may be thickened.

Differential diagnosis Sclerema neonatorum may be distinguished from subcutaneous fat necrosis of the newborn on clinical and histopathologic grounds.50 Some believe them to be variants of the same disease, with sclerema occurring at birth and in severely ill infants.59

SCLEREMA NEONATORUM

Therapy and prognosis

In the past, there was considerable confusion between sclerema neonatorum and subcutaneous fat necrosis of the newborn. They are now classified as distinct disorders, although the distinction could be a result of disease severity. They have been observed together in the same infant.59

Therapy for sclerema neonatorum is directed at the infant’s underlying disease, and supportive care. Antibiotics may be necessary for intercurrent infection. The use of systemic corticosteroids is controversial.53 The prognosis for infants in whom this skin disorder develops is grave. Exchange transfusion has been beneficial in cases associated with neonatal sepsis.59

Epidemiology Sclerema occurs in extremely ill premature newborns.53,59 The incidence has decreased significantly since the 19th century and it is now a rare condition in North America.

Presenting history Sclerema is characterized by the rapid onset of diffuse hardening of the subcutaneous fat. All skin mobility is lost on the back,

58. Rice AM, Rivkees SA. Etidronate therapy for hypercalcemia in subcutaneous fat necrosis of the newborn. J Pediatr. 1999;134:349–351. 59. Zeb A, Darmstadt GL. Sclerema neonatorum: a review of nomenclature, clinical presentation, histological features, differential diagnoses and management. J Perinatol. 2008;28:453–460.

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LUPUS PANNICULITIS Lupus panniculitis (lupus profundus) is a disease characterized by purple nodules in a patient with systemic lupus erythematosus (SLE), discoid LE (DLE), or without clinical evidence of either. Kaposi is credited with the first description of subcutaneous nodules occurring in LE in 1869.60 He thought it to be LE plus sarcoidosis. In 1940, Irgang61 suggested that the subcutaneous nodules represented lupus panniculitis.

60. Fountain RB. Lupus erythematosus profundus. Br J Dermatol. 1968;80:571–579. 61. Irgang S. Lupus erythematosus profundus. Arch Dermatol Syphilol. 1940;42:97–108.

Diseases of the dermis and subcutaneous tissues

Pathophysiology and histogenesis 60,62

Lupus panniculitis is a rare manifestation of SLE. It may also occur in association with DLE and in the absence of distinctive features of either SLE or DLE.36 Dubois reported nodules in 11 of 150 patients with SLE, and Tuffanelli62 observed nodules in 6 of 228 patients with LE. Most cases begin after age 20 but may have their onset during late childhood.62 The disease has also been reported occasionally in children younger than 12 years of age.63,64 In at least two cases, lupus panniculitis was familial.62 Most reported cases have been in female patients.65,66 There is no racial predilection.

Presenting history Some patients with lupus panniculitis have a history of other symptoms of SLE. Arthralgias or arthritis may be particularly prominent. Fever, lymphadenopathy, discoid skin lesions, and thrombocytopenic purpura may be present.62 Individual skin lesions are usually described as purple bumps and may occasionally be tender.

Physical examination Lupus panniculitis lesions are firm, sharply defined, purple, 1-cm to 3-cm nodules, which may be found on the forehead, cheeks, buttocks, and upper arms. The lesions often heal with skin depressions as a result of associated lipoatrophy, and there may be overlying cutaneous hyperpigmentation.63 Discoid skin lesions,62 papulosquamous lesions, purpura, and cuticular telangiectasia should be sought. In addition, a general physical examination may reveal redness and swelling of joints, hypertension, or other systemic manifestations of LE.62

Laboratory findings A positive antinuclear antibody (ANA) test is usually obtained, and total hemolytic complement may be depressed in a patient with SLE.62 The ANA titer may be negative in patients without evidence of systemic disease.63 A child with lupus panniculitis and partial deficiency of C2 and C4 has been described.67 One case of generalized lupus panniculitis in a child was associated with the antiphospholipid antibody syndrome.64 Other laboratory findings of SLE may be present, such as leucopenia, anemia, thrombocytopenia, elevated blood urea nitrogen concentration, and elevated creatinine level.62 Urinary sediment changes, such as the presence of red cells, white cells, and casts, are found when renal disease is present.

62. Tuffanelli D. LE panniculitis (profundus). Arch Dermatol. 1971;103: 231–242. 63. Fox JN, Klapman MH, Rowe L. Lupus profundus in children: treatment with hydroxychloroquine. J Am Acad Dermatol. 1987;16:839–844. 64. Noussari HC, Kimyai-Asadi A, Santana HM, et al. Generalized lupus panniculitis and antiphospholipid antibody syndrome in a patient without complement deficiency. Pediatr Dermatol. 1999;16:273–276. 65. Bachmeyer C. Aractingi S, Blanc F, et al. Deep lupus erythematosus in children. Ann Dermatol Venereol. 1992;119:535–541.

Vacuolar damage of the basal cell, and a periadnexal and perivascular infiltrate in the segment of skin overlying the panniculitis, are useful diagnostic findings when present. However, the overlying skin is involved in less than 50% of cases. The characteristic histopathologic changes in lupus panniculitis are hyaline degeneration of fat lobules and a lymphocytic infiltrate, often with lymphoid nodules.36 Plasma cells and histiocytes are also seen. Fibrinoid deposits around the subcutaneous vessels and perivascular inflammatory cells may be observed. Vasculitis is not often seen.62 Calcification is sometimes found in areas of hyaline fat necrosis. On immunofluorescence, immunoglobulin (Ig), IgG, IgM, and C3 deposits may be observed in the blood vessel walls or at the dermoepidermal junction. The role of autoantibodies or of cellular immunity in the tissue damage in lupus panniculitis is not known.

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Epidemiology

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Differential diagnosis In EN, the skin involved is usually limited to the anterior lower extremities, whereas in lupus panniculitis, the upper half of the body is more likely to be involved. Lupus panniculitis lesions are more persistent, often lasting months in the same area without much change, whereas it is characteristic for EN to undergo significant changes over a 10–14-day period. The nodules of polyarteritis nodosa are accompanied by a mottled vascular pattern (livedo reticularis) of the overlying skin. The lesions of cold panniculitis are more transient, often resolving within a few weeks. Lupus panniculitis with lipoatrophy must be distinguished from lipoatrophy caused by injections, factitial panniculitis, trauma, and other forms of lipoatrophic panniculitis.

Therapy and prognosis Antimalarials are the most reliable therapy for lupus panniculitis.63,65,67,68 Chloroquine 4 mg/kg per day or hydroxychloroquine 5–6 mg/kg per day, with the dosage based on lean body weight, is the treatment of choice.68 Treatment for 2–6 months may be required. Systemic steroids are not recommended for lupus panniculitis unless they are indicated for other manifestations of SLE. Lipoatrophy is a common sequela. The risk of lipoatrophy should be considered before intralesional injection of steroids is performed.62 Topical steroids are not effective. Lupus panniculitis lesions may be cosmetically disfiguring and have significant psychosocial effects on the adolescent. Accompanying SLE may also restrict physical activities because of arthritis, thrombocytopenia, or renal disease. A comprehensive approach to the patient is advised. Consultation with other specialists is advisable for the child with multisystem involvement.

66. Martens PB, Moder KG, Ahmed I. Lupus panniculitis: clinical perspectives from a case series. J Rheumatol. 1999;26:68–72. 67. Taieb A, Hehunstre JP, Goeta J. Lupus erythematosus panniculitis with partial genetic deficiency of C2 and C4 in a child. Arch Dermatol. 1986;125:576–582. 68. Ziering CL, Rabinowitz LG, Esterly NB. Antimalarials for children: indications, toxicities, and guidelines. J Am Acad Dermatol. 1993;28:764–770.

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POLYARTERITIS NODOSA Polyarteritis nodosa is a term credited to Kussmaul in 1866 to describe segmental inflammation of small and medium-sized arteries and presenting as a systemic disease.1 It is not a common disorder in childhood.69,70 In 1980, Borrie71 recognized a chronic cutaneous form with a more benign prognosis. There have been a number of reports of cutaneous polyarteritis nodosa in children.72–81 It is controversial whether these are different disease entities and they may be considered to be closely related variants of the same disorder.82 Three newborn infants with cutaneous lesions of polyarteritic nodosa born to mothers with cutaneous disease have been described.83

Epidemiology SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

Both the systemic and predominantly cutaneous forms of poly­ arteritis nodosa are rare in childhood.

Presenting history Patients with polyarteritis nodosa present with painful or tender bumps with overlying skin discoloration. Fever, malaise and/or arthralgias may accompany the skin eruption.72 A history of a sore throat and fever, or a documented streptococcal pharyngitis may be obtained.79–81 The possibility of multisystem disease should be considered with particular reference to fever, weight loss, abdominal pain, renal disease, musculoskeletal symptoms, and peripheral neuropathy.69,84

Physical examination The typical cutaneous lesions are linear or oval nodules with livedo reticularis of the surrounding skin (Fig. 17.7). The lower legs and feet are most commonly involved. The livedo pattern may extend well beyond the nodules.72 Careful palpation of the area of livedo reveals the nodule. The skin overlying a palpable nodule may have a dusky discoloration or may be skin colored, eroded or ulcerated. Stellate necrosis is a common feature. A general physical examination should be performed to look for systemic signs of polyarteritis nodosa.69,84

69. Ozen S, Besbas N, Saatci U, et al. Diagnostic criteria for polyarteritis in childhood. J Pediatr. 1992;120:206–209. 70. Reimold EW, Weinberg AG, Fink CW, et al. Polyarteritis in children. Am J Dis Child. 1976;130:534–541. 71. Borrie P. Cutaneous polyarteritis nodosa. Br J Dermatol. 1972;55:87–95. 72. Jones SK, Lane AT, Golitz LE, et al. Cutaneous periarteritis nodosa in childhood. Am J Dis Child. 1985;139:920–922. 73. Fathella BM, Miller L, Brady S, Schaller JG. Cutaneous polyarteritis in children. J Am Acad Dermatol. 2005;53:724–728. 74. Sheth AP, Olson JC, Esterly NB. Cutaneous polyarteritis nodosa of childhood. J Am Acad Dermatol. 1994;31:561–563. 75. Ginarte M, Pereiro M, Toribio J. Cutaneous polyarteritis nodosa in a child. Pediatr Dermatol. 1998;15:103–107. 76. Siberry GK, Cohen BA, Johnson B. Cutaneous polyarteritis nodosa: reports of two cases and review of the literature. Arch Dermatol. 1994;130: 884–889. 77. Kumar L, Thapa BR, Sarkar B, et al. Benign cutaneous polyarteritis in children below 10 years of age – a clinical experience. Ann Rheum Dis. 1995;54:134–136. 78. Mocan H, Mocan MC, Peru H, et al. Cutaneous polyarteritis nodosa in a child and a review of the literature. Acta Paediatrica. 1998;87:351–352.

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Figure 17.7  Linear, dusky red nodules of cutaneous polyarteritis nodosa on the trunk of a 6-year-old child.

Laboratory findings In some well-documented childhood cases of chronic cutaneous polyarteritis nodosa, there were elevated erythrocyte sedimentation rates and positive antistreptolysin titers.81 All other laboratory parameters were normal including complete blood count, antinuclear antibody titer, and urinalysis. Patients with systemic polyarteritis nodosa may have anemia, thrombocytopenia, leukocytosis and elevated acute phase reactants as well as a positive antinuclear cytoplasmic antibody (ANCA) titer.

Pathophysiology and histogenesis Excisional biopsy of a palpable skin nodule shows vasculitis involving medium-sized arteries and arterioles in the septa of the subcutaneous fat.36,85 There is fibrinoid necrosis of the tunica intima, with infiltration of the vessel wall by neutrophils and other inflammatory cells. The inflammation is segmental, and a biopsy that does not include a nodule may show no vessel changes at all. IgM and C3 deposits in vessel walls are sometimes found with immunofluorescence examination of tissue

79. Sasamoto M, Shigeta Y, Hisashi K, et al. Cutaneous polyarteritis nodosa associated with streptococcal infection in a child and a review of the literature. Nihon Rinsho Meneki Gakkai Kaishi. 1999;22:144–150. 80. Albornoz MA, Benedetto AV, Korman M, et al. Relapsing cutaneous polyarteritis nodosa associated with streptococcal infections. Int J Dermatol. 1998;37:664–666. 81. Till SH, Amos RS. Long-term follow-up of juvenile-onset cutaneous polyarteritis nodosa associated with streptococcal infection. Br J Rheumatol. 1997;36:909–911. 82. Minkowitz G, Smoller BR, McNutt NS. Benign cutaneous polyarteritis nodosa: relationship to systemic polyarteritis nodosa and hepatitis B infection. Arch Dermatol. 1991;127:1520–1523. 83. Stone MS, Olson RR, Weismann DN, et al. Cutaneous vasculitis in the newborn of a mother with cutaneous polyarteritis nodosa. J Am Acad Dermatol. 1993;28:101–105. 84. Lightfoot RW, Beat AM, Blocher DA, et al. The American Academy of Rheumatology 1990 Criteria for the Classification of Polyarteritis Nodosa. Arthritis Rheum. 1990;33:1088–1093. 85. Daoud MS, Hutton KP, Gibson LE. Cutaneous periarteritis nodosa: a clinicopathologic study of 79 cases. Br J Dermatol. 1997;136:706–713.

Diseases of the dermis and subcutaneous tissues

Differential diagnosis Erythema nodosum may be confused with the cutaneous findings of polyarteritis nodosa and both can be associated with arthritis. The mottled, purple-red appearance of the skin in poly­ arteritis nodosa with segmental and linear nodules, rather than the round nodules of EN, is a useful distinguishing feature. In lupus panniculitis, the upper half of the body is involved rather than the lower extremities. Cold panniculitis may also mimic cutaneous polyarteritis nodosa but has a different distribution. Factitial panniculitis can result in linear nodules similar to poly­ arteritis nodosa, and careful inspection of the nodule surface for a punctum or injection site is mandatory. In factitial panniculitis, usually only one acute lesion is present, whereas many are present simultaneously in polyarteritis nodosa and the liviedo pattern is not present.

Therapy and prognosis The course of cutaneous polyarteritis nodosa in childhood is often one of relapses, each lasting 6 weeks to 6 months, with a chronic course.72 The long-term outlook is uncertain. In adults, the disorder may remain chronic and limited to the skin, only to have systemic involvement appear years later. One should therefore consider cutaneous polyarteritis nodosa as part of the spectrum of systemic polyarteritis nodosa, just as discoid skin lesions may be observed in SLE. A beneficial response to aspirin alone has been reported in one childhood case of cutaneous disease; another patient required the addition of low-dose alternate-day prednisolone.72 Other nonsteroidal agents may be beneficial. Intravenous immunoglobulin therapy has been found to be effective.88 If streptococcal infection is identified as an associated factor, prompt treatment of upper respiratory infections with appropriate antibiotics, such as penicillin, is recommended.73 Systemic steroids and/or cyclophosphamide are the treatments of choice for systemic disease. The mortality rate for systemic polyarteritis nodosa in children may be as high as 16%.69 The disease may restrict the

86. Meyrick-Thomas R, Black MM. The wide clinical spectrum of polyarteritis nodosa with cutaneous involvement. Clin Exp Dermatol. 1983;8:47–59. 87. Blau EB, Morris RF, Yunis EJ. Polyarteritis in older children. Pediatrics. 1977;60:227–234. 88. Uziel Y, Silverman ED. Intravenous immunoglobulin therapy in a child with cutaneous polyarteritis nodosa. Clin Exp Rheumatol. 1998;16; 187–189. 89. Ackermann AB, Mosher DT, Schwamm HA. Factitial Weber-Christian syndrome. JAMA. 1966;198:731–736.

physical activities of the child because of painful skin nodules or associated systemic disease. The psychological burden of a chronic relapsing disease can have a significant emotional impact on the child.

FACTITIAL PANNICULITIS Factitial panniculitis is a condition in which red or purple-red nodules result from injection of foreign material into the fat layer.89–91 Beerman92 first appreciated that at least some patients with the diagnosis of Weber–Christian panniculitis had factitial panniculitis due to subcutaneous injections. Ackermann et al.89 published the first well-documented case of self-injection producing factitial panniculitis in a child. SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

specimens.86 Immune complexes may be found in the circulation.86,87 An infectious agent is suspected as an initiating factor in poly­ arteritis nodosa. Hepatitis B and C have been implicated in systemic PAN in adults.82,85 In chronic cutaneous polyarteritis nodosa in children, streptococcal-associated disease has been reported.79,81 Circulating immune complexes generated as a response to an infectious agent, such as Streptococcus, may injure cutaneous vessels, fix complement, and attract neutrophils with subsequent damage to the subcutaneous blood vessels; other immune mechanisms may modify or amplify the inflammatory response.

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Epidemiology Factitial panniculitis has been recognized most frequently in female patients.89–92 It is usually seen in adolescence or preadolescence rather than in young children. There is no racial predilection.

Presenting history Frequently, a history of visits to many different doctors is obtained. Invariably, trauma or injection is denied. The history of the present illness is highly variable and often contradictory from visit to visit or from doctor to doctor. The appearance of the lesions varies, as well as their duration.89–92 Often, the psychosocial history is most revealing, with family separation, death, conflict, or other emotional upsets being events preceding the onset of the skin lesions. Asking the patient, ‘Do you know the cause of these lumps?’ may result in important clues. The lesions are an attention-gaining strategy in a child whose emotional needs are not being met. In small children, factitial lesions should always raise the possibility of Munchausen syndrome by proxy.93

Physical examination Red or bruise-like nodules of different ages are noted usually on the anterior legs. Usually, only one lesion is in the red, acute inflammatory stage, but numerous older lesions may be present. Careful inspection may reveal an injection site, but this can easily be missed, particularly if only older lesions are present. Observation in a hospital situation may be required. Direct observation of injection is the most definitive measure in making the diagnosis. An important clue is the indifferent affect of the patient toward the illness. Some patients may be withdrawn or reclusive. Low-grade fever may follow an injection, but arthralgias and other systemic systems are conspicuously absent.

90. Lyell A. Cutaneous artefactual disease. J Am Acad Dermatol. 1979;1:391–407. 91. Spraker MK. Cutaneous artefactual disease, an appeal for help. Pediatr Clin North Am. 1983;30:659–668. 92. Beerman H. Weber-Christian syndrome. Am J Med. 1953;225:446. 93. Bools CN, Neale BA, Meadow SR. Co-morbidity associated with fabricated illness (Munchausen syndrome by proxy). Arch Dis Child. 1992;67:77–79.

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Laboratory findings All laboratory findings are usually normal, including the erythrocyte sedimentation rate and the white blood cell count.89–91 Normal laboratory test results in the face of active inflammation should make one suspect factitial disease.

Pathophysiology and histogenesis

SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

The response of the fat layer is inflammatory, and the character of the response is determined by the nature of the injected material. Milk, feces, mineral oil, paraffin, silicone, and pentazocine have all been reported to be injected.89–92,94 Focal necrosis of fat and a neutrophilic accumulation may be observed. Hemorrhage, infiltration with lymphocytes, and foreign body giant cells may be present. A biopsy of a late lesion shows considerable fibrosis of the fat layer. In addition, birefringent particles may be present in the fat layer.36 In every biopsy in which factitial panniculitis is suspected, examination with polarized light is recommended. Occasionally, the material contains pigment, and bizarre pigmented areas are observed in the fat layer. The absence of inflammation of the blood vessels is an important histologic clue to the possibility of factitial panniculitis.

Differential diagnosis Erythema nodosum often has several red nodules present in the same stage of development, whereas factitial panniculitis usually has only one. The presence of arthritis and an elevated erythrocyte sedimentation rate are suggestive of erythema nodosum. In cutaneous polyarteritis nodosa, a mottled pattern of the skin is helpful. In all circumstances, an excisional biopsy of a nodular lesion is recommended. Biopsy of both an early and a late lesion may be good strategy to help find foreign body giant cells in late lesions and foreign material in early lesions.

Therapy and prognosis Therapy is primarily psychiatric. Supportive care for the area of panniculitis includes keeping the weight off the area and rest. Understanding that this represents an emotional problem and being supportive of the child are essential for the clinician. The lesions heal once injections are stopped, but those with severe fat necrosis may heal with atrophy of the fat layer.89,92,94 Longterm psychiatric care is often required. The emotional problem leading to factitial panniculitis may influence school performance, interaction with peers, and physical activities.90,91 The psychiatric and emotional aspects of this disease predominate over

94. Forstrom L, Winklemann RK. Factitial panniculitis. Arch Dermatol. 1974;110:747–750. 95. Edmonds BK, Hodge JA, Rietschel RL. Alpha 1-antitrypsin deficiencyassociated panniculitis: case report and review of the literature. Pediatr Dermatol. 1991;8:296–299. 96. Breit SN, Clark P, Robinson JP, et al. Familial occurrence of alpha 1-antitrypsin deficiency and Weber-Christian disease. Arch Dermatol. 1983;119:198–202. 97. Warter J, Storck D, Grosshans E, et al. Syndrome de Weber-Christian associé a un déficit en alpha 1-antitrypsine. Enquête familiale. Ann Med Interne (Paris). 1972;123:877–882. 98. Smith KC, Su WPD, Pittelkow MR, et al. Clinical and pathologic correlations in 96 patients with panniculitis, including 15 patients with

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the clinical picture. (See Ch. 2 for additional treatment of psychocutaneous disorders.)

α1-ANTITRYPSIN DEFICIENCY α1-Antitrypsin is a serine protease inhibitor that regulates the action of proteolytic enzymes, including elastase and collagenase.36 There are more than 33 different alleles for this enzyme, each of which is designated by a letter of the alphabet.95 In any individual, two of these combine to determine the α1-antitrypsin phenotype.96 There is thus a spectrum of enzyme phenotypes from the homozygous MM phenotype, present in most of the population, to the homozygous ZZ variant, which has the lowest plasma levels of α1-antitrypsin activity.95 α1-Antitrypsin deficiency is inherited as an autosomal codominant disorder, with each inherited allele being of equal importance in determining the phenotype. It has been linked principally to emphysema and liver disease. An association with panniculitis was recognized in 1972.97

Epidemiology Most reported cases of panniculitis have occurred in adults.96–98 There have been reports of α1-antitrypsin deficiency presenting as panniculitis in childhood and adolescence.95,96,99,100 Familial occurrence has been documented.96

Clinical features Lesions are located on the trunk or extremities and present as recurrent painful, ulcerated, subcutaneous nodules that drain an oily serosanguineous fluid. The lesions may be mistaken for bacterial cellulitis. There is often a history of preceding trauma.

Pathogenesis and histogenesis The typical histopathologic features are those of an acute lobular panniculitis with numerous neutrophils and necrosis of fat.36,101 There are often large areas of normal panniculus adjacent to necrotic fat lobules. Hemorrhage and an inflammatory infiltrate may be present at the periphery of the area of panniculitis. Histiocytes and foam cells may be seen. Vasculitis does not occur. Older lesions show lymphocytes, foamy macrophages, and varying degrees of fibrosis.102 The mechanisms whereby α1-antitrypsin deficiency leads to panniculitis are not fully understood. The histopathologic changes of liquefactive necrosis of fat and inflammation may be explained by lack of inhibition of proteolytic enzymes, which

99. 100. 101. 102.

deficient levels of alpha 1-antitrypsin. J Am Acad Dermatol. 1989;21:1192–1196. Hendrick SJ, Silverman AK, Solomon AR, et al. Alpha 1-antitrypsin deficiency associated with panniculitis. J Am Acad Dermatol. 1988;18:684–692. Chng WJ, Henderson CA. Suppurative panniculitis associated with alpha 1-antitrypsin deficiency (PiSZ phenotype) treated with doxycycline. Br J Dermatol. 2001;144:1282–1283. Geller JD, Su WPD. A subtle clue to the histologic diagnosis of early alpha 1-antitrypsin deficiency. J Am Acad Dermatol. 1994;31:241–245. Requena L, Sanchez Yus E. Panniculitis. J Am Acad Dermatol. 2001;45:325–361.

Diseases of the dermis and subcutaneous tissues

results in dissolution of collagen in the dermis and fibrous septa of the subcutis.95 Lack of neutral proteases that modulate inflammation and chemotaxis may also be implicated.36

Laboratory tests The diagnosis is established by the finding of decreased quantitative serum levels of α1-antitrypsin. Enzyme phenotyping may also be useful.

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Pathogenesis and histogenesis The histopathologic features are similar to those of subcutaneous fat necrosis of the newborn.102 The needle-like clefts are not as numerous as in the newborn disease. The pathogenesis is poorly understood. It is possible that withdrawal of steroids upsets the normal ratio of saturated and unsaturated fat in the panniculus, leading to crystal formation.105

Therapy and prognosis A combination of panniculitis with ulceration and consistent histopathologic findings should raise the possibility of α1antitrypsin deficiency. Factitial panniculitis may be considered in the differential diagnosis because of the presence of ulceration. Ulceration also occurs in pancreatic panniculitis, but the histologic features of this disease are distinctive with fat necrosis, presence of ‘ghost cells,’ and saponification. A history of trauma may be misleading and suggest a diagnosis of traumatic fat necrosis or bacterial infection. An infectious cause should always be excluded because these cases resemble cellulitis clinically and may have a heavy neutrophilic infiltrate.36

Treatment Dapsone is the traditional treatment of choice.98 Doxycycline and colchicine are also reported to be effective.100,103 Infusion of proteinase inhibitor concentrate obtained from healthy donors has been used.104 Corticosteroids and antibiotics are ineffective, and surgical débridement may be detrimental.

POST-STEROID PANNICULITIS Post-steroid panniculitis is a very rare complication of tapering or stopping systemic steroids.105,106 It has been reported in children receiving long-term, high-dose steroids.

Clinical features Post-steroid panniculitis presents with tender, erythematous nodules during tapering or cessation of systemic steroids. Lesions develop on the cheeks, arms, trunk, or jawline.105

103. Linnares-Barrios M, Conijo-Mir JS, Artola-Igarza JL, et al. Panniculitis due to α1-antitrypsin deficiency induced by cryosurgery. Br J Dermatol. 1998;138:552–553. 104. Smith KC, Pittelkow MR, Su WPD. Panniculitis associated with severe alpha-1 antitrypsin deficiency. Arch Dermatol. 1987;123:1655–1661. 105. Reichel M, Diaz Cascajo C. Bilateral jawline nodules in a child with a brain-stem glioma. Arch Dermatol. 1995;131:1447–1452. 106. Silverman RA, Newman AJ, LeVine MJ. Post-steroid panniculitis: a case report. Pediatr Dermatol. 1988;5:92–93. 107. Winkelmann RK, Bowie EJW. Hemorrhagic diathesis associated with benign histiocytic, cytophagic panniculitis and systemic histiocytosis. Arch Intern Med. 1980;140:1460–1463. 108. Hytiroglou P, Phelps RG, Wattenberg DJ, et al. Histiocytic cytophagic panniculitis: molecular evidence for a clonal T-cell disorder. J Am Acad Dermatol. 1992;27:333–336. 109. Craig AJ, Cualing H, Thomas G, et al. Cytophagic histiocytic panniculitis – a syndrome associated with benign and malignant panniculitis: case comparison and review of the literature. J Am Acad Dermatol. 1998;39:721–736.

The lesions usually resolve spontaneously with time.102 A temporary increase in dose and slower tapering of the systemic steroid may be necessary. SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

Differential diagnosis

HISTIOCYTIC CYTOPHAGIC PANNICULITIS AND SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA Histiocytic cytophagic panniculitis was first described in 1980 by Winkelmann and Bowie.107 It is associated with the hemophagocytic syndrome.107–111 Although histiocytic cytophagic panniculitis may sometimes follow a benign course, there is convincing evidence that this disorder belongs within the spectrum of malignant T-cell lymphoma.108,110,111 The term subcutaneous panniculitislike T-cell lymphoma is considered more appropriate by some authors.111 It is characterized histopathologically by histiocytosis and hemophagocytosis in the skin, subcutaneous fat, and other organs.36,102 Clinically, it presents as inflammatory subcutaneous nodules associated with fever, serositis, hepatosplenomegaly, lymphadenopathy, and an often fatal hemorrhagic diathesis. Childhood cases have been reported.109,112–116

Presenting features The condition presents with painful, indurated, inflammatory skin nodules associated with fever and malaise. There is often ulceration of the skin overlying the nodules and plaques. The disease may be initially localized to one body area and later become generalized. Initial sites involved the face in two children and the gluteal region or the extremities in other instances.112–114 Mucosal ulceration may also occur.114

110. Marzano AV, Berti E, Paulli M, et al. Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma. Arch Dermatol. 2000;136:889–896. 111. Wick MR, Patterson JW. Cytophagic histiocytic panniculitis – a critical reappraisal. Arch Dermatol. 2000;136:922–924. 112. Hung IJ, Kuo TT, Sun CF. Subcutaneous panniculitic T-cell lymphoma developing in a child with idiopathic myelofibrosis. J Pediatr Hem Onc. 1999;21:38–41. 113. Chan YF, Lee KC, Llewellyn H. Subcutaneous T-cell lymphoma presenting as panniculitis in children: report of 2 cases. Pediatr Pathol. 1994;14:595–608. 114. Shani-Adir A, Lucky AW, Prendiville J, et al. Subcutaneous panniculitic T-cell lymphoma in children: Response to combination therapy with cyclosporine and chemotherapy. J Am Acad Dermatol. 2004;50:S18–S22. 115. Garcia-Consuegra J, Barrio MI, Fonseca E, et al. Histiocytic cytophagic panniculitis: report of a case in a 12-year-old girl. Eur J Pediatr. 1991;150:468–469. 116. Koh MJ, Sadarangani S, Chan Y-C, et al. Aggressive panniculitis-like T-cell lymphoma with hemophagocytosis in 2 children. J Am Acad Dermatol. 2009;60.

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Laboratory findings Pancytopenia and a coagulopathy are associated laboratory findings. Liver function tests may be abnormal.

Pathophysiology and histogenesis

SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

The histology is characterized by a lobular panniculitis consisting of a lymphocytic infiltrate admixed with histiocytes that phagocytose erythrocytes, leukocytes, and platelets.36,102 These large phagocytic cells are termed ‘beanbag’ histiocytes. Despite the often apparently benign appearance of the lymphocytic cellular infiltrate, this may be a clonal T-cell disorder and, probably in most cases, represents a subcutaneous form of malignant T-cell lymphoma.108,110,111 Rimming of neoplastic T cells may be seen around fat cells. Immunophenotyping may be positive for cytotoxic markers CD8, TIA-1 and Granzyme B.114,116

Differential diagnosis The characteristic histologic findings distinguish this disease from other forms of panniculitis. Immunophenotyping and gene rearrangement studies should be performed to evaluate for T-cell lymphoma.108

Treatment The disorder may be associated with a rapidly fatal hemophagocytic syndrome or run a more protracted indolent course. Combination chemotherapy and cyclosporine have been used to treat subcutaneous T-cell lymphoma.112–115 Children with more indolent disease have been treated successfully with cyclosporine or prednisone.109,111 Death may occur despite treatment with systemic steroids and chemotherapy.113,115 Bone marrow transplantation has been performed.116

IDIOPATHIC AND LIPOATROPHIC PANNICULITIS IN CHILDHOOD The term lipoatrophy refers to loss of subcutaneous fat. It may appear without signs of preceding inflammation or in association with clinical or histologic evidence of panniculitis. This distinction is not always clear-cut.117 Lipoatrophy is known to occur in lupus panniculitis, in panniculitis associated with morphea and dermatomyositis,118–120 and following injections and traumatic fat necrosis.121 When these and other well-defined

117. Aronson IK, Zeitz HJ, Variakojis D. Panniculitis in childhood. Pediatr Dermatol. 1988;5:216–230. 118. Kavanagh G, Colaco CB, Kennedy CTC. Juvenile dermatomyositis associated with partial lipoatrophy. J Am Acad Dermatol. 1993;28:348-. 119. Commens C, O’Neill P, Walker G. Dermatomyositis associated with multifocal lipoatrophy. J Am Acad Dermatol. 1990;22:966–969. 120. Ghali FE, Reed AM, Groben PA, et al. Panniculitis in dermatomyositis. Pediatr Dermatol. 1999;16:270–272. 121. Dahl PR, Zalla MJ, Winkelmann RK. Localized involutional lipoatrophy: a clinicopathologic study of 16 patients. J Am Acad Dermatol. 1996;35:523–528. 122. Sorensen RU, Abramowsky CR, Stern RC. Ten-year course of early onset Weber-Christian syndrome with recurrent pneumonia: a suggestion for pathogenesis. Pediatrics. 1986;78:115–120.

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entities have been excluded, there remain a number of descriptions in the literature of idiopathic panniculitis, often associated with fever and/or subsequent development of lipoatrophy.117 Other organ systems may also be involved. Many similar cases have been reported in the past as examples of Weber–Christian disease.122,123 Winkelmann124 used the term ‘connective tissue panniculitis’ to refer to a syndrome of recurrent, progressive, lobular lymphocytic panniculitis with intermittent low-grade fever. The term connective tissue panniculitis was justified by the finding of occasional positive ANA titers in the serum. The lymphoid nodules and hyaline necrosis of lupus panniculitis were not observed. Some lesions healed without sequelae, and others resulted in subcutaneous atrophy and cutaneous hyperpigmentation. A potential association with autoimmune disease was also postulated by Billings et al.125 who described three children with a lobular panniculitis that resulted in extensive lipoatrophy. Two of these children had associated low-grade fevers during episodes of panniculitis. Two patients had insulin-dependent diabetes mellitus; one child also had Hashimoto’s thyroiditis, and in a third patient, juvenile rheumatoid arthritis developed. Winkelmann et al.126 described three children with a lipophagic granulomatous lipoatrophy, which they termed lipophagic panniculitis of childhood. The histologic findings were those of a panlobular panniculitis with lipophagic histiocytes and giant cells. Two children had recurrent fever. One child had an elevated ANA titer. Fourteen similar cases previously reported as Weber–Christian disease were reviewed by these authors. This condition may be the same entity as cytophagic histiocytic panniculitis. Solomon et al.127 described a case of fever and recurrent lobular panniculitis in a child. The lymphocytic infiltrate in the subcutis consisted predominantly of suppressor-cytotoxic T lymphocytes. Associated lipoatrophy was not described. Roth et al.128 reported panniculitis localized to the ankles with a lobular lymphohistiocytic infiltrate and masses of foam cells. There was associated annular lipoatrophy, and the authors termed this condition ‘annular atrophic connective tissue panniculitis of the ankles.’ Randle et al.129 reported four children with idiopathic panniculitis, three of whom had a lobular panniculitis with subsequent lipoatrophy. These patients responded well to systemic corticosteroids. Sorensen et al.123 reported a good response to hydroxychloroquine in a 10-year-old patient with infantileonset ‘Weber–Christian’ panniculitis and associated recurrent pneumonitis.

123. Sorensen RU, Abramowsky CR, Stern RC. Corticosteroid-sparing effect of hydroxychloroquine in a patient with early-onset Weber-Christian syndrome. J Am Acad Dermatol. 1990;23:1172–1174. 124. Winkelmann RK. Panniculitis in connective tissue disease. Arch Dermatol. 1983;119:336–344. 125. Billings JK, Milgraum SS, Gupta AK, et al. Lipoatrophic panniculitis: a possible autoimmune inflammatory disease of fat. Report of three cases. Arch Dermatol. 1987;123:1662–1666. 126. Winkelmann RK, McEvoy MT, Peters MS. Lipophagic panniculitis of childhood. J Am Acad Dermatol. 1989;21:971–978. 127. Solomon AR, Kantak AG, Ramirez JE, et al. Suppressor-cytotoxic T-lymphocyte panniculitis. Pediatr Dermatol. 1986;3:295–299. 128. Roth DE, Schikler KN, Callen JP. Annular atrophic connective tissue panniculitis of the ankles. J Am Acad Dermatol. 1989;21:1152–1156. 129. Randle SM, Richter MB, Palmer RG, et al. Panniculitis: report of four cases and literature review. Arch Dis Child. 1991;66:1057–1060.

Diseases of the dermis and subcutaneous tissues

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Martinez et al.130 postulated an association between extensive lipoatrophic panniculitis and a chromosome 10 abnormality in a 3-year-old girl because the human pancreatic lipase gene maps to chromosome 10q24–26. The pathogenesis of these idiopathic forms of panniculitis38,37 and lipoatrophy is poorly understood.

EOSINOPHILIC CELLULITIS

Figure 17.8  Eosinophilic cellulitis. Acute, vesiculobullous stage. SKIN NODULES WITH COLOR CHANGE OF THE OVERLYING SKIN

Eosinophilic cellulitis, or Wells syndrome, is a rare recurrent dermatosis characterized clinically by erythematous, urticarial plaques that resolve slowly with induration and a blue-black discoloration, and histopathologically by a distinctive pattern of tissue eosinophilia and the presence of flame figures.131–142

Historical aspects Eosinophilic cellulitis was described first by Wells in 1971 as ‘recurrent granulomatous dermatitis with eosinophilia.’ The term eosinophilic cellulitis was introduced by Wells and Smith131 in 1979. Although these and later authors recognized that a dermal eosinophilic infiltrate with flame figures may be seen in other disorders, the term eosinophilic cellulitis is often used to designate this histopathologic pattern.131,135,139 To avoid semantic confusion, some authors prefer the eponym, Wells syndrome, to denote the distinctive dermatosis.

Epidemiology Eosinophilic cellulitis is a rare disorder. It has been described predominantly in adults but there have been reported cases in children.132,134–138 The majority of childhood cases have been male, although there appears to be no sex preponderance in adults.133,136 There is no known genetic predisposition. Eosinophilic cellulitis has been encountered in association with insect bites, bee stings, onchocerciasis, giardiasis, toxocariasis, varicella, mumps, drug reactions, malignancy, myeloproliferative disorders, atopic dermatitis, and Trichophyton rubrum infection.131–133,136,137,140–142

Clinical features The clinical picture of eosinophilic cellulitis evolves through an acute, subacute, and chronic stage before eventual resolution. Lesions may occur on the extremities, face, or trunk. Similar episodes, often at the same anatomic sites, recur over several

130. Martinez A, Malone M, Hoeger P, et al. Lipoatrophic panniculitis and chromosome 10 abnormality. Br J Dermatol. 2000;142:1034–1039. 131. Wells GC, Smith NP. Eosinophilic cellulitis. Br J Dermatol. 1979;100:101–109. 132. Gilliam AE, Bruckner AL, Howard RM, et al. Bullous ‘cellulitis’ with eosinophilia: case report and review of Well’s syndrome in childhood. Pediatrics. 2005;116:e149–e155. 133. Melski JW. Wells’ syndrome, insect bites, and eosinophils. Dermatol Clin. 1990;8:287–293. 134. Lindskov R, Illum N, Weismann K, et al. Eosinophilic cellulitis: five cases. Acta Derm Venereol (Stockh). 1988;68:325–330. 135. Nielsen T, Schmidt H, Sogaard H. Eosinophilic cellulitis (Wells’ syndrome) in a child. Arch Dermatol. 1981;117:427–429. 136. Reichel M, Isseroff RR, Vogt PJ, et al. Wells’ syndrome in children: varicella infection as a precipitating event. Br J Dermatol. 1991;124:187–190.

months or years. The acute stage is characterized by erythematous, urticarial, edematous plaques that resemble bacterial cellulitis but are relatively cool on palpation. There may be a history of prodromal burning or itching. Blisters may develop on the surface and are sometimes hemorrhagic (Fig. 17.8).132 After several days, the lesions expand with central flattening and develop an indurated consistency resembling morphea, with a bluish or greenish discoloration. This resolves without scarring over a period of several weeks. The patient is usually otherwise healthy although there may be associated fever, malaise, or arthralgia.133

Laboratory investigations A peripheral blood eosinophilia is found in at least 50% of cases. The erythrocyte sedimentation rate is occasionally elevated.

Histopathology In the acute stage, there is an intense dermal infiltrate, predominantly composed of eosinophils, and dermal edema.131,133,139 Blisters may be subepidermal or intraepidermal. In the subacute stage, there are multiple histiocytes and eosinophils in addition to the characteristic flame figures. A flame figure consists of granular eosinophilic material that is adherent to collagen and is surrounded by histiocytes and giant cells of the foreign body type. The eosinophilic material has been shown to contain eosinophil major basic protein. As the lesions resolve, the eosinophils disappear, and the phagocytic histiocytes

137. Anderson CR, Jenkins D, Tron V, et al. Well’s syndrome in childhood: case report and review of the literature. J Am Acad Dermatol. 1995;33:857–864. 138. Garty B-Z, Feinmesser M, David M, et al. Congenital Wells syndrome. Pediatr Dermatol. 1997;14:312–315. 139. Aberer W, Konrad K, Wolff K. Wells’ syndrome is a distinctive disease entity and not a histologic diagnosis. J Am Acad Dermatol. 1988;18:105–114. 140. Prendiville JS, Russell Jones R, Bryceson A. Eosinophilic cellulitis as a manifestation of onchocerciasis. J R Soc Med. 1985;78(suppl. 11):21–22. 141. Hurni MA, Gerbig AW, Braathen LR, et al. Toxocariasis and Wells’ syndrome: a causal relationship? Dermatology. 1997;195:325–328. 142. Canonne D, Dubost-Brama A, Segard M, et al. Wells’ syndrome associated with recurrent giardiasis. Br J Dermatol. 2000;143:425–427.

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surrounding flame figures remain in the dermis. Vasculitis is not observed.

Table 17.1  Classification of amyloidosis SOURCE OF AMYLOID

Pathogenesis and histogenesis

AMYLOIDOSIS

The cause of eosinophilic cellulitis remains unclear. Some controversy and confusion has arisen because the histopathologic pattern of eosinophilia and flame figures may be shared by a number of other inflammatory dermatoses, including atopic eczema, prurigo, bullous pemphigoid, and tinea infections.139 Similar clinical and histologic findings have been observed with insect bite reactions and parasitic diseases such as onchocerciasis.133,139,140 Some authors consider eosinophilic cellulitis a histopathologic diagnosis rather than a distinct disease entity, but this has been disputed by others.139 It is probable that the disorder has more than one etiologic agent in a manner analogous to vasculitis.139 Precipitating agents appear to have in common an ability to induce tissue eosinophilia. The pathogenetic mechanisms whereby an exaggerated and abnormal eosinophilic response occurs in cases of Wells syndrome are unclear at present. Raised levels of interleukin (IL)-5 and eosinophilic cation protein (ECP) have been found in the peripheral blood and in blister fluid.143

Cutaneous amyloidosis (PLCA)   Macular   Papular (lichenoid)   Biphasic   Bullous   Nodular Localized organ deposition   Small deposits in and around tumors and blood vessels in   aging Systemic amyloidosis   Associated with immune dyscrasias (e.g., myeloma)   Reactive due to chronic inflammatory disease (e.g., tuberculosis, juvenile rheumatoid arthritis, or Hodgkin’s disease) Heredofamilial   Neurotropic   Non-neurotropic

Keratinocytes

Immunoglobin AL protein Keratinocytes

Immunoglobin AL protein SAA protein → AA protein

Transthyretin (prealbumin) SAA protein → AA protein

Differential diagnosis The diagnosis of eosinophilic cellulitis is based on a combination of the clinical findings, course of the disease, and the characteristic histopathology. In the acute stage, bacterial cellulitis, erysipelas, parasitic infections, insect bites, and drug reactions must be considered. Other conditions characterized by tissue eosinophilia, such as Churg–Strauss vasculitis or the hypereosinophilia syndrome (HES), can usually be distinguished by the absence of vasculitis or multiorgan involvement and presence of flame figures in Wells syndrome. Many authors have emphasized that a diagnosis of eosinophilic cellulitis should not be made on the basis of the histopathologic features alone.139

Treatment and prognosis Episodes of eosinophilic cellulitis recur over several months or years. Eventual spontaneous remission of the disease without adverse sequelae is the rule. Atrophic scarring of the scalp after secondary bacterial infection has been reported.135,137 Treatment is not always necessary. Every attempt should be made to rule out and treat an underlying infectious disease or association with systemic organ involvement, as in HES. Secondary bacterial infection should be treated with appropriate antibiotic therapy. Systemic steroids may be beneficial.136,137 There are also reports of benefit from dapsone and phototherapy in adult patients.143,144

143. Espana A, Sanz ML, Sola J, et al. Wells’ syndrome (eosinophilic cellulitis): correlation between clinical activity, eosinophil levels, eosinophil cation protein and interleukin-5. Br J Dermatol. 1999;140:127–130. 144. Diridl E, Honigsmann H, Tanew A. Wells’ syndrome responsive to PUVA therapy. Br J Dermatol. 1997;137:467–484. 145. Cunnane G. Amyloid precursors and amyloidosis in inflammatory arthritis. Curr Opin Rheumatol. 2001;13:67–73. 146. Wong C-K. History and modern concepts. Clin Derm. 1990;8:1–6.

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AMYLOIDOSIS Alfons L. Krol Amyloidosis is the name given to a group of distinct syndromes caused by the deposition of an insoluble fibrillar protein in various tissue; this may result in organ dysfunction or failure.145 Schleiden introduced the term ‘amyloid’ to describe the reactions of plant cellulose to iodine and sulfuric acid.146 Virchow observed this waxy homogeneous material in human tissue, and used the term ‘amyloid change’ because of the similar characteristics of positive staining with iodine.147 Konigsstein147 is credited with the first description of cutaneous amyloidosis, describing a child with this disorder in 1925. Amyloidosis is classified into two forms based on its distribution: localized and systemic. Each form is further characterized according to the type of amyloid protein within the fibril (amyloid AA, amyloid AL, or keratinocyte derived amyloid, KA) (Table 17.1).148,149 The amount and site of deposition often determine whether its presence is significant or incidental. Cutaneous amyloidosis is a rare disease in childhood, usually seen as macular or lichen amyloidosis, which are the most frequent forms of primary localized cutaneous amyloidosis (PLCA).

147. Konigsstein H. Uber Amyloidose der Haut. Arch Dermatol Syph. 1925;148:330. 148. Glenner GG. Amyloid deposits and amyloidosis. The beta-fibrilloses, Part 2. N Engl J Med. 1980;302:1333–1343. 149. Breathnach SM. Amyloid and amyloidosis. J Am Acad Dermatol. 1988;18:1–16.

Diseases of the dermis and subcutaneous tissues

Epidemiology Localized cutaneous amyloidosis usually begins in adolescence. The most common forms seen in children are the macular and lichenoid variants that are often seen in those of Asian, Middle Eastern or Latin American origin.159–161 Familial variants162–164 inherited in an autosomal dominant manner have been reported. These often present as a ‘biphasic’ illness with both macular and lichenoid papular lesions present in the same patient.162,165–167 Lichen amyloidosis has been reported with Sipple syndrome (MEN 2A),168,169 and in a rare autosomal-dominant disorder

150. Buxbaum J. The amyloidoses. In: Klippel JH, Dieppe PA, ed. Rheumatology. ed 2. London: Mosby International. 1998;13:615–628. 151. Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Medicine. 1991;70:246–256. 152. Savolainen HA, Isomaki HA. Decrease in the number of deaths from secondary amyloidosis in patients with juvenile rheumatoid arthritis. J Rheumatol. 1993;20:1201–1203. 153. Rubinow A, Cohen AS. Skin involvement in generalized amyloidosis: a study of clinically involved and uninvolved skin in 50 patients with primary and secondary amyloidosis. Ann Intern Med. 1978;88:781. 154. Bywaters EGL. Deaths in juvenile chronic polyarthritis. Arthritis Rheum. 1977;20:256. 155. Cohen AS. An update of clinical, pathologic and biochemical aspects of amyloidosis. Int J Dermatol. 1981;20:515. 156. Benson MD. Inherited amyloidosis. J Med. 1991;28:73–78. 157. Meretoja J. Familial systemic paramyloidosis with lattice dystrophy of the cornea, progressive cranial neuropathy, skin changes and various internal symptoms; a previously unrecognized heritable syndrome. Ann Clin Res. 1969;1:314–324. 158. Wong C-K, Lin C-S. Friction amyloidosis. Int J Dermatol. 1988;27:302–307. 159. Wang W-J. Clinical features of cutaneous amyloidoses. Clin Derm. 1990;8:13–19. 160. Venkataram MN, Bhushnurmath SR, Muirhead DE, et al. Frictional amyloidosis: A study of ten cases. Australas J Dermatol. 2001;42(3): 176–179. 161. Kyle RA, Bayrd ED. Amyloidosis: review of 236 cases. Medicine (Balt). 1975;54:271. 162. Newton JA, Jagjivan A, Bhogal B, et al. Familial primary cutaneous amyloidosis. Br J Dermatol. 1985;112:201–208. 163. Sagher F, Shanon J. Amyloidosis cutis: familial occurrence in three generations. Arch Dermatol. 1963;87:171. 164. Toutant DM, San P. Cutaneous deposition disorders, Part 1. J Am Acad Dermatol. 1998;39:149–171.

associated with poikiloderma, short stature, photosensitivity and blistering.170 Macular amyloidosis has been reported in association with pachyonychia congenita,171 epidermolysis bullosa (Weber Cockayne type),172 dyskeratosis congenita,173 and the Nageli–Franceshetti–Jadassohn syndrome.174 There is no risk of transformation of the sporadic and familial forms of cutaneous amyloidosis to the systemic form.

Presenting history Cutaneous amyloidosis presents with a history of itching which is at first intermittent and then more intense and continuous as the lesions become more fully developed. The most commonly affected areas are the upper back and anterior tibial regions. Hyperpigmentation is often subtle but increases over time.175–178 A family history of similar skin disorders should be sought in each patient.164

AMYLOIDOSIS

The most common systemic form of amyloidosis worldwide is that which occurs secondary to chronic inflammation, in which amyloid fibrils are derived from high circulating concentrations of serum amyloid A (SAA).150 In developed countries rheumatoid arthritis and juvenile rheumatoid arthritis are the most common diseases complicated by secondary amyloidosis,151 with 50% of the deaths in JRA patients occurring as a result of amyloid-induced renal disease.152 Renal amyloidosis has also been observed in children with cystic fibrosis and epidermolysis bullosa.153–155 The heredofamilial forms of systemic amyloid may be associated with neuropathy beginning in adolescence, with progression to painless ulceration, atrophic scarring, and sclerodermatous skin changes along with hepatic and cardiac involvement occurring in adulthood.156–158 Cutaneous lesions occur in 30–40% of cases of systemic amyloidosis; these include macroglossia and periorbital waxy papules and plaques with ecchymosis and pinch purpura. Rarely bullous lesions may be seen.149,153 The localized cutaneous forms will be the major focus of this section.

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Physical examination Primary localized cutaneous amyloidosis (PLCA) presents as macular or lichenoid lesions. The lichenoid variety is the most common form seen in adults, but it may occur in adolescence. It presents with itchy, closely set, aggregated papules, 1–10 mm in size, typically on the anterior tibial or other extensor surfaces. The lesions may vary from skin-colored to shades of gray or yellow-brown. Macular amyloidosis presents with flat hyperpigmented macules, most commonly on the upper back and distal limbs. Close inspection reveals a ‘rippled’ or ‘wavy’ pattern on the skin surface which may be accompanied by mild lichenification. The color is brown to grayish brown and itch is usually less than in

165. Rajagopalan K, Tay CH. Familial lichen amyloidosis. Report of 19 cases in four generations of a Chinese family in Malaysia. Br J Derm. 1972;87: 123–129. 166. Ozaka M. Familial lichen amyloidosis. Int J Dermatol. 1984;23:190–193. 167. De Pietro WP. Primary familial cutaneous amyloidosis: a study of HLA antigens in a Puerto Rican family. Arch Derm. 1981;117:639–642. 168. Kousseff BG, Espinoza C, Zamore GA. Sipple syndrome with lichen amyloidosis as a paracrinopathy: pleiotropy, heterogeneity, or a contiguous gene? J Am Acad Dermatol. 1991;25:651–657. 169. Robinson MF, Furst EJ, Nunziata V, et al. Characterization of the clinical features of five families with hereditary primary cutaneous lichen amyloidosis and multiple endocrine neoplasia type 2. Henry Ford Hosp Med J. 1992;40:249–252. 170. Ogino A, Tanaca S. Poikiloderma-like cutaneous amyloidosis. Dermatologica. 1977;155:301–309. 171. Tidman MJ, Wells RS, Macdonald DM. Pachyonychia congenita with cutaneous amyloidosis and hyperpigmentation: a distinct variant. J Am Acad Dermatol. 1987;16:935–940. 172. Kantor GR, Kasick JM, Bergfeld WF, et al. Epidermolysis bullosa of the Weber-Cockayne type with macular amyloidosis. Cleve Clin Q. 1985;52:425–428. 173. Llistosella E, Moreno A, deMoragas JM. Dyskeratosis congenita with macular cutaneous amyloid deposits. Arch Dermatol. 1984;120:1381–1382. 174. Frenk E, Mevorah B, Hohl D. The Nageli-Franceschetti-Jadassohn syndrome: a hereditary ectodermal defect leading to colloid-amyloid formation in the dermis. Dermatology. 1993;187:169–173. 175. MacDonald DM, Fergin PE, Black MM. Localized cutaneous amyloidosis. In: Glenner GG, Pinho E, Costa P, de Freitas F, eds. Amyloid and amyloidosis. Amsterdam: Excerpta Medica; 1980:239. 176. Breathnach SM, Black MM. Systemic amyloidosis and the skin. Clin Exp Dermatol. 1979;4:517. 177. Westermark P. Amyloidosis of the skin: a comparison between localized and systemic amyloidosis. Acta Derm Venereol (Stockh). 1979;59:341. 178. Black MM. Primary localized amyloidosis of the skin: clinical variants, histochemistry and ultrastructure. In: Wegelius O, Pasternack A, eds. Amyloidosis. New York: Academic Press; 1976:479.

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Laboratory findings There are no laboratory abnormalities in the localized cutaneous forms of amyloidosis. In systemic amyloidosis, the type and degree of laboratory abnormalities will vary depending on the extent of the disease and which organ system is involved.185

Pathophysiology and histogenesis

AMYLOIDOSIS

Figure 17.9  Amyloidosis on the face of a child.

the lichenoid variety. Friction may play an important role in the evolution of this form of amyloid.161 Biphasic amyloidosis is the coexistence of both macular and lichenoid amyloidosis in the same patient.160 Rubbing, scratching, and friction from brushes or bath sponges may convert the macular form to lichenoid and treatment may reverse the process.159,160 Primary systemic or immunocytic amyloidosis is exceedingly rare in childhood,179 as is secondary systemic amyloidosis.180,181 Macroglossia, waxy papules (Fig. 17.9) which exhibit ‘pinch purpura’ and sclerodermatous skin changes may occur.149 Rectal biopsy is usually diagnostic.149 Amyloid infiltration occurs in the kidneys, liver, heart, and spleen. Skin lesions are rare. Heredofamilial syndromes such as familial Mediterranean fever may culminate in amyloid nephropathy and renal failure in childhood.182 Muckle–Wells syndrome is an autosomal-dominant disorder characterized by chronic recurrent episodes of urticaria beginning in adolescence followed by progressive deafness and amyloid nephropathy in adult life.183 Muckle–Wells syndrome is now known to be part of the spectrum of autoinflammatory disease of childhood caused by mutations in the gene encoding cryopyrin.184

179. Pick AI, Versano I, Schreibman S, et al. Agammaglobulinemia, plasma cell dyscrasia, and amyloidosis in a 12-year-old child. Am J Dis Child. 1977;131:682–686. 180. Woo P. Amyloidosis in pediatric rheumatic diseases. J Rheum. 1992;19:10–16. 181. Woo P. Amyloidosis in children. Ballière’s Clin Rheumatol. 1994;8:691–697. 182. Gedalia A, Adar A, Gorodischer R. Familial Mediterranean fever in children. J Rheum. 1992;19:1–9. 183. Muckle TJ. The Muckle-Wells syndrome. Br J Dermatol. 1979;100:87–92. 184. Gattorno M, Federici S, Antonietta M, et al. Diagnosis and management of the autoinflammatory diseases in childhood. J Clin Immunol. 2008;28(suppl 1):S73–S83. 185. Glenner GG. Amyloid deposits and amyloidosis. The beta-fibrilloses. N Engl J Med. 1980;302:1283. 186. Elder DE. Lever’s histopathology of the skin. ed 10. Philadelphia: Lippincott Williams & Wilkins; 2009.

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Regardless of the source or form of amyloidosis, the histological characteristics are the same.186 In hematoxylin and eosin-stained sections the lesions appear as a homogeneous, pink deposit that replaces collagen bundles.175,176 Amyloid stains metachromatically with methyl violet or crystal violet and Congo red stain shows a characteristic apple green birefringence, with yellowgreen birefringence when using thioflavin T under fluorescent microscopy. Ultrastructurally, amyloid appears as straight, non-branching fibrils, 7.5–10  nm in diameter. They are configured in an antiparallel (β-pleated) array.185 Fifteen sources of amyloid fibrillar proteins have been identified.187 Plasma cells secrete AL protein derived from IgG lambda light chains, which results in the immunocytic forms of amyloidosis. Serum amyloid A protein (SAA) is the precursor of the AA fibrils. Humans have four types of SAA genes located on the short arm of chromosome 11. SAA1 and SAA2 are highly homologous and increase sharply in response to inflammation.188 The main source of SAA is the liver, with other identified sources including endothelial cells, macrophages, and rheumatoid synovium, as well as normal epithelium.145,189 SAA has significant immunomodulatory effects in upregulating or activation of adhesion molecules, neutrophils, interferon-γ, and metalloproteinases.145 SAA concentrations are increased by IL-1, TNFα and IL-6.190 Damaged and degenerating keratinocytes are the source of keratinocytic amyloid (KA)191,192 seen in macular and lichenoid amyloidosis.

Differential diagnosis The main differential diagnosis for the papular or lichenoid form is chronic eczema, either lichen simplex chronicus or atopic

187. Westermark P, Benson MD, Buxbaum JN, et al. Amyloid: toward terminology clarification. Report from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid. 2005;12:1–4. 188. Steel DM, Whitehead AS. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today. 1994;15:81–88. 189. Urieli-Shoval S, Cohen P, Eisenberg S, et al. Widespread expression of serum amyloid A in histologically normal human tissues: predominant localization to the epithelium. J Histochem Cytochem. 1998;46:1377–1384. 190. Charles P, Elliott MJ, Davis D, et al. Regulation of cytokines, cytokine inhibitors and acute phase proteins following anti-TNF-alpha therapy in rheumatoid arthritis. J Immunol. 1999;163:1521–1528. 191. Black MM, Heather CJ. The ultrastructure of lichen amyloidosis with special reference to the epidermal change. Br J Dermatol. 1972;87:117. 192. Husebekk A, Skogen B, Husby G, et al. Transformation of amyloid precursor SAA to protein AA and incorporation in amyloid fibrils in vivo. Scand J Immunol. 1985;21:283–287.

Diseases of the dermis and subcutaneous tissues

Therapy and prognosis The main goals of therapy are to alleviate itch and flatten unsightly lesions. This can be achieved through the use of highpotency topical steroids or intralesional steroid injection. Oral antihistamines may be of benefit to alleviate the itch in some patients. Cryosurgery and dermabrasion have been successful in some patients, particularly in the lichenoid or nodular form.193,194 Acitretin has been reported to be effective in a case of biphasic amyloidosis.195 The long-term prognosis for cutaneous amyloidosis is for persistence or gradual progression of lesions in the skin. Treatment of systemic amyloid is directed at the underlying disease process. With greater understanding of the mechanisms and control of amyloid production and metabolism, immunomodulatory, targeted drug therapy may prove successful in the future.196 Growth development, nutrition, and physical activities are usually unaffected in the localized cutaneous forms of amyloidosis. In systemic forms, organ deposition of amyloid may result in renal, cardiac or hepatic dysfunction.

MYXEDEMA Myxedema refers to the accumulation of glycosaminoglycans (GAGs) in the form of hyaluronic acid in the skin, giving it a shiny, taut, edematous appearance.197 Two forms of myxedema are recognized: generalized and localized, or pretibial myx­ edema. Both forms are related to thyroid abnormalities. Only one report of two pediatric cases with pretibial myxedema has been described.198 Generalized myxedema is a consequence of congenital hypothyroidism. Sir William Gull is credited with describing myxedema in the skin in 1873, using the term ‘cretinoid edema.’199 In 1877, Ord suggested the term myxedema after determining that it was due to a deposit of mucinous material.

193. Lien M, Railan D, Nelson B. The efficacy of dermabrasion in the treatment of nodular amyloidosis. J Am Acad Dermatol. 1997;36:315–316. 194. Wong C-K, Li W-M. Dermabrasion for lichen amyloidosus. Arch Dermatol. 1982;118:302–304. 195. Hernandez-Nunez A, Dauden E, Moreno de Vega MJ, et al. Widespread biphasic amyloidosis: response to acitretin. Clin Exp Dermatol. 2001; 26(3):256–259. 196. Cunnane G. Amyloid proteins in pathogenesis of AA amyloidosis. Lancet. 2001;358:4–5. 197. Gabrilove JL, Ludwig AW. The histogenesis of myxoedema. J Clin Endocrinol Metab. 1957;17:925–932. 198. Maldonado Regalado S, Barrio Castellanos R, Alonso Blanco M, et al. Graves’ disease in childhood. An Esp Pediatr. 1988;29(6):440–444. 199. Pusey WA. The history of dermatology. Springfield, IL: Charles C. Thomas; 1932. 200. LaFranchi S. Congenital hypothyroidism: etiologies, diagnosis and management. Thyroid. 1999;9(7):735–740. 201. Waller DK, Anderson JL, Lorey F, et al. Risk factors for congenital hypothyroidism: an investigation of infant’s birth weight, ethnicity, and gender in California, 1990–1998. Teratology. 2000;62(1):36–41.

Epidemiology Congenital hypothyroidism occurs in approximately 1 : 4000 births. Females are affected about twice as often as males. Eightyfive percent of cases are sporadic, while 15% are hereditary. The most common sporadic etiology is thyroid dysgenesis, with ectopic glands being more common than aplasia or hypoplasia. The vast majority of infants are now detected through newborn screening programs.200 The features of congenital hypothyroidism are noted between 1 and 2 months of age. Risk associations with congenital hypothyroidism are increased in Caucasian infants and those with low or high birth weight (4500 g). African-American infants have a lower risk.201 Congenital hypothyroidism is an important, common, preventable cause of mental retardation. Response to treatment is often dramatic with resumption of growth and skeletal maturation. Early treatment, within the first 2–4 weeks of life, is important to prevent or minimize neurocognitive deficits in later life.202

MYXEDEMA

dermatitis.162,175,177 Pretibial myxedema, which may be associated with similar epidermal changes of thickening and lichenification, is exceedingly rare in childhood. The macular forms may be confused with tinea versicolor or confluent and reticulated papillomatosis of Gougerot and Carteaud. Biopsy, with special stains to identify amyloid, is required to confirm the diagnosis.

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Presenting history With the introduction of widespread screening programs in North America, florid congenital hypothyroidism with widespread myxedematous skin changes is uncommon. Early signs include a hoarse cry at birth, extensive cutis marmorata that does not respond to warming, and translucent pallor of the skin with an alabaster hue.203 Other early signs include prolonged neonatal jaundice, umbilical hernia, prominent fontanelles, bradycardia, and hypotonia.204,205 Feeding difficulties, lethargy, constipation, thermal instability and hypothermia may be present.203 Once the disease becomes well established, growth failure and neurodevelopmental delay will be apparent.206 Acquired hypothyroidism in older children often presents with general symptoms of lethargy, weight gain, constipation, poor school performance, cold intolerance, myalgias and arthralgias, delayed puberty and rarely neuropsychiatric illness.207–209

Physical examination The skin is pale, or sallow in color from accumulation of GAGs as well as the effects of anemia, poor peripheral perfusion, and associated neonatal jaundice or carotenemia. Extensive cutis marmorata is seen. The infant’s face may be swollen including

202. Rovet JF. Congenital hypothyroidism: long-term outcome. Thyroid. 1999; 9(7):741–748. 203. Grant DB, Smith I, Fuggle PW, et al. Congenital hypothyroidism detected by neonatal screening: relationship between biochemical severity and early clinical features. Arch Dis Child. 1992;67:87–90. 204. Shanker SM, Menon PSN, Karmarker MG, et al. Dysgenesis of the thyroid is the common type of childhood hypothyroidism in environmentally iodine deficient areas of North India. Acta Paediatr. 1994;83:1047–1051. 205. Tsai WY, Lee JS, Wang TR, et al. Clinical characteristics of congenital hypothyroidism detected by neonatal screening. J Formos Med Assoc. 1993;92:20–23. 206. Tarim OF, Yordam N. Congenital hypothyroidism in Turkey: a retrospective evaluation of 1000 cases. Turk J Pediatr. 1992;34:197–202. 207. Callas JS, Foley TP. Hypothyroidism. In: Lifshitz F, ed. Pediatric endocrinology: a clinical guide. 2nd rev. New York: Dekker; 1990:478–493. 208. Keenan GF, Ostrov BE, Goldsmith DP, et al. Rheumatic symptoms associated with hypothyroidism in children. J Pediatr. 1993;123:586–588. 209. Foley TP, Abbassi V, Copeland KC, et al. Brief report: hypothyroidism caused by chronic autoimmune thyroiditis in very young infants. N Engl J Med. 1994;330:466–468.

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MYXEDEMA

the skin of the eyelids, external genitalia, and dorsa of the hands and feet.210 With time, macroglossia is noted and the characteristic facial features – thickened facial skin, protruding thick tongue, depressed nasal bridge, and mild hypertelorism – are seen. The thickened skin does not pit, and has a ‘doughy’ consistency on palpation. The overlying skin surface is dry and cool. The infant is often lethargic, with poor head movement due to hypotonic muscles. The abdomen is large and there is often an umbilical hernia present. Rarely ascites is present. The pulse is slow, and heart murmurs, cardiomegaly and asymptomatic pericardial effusion may be present.211 If stimulated to cry, there is a delay in the onset of the cry which is hoarse and weak.210 In older children with acquired myxedema, the cutaneous changes of pale, cool xerotic skin, with puffiness of the face and lips, may be the only features noted, along with poor hair and nail growth, and general symptoms of weight gain.

Laboratory findings Thyroid function studies are abnormal in both congenital and acquired hypothyroidism. A serum thyroxine (T4) level, and TSH, which is more sensitive, should be obtained along with radiographic examination of the wrists for bone age. Infants with congenital primary hypothyroidism should undergo radio-isotope scanning to determine the presence and location of thyroid tissue.200 Elevated serum carotene, cholesterol, and triglyceride levels may be seen. In the neonate, topical iodine containing antiseptics used in nurseries and by surgeons may lead to abnormal results on screening tests and cause transient congenital hypothyroidism, especially in low birthweight infants.212

Pathophysiology and histogenesis

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addition, effects on cutaneous blood flow, diminished sebaceous and eccrine gland activity and reduced hair growth are seen. Histological changes on routine hematoxylin and eosin sections may show little other than swollen collagen bundles. Special stains with Alcian blue or toluidine blue reveal the hyaluronic acid deposits, particularly around blood vessels and appendages.

Differential diagnosis Generalized myxedema must be distinguished from edema, which pits on compression of the surface, while myxedema does not. Accumulation of other mucopolysaccharidoses within the skin may mimic myxedema. Both are accumulations of GAGs. Separation depends on thyroid function tests, analysis of urinary mucopolysaccharides, and the clinical presence of marked hepatosplenomegaly in the mucopolysaccharidoses. Sclerema neonatorum occurs in the immediate newborn period, whereas myxedema takes longer to develop. Infants with lipoid proteinosis will show discrete skin swelling and thickening of the extremities with gradual onset in infancy and a hoarse cry in the neonatal period. Trisomy 21 may have lymphedema and Turner syndrome has lymphedema but are easily distinguished by other clinical features including epicanthic folds and transverse palmar creases in Down syndrome, and webbed neck and pedal edema in Turner syndrome, and chromosomal studies which show XO. Children with Beckwith–Wiedemann syndrome present with macroglossia, but have normal thyroid function and accelerated growth.

Therapy and prognosis

Thyroid dysgenesis is the most common cause of congenital hypothyroidism. Mutations in several gene transcription factors, including TTF1, TTF2, and PAX8,213,214 which play a role in thyroid gland embryogenesis, have been found. Hereditary defects in almost all the steps of thyroid hormone synthesis, secretion, and action have been described, most commonly due to defects in the thyroid peroxidase gene (TPO).215 Pendred syndrome, an association of congenital hypothyroidism and sensorineural deafness, results from a mutation in a chloride-iodide transport protein which leads to defective iodine binding to thyroglobulin, and cochlear dysfunction from abnormal endo­ lymph transport in the ear.216 Rarely, large hemangiomas may produce type 3 iodothyronine deiodinase, which inactivates thyroid hormone, resulting in severe hypothyroidism in affected infants.217 The cutaneous changes resulting in myxedema are attributable to low levels of circulating thyroxine, resulting in excess accumulation of GAGs, particularly hyaluronic acid in the dermis. In

Congenital myxedema is one of the most common preventable causes of mental retardation. There is a firm relationship between when treatment is started and psychometric outcome.200 Treatment is with levothyroxine (thyroxine). The recommended initial dosage is 10–15 µg/kg per day. The goal is to raise the T4 as rapidly as possible into the normal range to minimize the exposure of the neonatal brain to low thyroxine.200 Complete clearance of the skin lesions occurs within one to two weeks of institution of therapy.210 Congenital myxedema children show profound neurodevelopmental features if there is delay in diagnosis. Only 5% are diagnosed by physical examination at birth; the majority are diagnosed through screening programs.200 In the older child with acquired hypothyroidism, school performance may suddenly drop off, growth rate may flatten, energy is diminished, and delayed onset of puberty may occur. Monitoring of thyroid function on a regular basis throughout infancy and childhood until puberty and growth is complete is recommended for those with the disease.218 Overtreatment may result in premature closure of

210. Bacon GE, Spencer ML, Hopwood NJ, et al. A practical approach to pediatric endocrinology, ed 2. Chicago: Year Book Medical Publishers; 1983. 211. Behrman RE, Kliegman RM, Jensen HB. Nelson textbook of pediatrics. ed 16th. Philadelphia: WB Saunders; 2000. 212. Zahidi A, Draoui M, Mestassi M. Iodine status and the use of iodized antiseptics in the mother-newborn pair. Therapie. 1999;54(5):545–548. 213. Krude H, Biebermann H, Schnabel D, et al. Molecular pathogenesis of neonatal hypothyroidism. Horm Res. 2000;53(suppl 1):12–18. 214. Djemli A, Van Vliet G, Delvin E. Congenital hypothyroidism: from paraclesus to molecular diagnosis. Clin Biochem. 2006;39:511–518.

215. Ambrugger P, Stoeva I, Bierbermann H, et al. Novel mutations of the thyroid peroxidase gene in patients with permanent congenital hypothyroidism. Eur J Endocrinol. 2001;145(1):19–24. 216. Scott DA, Wang R, Kreman TM, et al. The Pendred gene encodes a chloride-iodide transport protein. Nat Genetics. 1999;20:440–443. 217. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by Type 3 iodothyronine deiodinase in infantile hemangiomas. New Engl J Med. 2000;343(3):185–189. 218. Rovet JF, Ehrlich RM. Long-term effects of l-thyroxine therapy for congenital hypothyroidism. J Pediatr. 1995;126:380–386.

Diseases of the dermis and subcutaneous tissues

17

the epiphyses and a nervous and jittery child with poor attention span and school performance.

LIPOID PROTEINOSIS

LIPOID PROTEINOSIS

Lipoid proteinosis (hyalinosis cutis et mucosae) is a rare autosomal-recessive disorder, that may present with multiple systemic manifestations involving mucosal deposition of hyaline material. Most affected children are hoarse from birth. Gradual development of diffuse papules and nodules on the face, plus thickening of the extremities develop, and the mucosae of the upper aerodigestive tract slowly become involved.219,220 The disorder was first described by Siebenmann in 1908; the first detailed description was by Urbach and Wiethe in 1929.221 Urbach proposed the term lipid proteinosis because histochemical investigations showed staining characteristics of both lipid and protein.221 Genome wide linkage analysis studies in 2002 discovered the causative mutations to be in the extracellular matrix protein 1 gene (ECM1) gene.222

Epidemiology Lipoid proteinosis is a rare disorder with less than 300 cases reported in the literature. A higher prevalence of cases occurs in South Africa and Sweden, with many patients being of Dutch or German ancestry.223,224 The disorder occurs equally in males and females.

Presenting history Two-thirds of the patients present with hoarseness in the newborn period. Cutaneous changes usually appear during the first 2 years of life but may be delayed until 10 years.225 Systemic involvement manifests as seizures or neuropsychiatric symptoms. The skin and mucous membrane changes increase with age.

Physical examination

Figure 17.10  Typical appearance of a child with congenital myxedema. (Courtesy of Dr Robert Couch.)

tion of the margin of the eyelids is associated with dryness and secondary eczematous changes (Figs 17.10, 17.11).

Laboratory findings Calcification of intracranial vessels, particularly in the temporal lobes or hippocampal area, may be seen on skull radiographs or CT scan. These are characteristically ‘bean shaped.’226 Routine hematology, chemistry, and lipid studies are normal.

Pathophysiology and histogenesis

The infant has a poor cry or is hoarse from birth. Initially the lesions are pruritic; subsequently scarring occurs, which is acneiform or varioliform. Numerous papules and nodules and coarse facial features are observed. There is diffuse, firm thickening of the skin of the extremities with hyperkeratosis of the elbows, knees, and dorsa of the hands that may result in decreased joint mobility. The vermilion border, tongue, gingival and buccal mucosa, and border of the eyelids commonly develop whitish papules which thicken and progress over time.223,224 The papular infiltra-

The pathogenesis of lipoid proteinosis has been clarified as the multifunctional role of ECM1 protein is better understood. Its most important function is to act as a biological ‘glue’ binding and regulating the activity of many matrix components and influencing cell signaling. ECM1 protein–protein interactions may occur directly with perlecan, and indirectly with fibronectin, laminin, type IV collagen, fibulin 2, dystroglycan, platelet derived growth factor 7 and fibroblast growth factor growth protein.227 ECM1 protein overexpression has also been implicated in several

219. Böhme M, Wahlgren CF. Lipoid proteinosis in three children. Acta Paediatr. 1996;85:1003–1005. 220. Rizzo R, Ruggieri M, Micali G, et al. Lipoid proteinosis: A case report. Pediatric Dermatol. 1997;14(1):22–25. 221. Urbach E, Wiethe C. Lipoidosis cutis et mucosae. Virchow’s Arch Path Anat. 1929;273:285–319. 222. Hamada T, McLean WH, Ramse M, et al. Lipoid proteinosis maps to Iq21 and is caused by mutations in the extra cellular matrix protein 1 gene (ECMI). Hum Mol Genetics. 2002;11(7):833–840. 223. Gorlin RJ, Cohen Jr MM, Levin LS. Hyalinosis cutis et mucosae (lipoid proteinosis, Urbach-Wiethe syndrome). In: Gorlin RJ, Cohen MM Jr, Levin LS, eds. Syndromes of the head and neck. ed 3. Oxford monographs and

medical genetics, No. 19. New York: Oxford University Press; 1990:507–511. 224. Hofer PA. Urbach-Wiethe disease. A review. Acta Dermatol Venereol. 1983;53(suppl):1–56. 225. Van Hougenhouck-Tulleken W, Chan I, Hamada T, et al. Clinical and molecular characteristics of lipoid proteinosis in Namaqualand, South Africa. Br J Dermatol. 2004;151:413–423. 226. Orlow SJ, Watsky KL, Bolognia JL. Skin and bones I. J Am Acad Dermatol. 1991;25:205. 227. Dunlevy J, Hassell J. Heparin sulphate proteoglycans in basement membranes. In: Iozzo RV, ed. Proteoglycans: structure, biology and molecular interactions. New York: Marcel Dekker; 2000:275–336.

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7, which reduce or abolish expression of the protein. Immunohistochemical stains using antibody to ECM1 protein are available and useful as a diagnostic probe.234 Patients with lichen sclerosus have been shown to have circulating autoantibodies to ECM1.235

Differential diagnosis

LIPOID PROTEINOSIS

Figure 17.11  Lipoid proteinosis showing morbilliform beaded papules on the eyelid.

malignant tumors while reduced expression is seen in aging.228,229 Dyer et al. have shown an inherent feature of lipoid proteinosis keratinocytes devoid of ECM1 is ‘free floating desmosomes’ which do not attach properly to the keratin filament network,230 thus predisposing these children to early vesicular and crusted skin lesions. ECM1 also inhibits the activity of matrix metalloproteinase inhibitor 9 (MMP-9) and increased activity of MMP-9 in lipoid proteinosis may contribute to both dermal and CNS changes.231 The earliest pathologic change is thickening of dermal capillary walls; positive periodic acid–Schiff and Alcian blue stains. There is hyaline material within and around the basement membrane of the vessel.232 Fully developed skin lesions show papillomatosis and hyperkeratosis of the epidermis, while the superficial and deep dermal vessels show a thick, homogeneous, eosinophilic hyaline perivascular deposit. Similar deposits are seen around sweat glands and ducts. Ultrastructurally, reduplication of the basement membrane of vessels and occasionally the dermoepidermal junction is seen.233 A total of 41 different pathogenic mutations in the ECM1 gene have been discovered, mainly nonsense mutations or small deletions/insertions. The majority of mutations occur in exon 6 or

228. Wang L, Yu J, Ni J, et al. Extracellular matrix protein1 is overexpressed in malignant epithelial tumors. Cancer Lett. 2003;200:57–67. 229. Sander C, Sercu S, Ziemer M, et al. Expression of extracellular matrix protein 1 (ECM1) in human skin is decreased by age and increased upon ultraviolet exposure. Br J Dermatol. 2006;154:218–224. 230. Dyer J, Qian-Chun Y, Paller A. ‘Free-floating’ desmosomes in lipoid proteinosis: an inherent defect in keratinocyte adhesion? Ped Dermatol. 2006;23(1):1–6. 231. Nagy V, Bozdagi O, Matynia A, et al. Matrix metalloproteinase-9 is required for hippocampal late-phase long term potentiation and memory. J Neurosci. 2006;26:1923–1934. 232. Caro I. Lipoid proteinosis. Int J Dermatol. 1978;17:388. 233. Fleischmajer R, Timpl R, Graves P. Hyalinosis cutis et mucosal: A basal lamina disease, (Abstr). J Invest Dermatol. 1981;76:314–315. 234. Chan I, Lu L, Hamada T, et al. The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1. Exp Dermatol. 2007;16:881–890. 235. Chan I, Oyama N, Neill S, et al. Characterization of autoantibodies to extracellular matrix protein 1 (ECM1) in lichen sclerosis. Clin Exp Dermatol. 2004;29:499–504.

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Myxedema may mimic lipoid proteinosis. In both conditions, infants present with hoarseness from birth, and have diffuse non-pitting swelling of the skin. Thyroid function tests distinguish other causes of edema causing pitting. The coarse facies of the infant and the diffusely thickened skin may mimic one of the forms of mucopolysaccharidoses. Analysis for urinary mucopolysaccharides and skin biopsy will help distinguish between the two. Diffuse thickening of sun-exposed areas of skin is observed in erythropoietic protoporphyria.186 The skin biopsy in erythropoietic protoporphyria may also show perivascular accumulation of PAS-positive material, but in porphyria it is limited to the superficial dermis, whereas in lipoid proteinosis the deposits are also found in the deep dermis and sweat glands. There is hoarseness in lipoid proteinosis but not erythropoietic protoporphyria.

Therapy and prognosis Effective therapy is not available. Improvement has been reported after dermabrasion of cutaneous lesions,236,237 and treatment with carbon dioxide laser for eyelid lesions.238 Oral dimethyl sulfoxide239 was reported to be effective in one patient but a long-term trial in three other patients produced no beneficial effects.240 Oral retinoid was helpful in three patients.241 The efficacy of these treatments in a disease with a fluctuating course is difficult to evaluate. The course is chronic, and other than mucocutaneous lesions and hoarseness, the major debility is when neurologic involvement occurs; this is uncommon and may include psychomotor and grand mal seizures, memory loss, rage attacks, and schizophrenic behaviour.242 The seizure disorder that some children experience requires control with anticonvulsants232 and the psychosocial stigma can be severe in the pre-adolescent and adolescent patient.

236. Vukas A. Hyalinosis cutis et mucosae: regenerative properties of tissues involved in chronic pathology. Dermatologica. 1972;144:168–175. 237. Bannerot H, Aubin F, Tropet Y, et al. Lipoid proteinosis: importance of dermabrasion. Apropos of a case. Ann Chir Plast Esthet. 1998;43(1):78–81. 238. Rosenthal G, Lifshitz T, Monos T, et al. Carbon dioxide laser treatment for lipoid proteinosis (Urbach–Wiethe syndrome) involving the eyelids. Br J Opthalmol. 1997;81(3):253. 239. Wong C, Lin CS. Remarkable response of lipoid proteinosis to oral dimethyl sulphoxide. Br J Dermatol. 1988;119:541–544. 240. Ozkaya-Bayazit E, Ozarmagan G, Baykal, et al. Oral DMSO therapy in three patients with lipoid proteinosis. Results of long-term therapy. Hautartz. 1997;48(7):477–481. 241. Toosi S, Ehsani AH. Treatment of lipoid proteinosis with acitretin: a case report. J Eur Acad Dermatol Venereol (JEADV). 2009;23:482–483. 242. Newton FH, Rosenberg RN, Lampert PW, et al. Neurologic involvement in Urbach–Wiethe’s disease (lipoid proteinosis): a clinical, ultrastructural, and chemical study. Neurology. 1971;21:1205–1213.

Diseases of the dermis and subcutaneous tissues

Granuloma annulare (GA) is a common disorder of childhood characterized by grouped dermal papules in an annular or ringed arrangement. The entity was first described by Fox in 1895; the term ‘granuloma annulare’ was introduced by Radcliff-Crocker in 1902.243 Although the cause is unknown, the common localized form is a benign condition that may persist for several years and usually resolves spontaneously.244 A generalized, disseminated form that presents with widespread, asymptomatic macules, papules and nodules that may coalesce into reticulate patterns is more common in adults.245

Epidemiology GA may occur at any age, but is most common in school-aged children.246 In a series of 100 cases of generalized GA only eight patients were under the age of 20 years.247 Females are affected twice as commonly as males.244,245 Although familial cases have been reported, the disease is usually sporadic. HLA studies are conflicting, with an increased incidence of HLA-Bw35 in Israel,248 HLA-B8 in Denmark,249 and HLA-A29, B14, and B15 in Belfast.250 These findings may reflect that HLA genes are population specific.

Presenting history Parents usually bring a child for medical care because of asymptomatic ringed papules, often misdiagnosed as tinea corporis and showing resistance to anti-fungal therapy. Lesions on the dorsa of the feet may occasionally cause discomfort under sports shoes or skates.

Physical examination Physical findings in GA are usually limited to the skin. The most common form of GA is the localized type, which presents as ringed papules on any part of the body, but is most commonly found on the dorsa of the hands and feet and lower extremities (Fig. 17.12). They begin as skin-colored or pale red papules without scale or epidermal change, that slowly expand to form

243. Radcliff-Crocker H. Granuloma annulare. Br J Dermatol. 1902;14:1–9. 244. Hurwitz S. The skin and systemic disease in children. ed 1. Chicago: Year Book Medical; 1985. 245. Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol. 1980;3:217. 246. Wells RS, Smith M. The natural history of granuloma annulare. Br J Dermatol. 1963;75:19. 247. Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. J Am Acad Dermatol. 1989;20:232. 248. Friedman-Birnbaum R, Haim S, Gideone O, et al. Histocompatibility antigens in granuloma annulare. Br J Dermatol. 1978;98:425. 249. Andersen BL, Verdich J. Granuloma annulare and diabetes mellitus. Clin Exp Dermatol. 1979;4:31–37. 250. Middleston D, Allen GE. HLA antigen frequency in granuloma annulare. Br J Dermatol. 1984;110:57–59. 251. Lucky AW, Prose NS, Bove K, et al. Papular umbilicated granuloma annulare. Arch Dermatol. 1992;128:1375. 252. Ghadially R, Sibbald RG, Walter JB, et al. Granuloma annulare in patients with human immunodeficiency virus infections. J Am Acad Dermatol. 1989;20:232. 253. Grogg KL, Nascimento AG. Subcutaneous granuloma annulare in childhood: clinicopathologic features in 34 cases. Pediatrics. 2001;107(3):e42.

rings with central clearing that has a normal or a violaceous color. The rings vary from one to several centimeters in size. Multiple lesions are common, but 50% of patients have single lesions.245 A papular umbilicated form of GA limited to the dorsa of the hands and fingers has been described in school-aged children.251 The generalized form of GA is characterized by hundreds of small asymptomatic papules forming symmetrical, ringed lesions that usually coalesce into reticulate, circinate patterns or linear bands.245 The palms, soles, and mucous membranes may occasionally be involved.246 Patients infected with the human immunodeficiency virus may have the generalized type or extensive localized form of GA.252 A subcutaneous form is seen most commonly on the pretibial area of the lower legs in children aged 2–5 years.253–255 Lesions may also be found on the scalp, buttocks, hands, and periorbital regions;245,256,257 appearing as asymptomatic deep dermal or subcutaneous nodules with no overlying epidermal change; they regress spontaneously (Fig. 17.12C). Lesions on the scalp are hard and bound down to the periosteum. Typical ringed lesions are only present in one-quarter of these patients.258 Perforating GA is a rare disorder consisting of asymptomatic grouped papules, some of which have a central crust or scale where damaged collagen perforates through the ulcerated epidermis. There have been several reports of panuveitis, associated with retinal vasculitis in patients with granuloma annulare including three childhood cases.259,260 A recent cross-sectional review of 19 adult patients with biopsy proven GA found only one case of associated uveitis with the onset of the two diseases temporally offset by 40 years; therefore the significance and prevalence of this association remain to be determined.261

GRANULOMA ANNULARE

GRANULOMA ANNULARE

17

Laboratory findings There are no specific findings.

Pathophysiology and histogenesis Histologically, GA is characterized by focal degeneration of collagen in the dermis with reactive inflammation and fibrosis186 and fragmentation of collagen bundles.262 The epidermis is normal except in perforating GA where degenerated collagen is

254. Felner EI, Steinberg JB, Weinberg AG. Subcutaneous granuloma annulare: a review of 47 cases. Pediatrics. 1997;100:965–967. 255. Evans MJ, Blessing K, Gray ES. Pseudorheumatoid nodule (deep granuloma annulare) of childhood: clinicopathologic features of 20 patients. Pediatr Dermatol. 1994;11:6–9. 256. Cronquist, SD, Stashower ME, Benson PM. Deep dermal granuloma annulare presenting as a eyelid tumor in a child, with review of pediatric eyelid lesions. Pediatric Dermatol. 1999;16(5):377–380. 257. Hata N, Inamura T, Imayama S, et al. Multiple palisading granulomas in the scalp of an infant: a case report. Surg Neurol. 2001;56(6):396–399. 258. Draheim JH, Johnson LC, Helwig EB. A clinicopathologic analysis of ‘rheumatoid’ nodules occurring in 54 children, abstracted. Am J Pathol. 1959;35:678. 259. Van Kooij B, Canninga van Dijk M, de Boer J, et al. Is granuloma annulare related to intermediate uveitis with retinal vasculitis? Br J Ophthalmol. 2003;87:763–766. 260. Arekapudi S, Whitfield K, Morrison D. Panuveitis associated with granuloma annulare in a child. J Pediatr Opthalmol Strabismus. 2009;46(1):45–46. 261. Brey N, Purkiss T, Sehgal, et al. Association of inflammatory eye disease with granuloma annulare? Arch Dermatol. 2008;144(6):803–804. 262. Nebesio CL, Lewis C, Chuang TY. Lack of an association between granuloma annulare and type 2 diabetes mellitus. Br J Dermatol. 2002;146:122–124.

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B

A

C

Figure 17.12  (A) Granuloma annulare on the leg. (B) Granuloma annulare on the foot. Subcutaneous granuloma annulare of the scalp. (Courtesy of Dr A. Torrelo.)

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extruded through the epidermis by transepidermal elimination. In the dermis, there is degeneration of collagen, surrounded by palisading histiocytes with lymphocytes and fibroblasts (the palisading granuloma). In the subcutaneous form, areas of degeneration are located in the subcutaneous layer. Collagen fibers are separated by mucinous material, some of which is hyaluronic acid, that can be demonstrated by special stains.245 With immunofluorescent staining, fibrin has been shown to be a constant feature in the necrobiotic foci.245,263 IgM, C3, or fibrinogen staining along the dermal-epidermal junction and IgM cytoid bodies have been reported by some authors.262,264

Although the cause of GA is unknown, numerous theories have been proposed to account for the degenerated collagen.264 Dahl et al.265 found vasculitis on routine biopsy of early lesions, and by direct immunofluorescence, and proposed that the initial event was vascular injury. This has not been substantiated by others.262 Bergman et al.,266 in a study of early lesions, confirmed the presence of neutrophils and nuclear dust, but found evidence of frank vasculitis in only one lesion, and there was no evidence of immune deposits. An underlying defect related to diabetes has been suggested,267 but the results of glucose tolerance tests and insulin studies are contradictory.268 Tuberculin skin testing, sarcoidosis,269,270 insect bites, trauma, herpes zoster,271 drugs,272

263. Umbert P, Winkelmann RK. Granuloma annulare. Br J Dermatol. 1976;95:487. 264. Dahl MV, Callen JP. Granuloma annulare. In: Thiers BH, Dobson RL, eds. Pathogenesis of skin disease. New York: Churchill Livingstone; 1986. 265. Dahl MV, Ullman S, Goltz RW. Vasculitis in granuloma annulare. Arch Dermatol. 1977;113:463. 266. Bergman R, Pam Z, Lichtig C, et al. Localized granuloma annulare. Am J Dermatopathol. 1993;15:544–548. 267. Rhodes EL, Hill DM, Ames AC, et al. Granuloma annulare. Br J Dermatol. 1966;78:532.

268. Blohme G, Mobacken H, Waldenstrom J. Early insulin response to glucose injected intravenously in patients with localized granuloma annulare. Acta Derm Venereol (Stockh). 1974;54:259. 269. Ehrich EW, McGuire JL, Kim YH. Association of granuloma annulare with sarcoidosis. Arch Dermatol. 1992;128:855. 270. Suite M, Jankey N. Familial granuloma annulare. Int J Dermatol. 1992;31:818. 271. Zanolli MD, Powell BL, McCalmont T, et al. Granuloma annulare and disseminated herpes zoster. Int J Dermatol. 1992;31:55. 272. Ross EV, Cobb M. Generalized granuloma annulare associated with quinidine therapy. J Assoc Mil Dermatol. 1991;17:16.

Diseases of the dermis and subcutaneous tissues

tinguish from GA but more commonly affects the face and the typical lesions of GA are not present. Biopsy of a lesion should establish the differences. Rheumatoid nodules may be confused with the subcutaneous form of GA but are usually seen in adults with a high-titer latex fixation test and arthritis. In children, rheumatic fever nodules may mimic the subcutaneous form, but fever, heart murmur, and arthritis are seen in rheumatic fever. Necrobiosis lipoidica is characterized by orange or yellow plaques with atrophy and telangiectasias in the center. This is mainly located on the pretibial areas, and clinically does not resemble GA although the histology may be similar with a necrobiotic histology seen at times in GA. The flat-topped violaceous plaques of annular lichen planus show Wickham’s striae on the surface and occasional scaling. Secondary syphilis can be ruled out with a positive VDRL. Tuberculoid leprosy demonstrates hypopigmentation, decreased sensation, and enlarged nerves. The disseminated or acral papular umbilicated form can mimic lichen nitidus, flat warts, mollusca, or sarcoidosis. Perforating GA can be confused with other perforating disorders such as perforating folliculitis, Kyrle’s disease, and elastosis perforans serpiginosa. It can also simulate pityriasis lichenoides et varioli­ formis acuta.

Prognosis and management

The classic clinical picture in a child is not difficult to recognize, but several other pediatric skin disorders may be confused with GA. Tinea corporis forms ringed lesions but has epidermal changes of scaling or vesiculation. Microscopically, hyphae can be recognized on scrapings. Sarcoidosis may be difficult to dis-

Lesions usually persist for an average of 1–4 years or may have a more chronic, relapsing course with recurrences.247,284 Seventythree percent of lesions disappear within 2 years,246 and reassurance is usually all that is necessary. The duration of the lesions may last for a few weeks to several decades. Because patients are often concerned about the cosmetic aspect, one may wish to try mid-range topical corticosteroids with or without occlusion. Flur­andrenolide tape, an adhesive tape impregnated with cortico­ steroid, aids penetration and may be helpful. The tape is cut to the size of the lesion and applied for several days at a time. Intralesional steroids (triamcinolone acetonide 2.5 mg/mL) injected directly into the lesion may hasten resolution. Cryotherapy has been used in older children or those with limited areas of involvement. A study of 31 patients showed clearing with cryotherapy in 25; however, due to the pain of the procedure, nitrous oxide anesthesia was required.285 Pulse dye laser therapy, 595 nm, has been successful but may result in temporary hypopigmentation.286 Imiquimod cream has been used in childhood GA with improvement as well as a report of

273. Stewart KA, Cooper PH, Greer KE, et al. Granuloma annulare temporally associated with carcinoma of the breast. J Am Acad Dermatol. 1989;21:309. 274. Schwartz RA, Hansen RC, Lynch PJ. Hodgkin’s disease and granuloma annulare. Arch Dermatol. 1981;117:185–186. 275. Barksdale SK, Perniciaro C, Halling KC, et al. Granuloma annulare in patients with malignant lymphoma: clinicopathologic study of 13 new cases. J Am Acad Dermatol. 1994;32:42–48. 276. Coldiron BM, Freeman RG, Beaudoing DL. Isolation of adenovirus from a granuloma annulare like lesion in the acquired immunodeficiency syndrome-related complex. Arch Dermatol. 1988;124:654. 277. Dahl MV. Is actinic granuloma really granuloma annulare? Arch Dermatol. 1986;122:39. 278. Buechner SA, Winkelmann RK, Banks PM. Identification of T-cell subpopulations in granuloma annulare. Arch Dermatol. 1983;119:125. 279. Modlin RL, Horwitz DA, Jordan RR, et al. Immunopathologic demonstration of T lymphocyte subpopulations and interleukin 2 in granuloma annulare. Pediatr Dermatol. 1984;2:26. 280. Umbert P, Winkelmann RK. Granuloma annulare and sarcoidosis. Br J Dermatol. 1977;97:481.

281. Padilla RS, Holguin T, Burgdorf WH, et al. Serum lysozyme in patients with localized and generalized granuloma annulare. Arch Dermatol. 1985;121:624. 282. Fayyazi A, Schweyer S, Eichmeyer B, et al. Expression of IFNgamma, coexpression of TNFalpha and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare. Arch Dermatol Res. 2000;292(8):384–390. 283. Baba T, Hoshino M, Uyeno K. Resolution of cutaneous lesions of granuloma annulare by intralesional injection of human fibroblast interferon. Arch Dermatol. 1988;124:1015. 284. Martinón-Torres F, Martinón-Sánchez JM, Martinón-Sánchez F. Localized granuloma annulare in children: a review of 42 cases. Eur J Pediatr. 1999;158:866–873. 285. Blueme-Peytavi U, Zouboulis CC, Jacobi H, et al. Successful outcome of cryosurgery in patients with granuloma annulare. Br J Dermatol. 1994; 130:494–497. 286. Sliger BN, Burk,CJ, Alvarez-Connelly E. Treatment of granuloma annulare with the 595 nm pulsed dye laser in a pediatric patient. Pediatr Dermatol. 2008;25(2):196–197.

Differential diagnosis

GRANULOMA ANNULARE

carcinoma,273 Hodgkin’s disease274 and other lymphomas,275 adenovirus,276 and solar radiation have all been reported as possible inciting causes in some patients. The precise antigenic stimulus, whether exogenous or endogenous, is unknown. An inciting event in the center of the lesion may set off a chain reaction of events peripheral to it, eliciting inflammation and causing the characteristic rings.277 Buechner et al.278 and others279 suggest that the cell-mediated immune response could be the dominant pathogenic event in GA. They demonstrated that most of the mononuclear cell infiltrate was reactive with Leu-1 antibody, which characterizes peripheral and activated T cells. Helper-inducer T cells (identified with Leu-3a) were the major component of the lymphocytic infiltrate; (Leu-2a) suppressor cytotoxic T cells were also found in the area, but to a lesser degree. They concluded that the pathogenesis of this disorder may involve a specific cell-mediated immune response. Umbert and Winkelmann280 proposed that sensitized lymphocytes within the dermis, which are consistently found around blood vessels in this condition, release lymphokines including macrophage inhibitory factor, which cause macrophages and histiocytes in the dermis to release lysosomal enzymes that partially degrade connective tissue. The serum lysozyme (muramidase) level has been shown to be elevated in generalized GA.281 Fayyazi et al. have shown interferon γ+ Th-1 lymphocytes cause the delayed-type hypersensitivity reaction, whereby macrophages are differentiated to aggressive effector cells expressing TNF-α and matrix metalloproteinases.282 Activation induced apoptosis of T cells and macrophages restricts the destructive potential of these inflammatory cells. Interferon-β1, which inhibits maturation of monocytes to macrophages, can cause resolution when injected into a lesion.283 The cause of GA remains uncertain. However, with new techniques to explore immunologic characteristics, an immune complex vasculitis or a cell-mediated delayed hypersensitivity reaction may be found resulting from multiple trigger factors.

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GRANULOMA FACIALE

worsening.287 Occasionally, biopsy of a lesion is followed by complete involution of the entire lesion. In adults, for cosmetically disfiguring GA, short-term systemic corticosteroid therapy, chlorambucil, etretinate,288 isotretinoin,289 dapsone,290 PUVA,291 and cyclosporin A292 have been used with some degree of success. Anti TNF-α therapy has been associated with both improvement and onset of GA during therapy.293 Recently, photodynamic therapy with methylaminolevulinate has been reported to give sustained remisions.294 Antimalarials were used successfully to clear six children with disseminated GA.295 Most children do not have disfiguring lesions and do not need such treatments. Subcutaneous lesions are histologically similar to rheumatoid nodules.296 Adults presenting with rheumatoid nodules, histologically identical to subcutaneous GA, are at significant risk for the development of rheumatoid arthritis or other connective tissue disease. Scattered reports of necrobiotic granulomas in children with rheumatoid disease have perpetuated concern about the association of these lesions and connective tissue disorders.297 Two reviews of 47 and 34 cases of subcutaneous GA have confirmed the self-limited course with no patients developing connective tissue disease after a lengthy follow-up period.253,254 In a retrospective study of 557 adult patients, Muhlemann and Williams298 found an association between localized GA and insulin dependent diabetes. The relevance of this study to the common form of childhood GA is unclear. A report of 42 children with localized GA followed for 3 years revealed no increased association with diabetes mellitus.284 Whether GA in a child has predictive value regarding development of diabetes mellitus is unknown. A recent case-controlled study of 126 patients found no association between GA and type 2 diabetes, while a previous case-controlled study of 61 patients with GA did show a relationship to type 1 diabetes.262 GA is most commonly seen in the pediatric age group. There is no known influence of GA on nutrition, physical activities, or school performance. It is mainly a cosmetic problem, and whether this entity is associated with insulin-dependent diabetes in childhood or whether there is any causal association with

287. Stephenson S, Nedorost S. Granuloma annulare: dramatically altered appearance after application of 5% imiquimod cream. Pediatr Dermatol. 2008;25(1):138–139. 288. Botella-Estrada R, Guillen C, Sanmartin O, et al. Disseminated granuloma annulare: resolution with etretinate therapy. J Am Acad Dermatol. 1992;26:777. 289. Schleicher SM, Milstein HJ, Lim SJM. Resolution of disseminated granuloma annulare with isotretinoin. Int J Dermatol. 1992;31:371. 290. Steiner A, Pehamberger H, Wolff K. Sulfone treatment of granuloma annulare. J Am Acad Dermatol. 1985;13:1004. 291. Kerker BJ, Huang CP, Morison WL. Photochemotherapy of generalized granuloma annulare. Arch Dermatol. 1990;126:359–361. 292. Filotico R, Vena GA, Coviello C, et al. Cyclosporine in the treatment of generalized granuloma annulare. J Am Acad Dermatol. 1994;30:487–488. 293. Rosmarin D, LaRaia A, Schlauder S, et al. Successful treatment of disseminated granuloma annulare with adalimumab. J Drugs Dermatol. 2009;8(2):169–171. 294. Piaserico S, Zattra E, Linder D, et al. Generalized granuloma annulare treated with methylaminolevulinate photodynamic therapy. Dermatology. 2009;18(3):282–284. 295. Simon M, von den Driesch P. Antimalarials for control of disseminated granuloma annulare in children. J Am Acad Dermatol. 1994;31: 1064–1065. 296. Patterson JW. Rheumatoid nodule and subcutaneous granuloma annulare. A comparative histologic study. Am J Dermatopathol. 1988;10:1. 297. Medlock MD, McComb JG, Raffel C, et al. Subcutaneous palisading granuloma of the scalp in childhood. Pediatr Neurosurg. 1994;21:113–116.

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uveitis requires further investigation. Treatment is limited in children but parental reassurance is usually all that is required.

GRANULOMA FACIALE Granuloma faciale is a rare dermatologic entity characterized by single or multiple, soft, brown-red to violaceous plaques, papules, or nodules that are found most frequently on the face and rarely on other areas. Lever and Leeper299 and Pinkus et al.300 separated this entity from Langerhans cell histiocytosis, eosinophilic granuloma of the bone, and other non-specific granulomas of the skin with eosinophilia.301 It is an uncommon, indolent, benign disorder of unknown cause.302

Epidemiology Granuloma faciale is rare in children. Two reviews of 77 patients303,304 do not include any childhood cases, Nevertheless the disorder has been reported in children as young as 18 months old.305 The majority of patients are middle-aged adults.306 Males are affected more commonly than females,307 and whites more commonly than other races.308 No genetic predisposition has been demonstrated.

Presenting history The patient presents with one or more well-circumscribed plaques, most commonly located on the face.309 Lesions are typically asymptomatic, although some patients report pruritus, burning, and tenderness.310 The lesions have usually been present for some time before the patient seeks help; a history of resistance to therapy is common.

Physical examination Lesions are circumscribed, soft, brownish-red macules, plaques, or nodules with a smooth surface.302 that are mainly seen on the

298. Muhlemann MF, Williams DR. Localized granuloma annulare is associated with insulin-dependent diabetes mellitus. Br J Dermatol. 1984;111:325. 299. Lever WF, Leeper RW. Eosinophilic granuloma of the skin: report of cases representing the two different diseases described as eosinophilic granuloma. Arch Dermatol. 1950;62:85. 300. Pinkus H, Straith CL, Cobane JH. Facial granulomas with eosinophilia. Arch Dermatol Syphilol. 1950;61:442. 301. Guill MA, Aton JK. Facial granuloma responding to dapsone therapy. Arch Dermatol. 1982;118:332. 302. Sears JK, Gitter DG, Stone MS. Extrafacial granuloma faciale. Arch Dermatol. 1991;127:742. 303. Ortonne N, Wechsler J, Bagot M, et al. Granuloma faciale: A clinicopathologic study of 66 patients. J Am Acad Dermatol. 2005; 53:1002–1009. 304. Marcoval J, Moreno A, Peyri J. Granuloma faciale: A clinicopathologic study of 11 cases. J Am Acad Dermatol. 2004;51:269–273. 305. Pedace FJ, Perry HO. Granuloma faciale. A clinical and histopathologic review. Arch Dermatol. 1966;94:387. 306. Black CI. Granuloma faciale. Cutis. 1977;20:66. 307. Fitzpatrick TB, ed. Dermatology in general medicine. ed 5. New York: McGraw-Hill; 1999. 308. Sonoda S, Ishikawa Y. A case of granuloma faciale. Excerpta Medica, Sect 13. Derm Venereol. 1965;19:554. 309. Johnson WC, Higdon RS, Helwig EB. Granuloma faciale. Arch Dermatol. 1959;79:42. 310. Dowlati B, Firooz A, Dowlati Y. Granuloma faciale: successful treatment of nine cases with a combination of cryotherapy and intralesional corticosteroid injection. Int J Dermatol. 1997;36:548–551.

Diseases of the dermis and subcutaneous tissues

Laboratory findings Laboratory findings are normal except for an occasional mild blood eosinophilia.309

Pathophysiology and histogenesis Biopsy of the skin shows distinctive changes in the dermis consisting of a dense polymorphous infiltrate of neutrophils and eosinophils.186 Lymphocytes, histiocytes, plasma cells, and mast cells may be seen. The infiltrate is in the upper dermis, but may extend into the lower dermis, and is separated from the epidermis and pilosebaceous appendages by a Grenz zone of normal collagen. Immunofluorescent microscopy demonstrates IgG and complement, and less consistently IgA and IgM, along the basement membrane zone and the perivascular areas.315,316 Fibrin can be demonstrated along the basement membrane zone and blood vessel walls. Indirect immunofluorescence is negative. Although the cause is obscure,301 it has been suggested that this is an immunologically mediated disorder, likened to a chronic leukocytoclastic vasculitis.186 Most current theories suggest that granuloma faciale may be a localized chronic hypersensitivity vasculitis, which involves an antigen–antibody reaction, with deposition of immunoglobulin and complement in the skin.316 According to this hypothesis, the heavy infiltrate of polymorphonuclear leukocytes perpetuates the inflammatory response by producing chemotactic factors. Smoller and Bortz317 demonstrated a predominance of T-helper lymphocytes which co-stained strongly for antibodies against interleukin and LFA-1, suggesting that the disorder may be mediated by γ-interferon. High local production of IL-5 occurs by clonal expansion of CD4+ T-cells which leads to attraction of eosinophils to the

311. Roustan G, Sanchez Yus E, Salas C, et al. Granuloma faciale with extrafacial lesions. Dermatology. 1999;198(1):79–82. 312. Castano E, Segurada A, Iglesias L, et al. Granuloma faciale entirely in an extrafacial location. Br J Dermatol. 1997;136(6):978–979. 313. Holmes DK, Panje WR. Intranasal granuloma faciale. Am J Otolaryngol. 1983;4:184. 314. Burns BV, Roberts PF, De Carpentier J, et al. Eosinophilic angiocentric fibrosis affecting the nasal cavity: a mucosal variant of the skin lesion granuloma faciale. J Laryngol Otol. 2001;115:223–226. 315. Schroeter AL, Copeman PMN, Jordan RE, et al. Immunofluorescence of cutaneous vasculitis associated with systemic disease. Arch Dermatol. 1971;104:254. 316. Nieboer C, Laksbeek GL. Immunofluorescence studies in granuloma eosinophilicum faciale. J Cutan Pathol. 1978;5:68. 317. Smoller BR, Bortz J. Immunophenotypic analysis suggests that granuloma faciale is a gamma-interferon-mediated process. J Cutan Pathol. 1993;20:442–446. 318. Gauger A, Ronet C, Schnopp C, et al. High local interleukin 5 production in granuloma faciale (eosinophilicum): role of clonally expanded skin-specific CD4+ cells. Br J Dermatol. 2005;153:454–457. 319. Schnitzler L, Verret JL, Schubert B. Granuloma faciale: ultrastructural study of three cases. J Cutan Pathol. 1977;4:123.

lesion.318 Electron microscopic studies have shown no evidence of bacterial or viral infection.319

Differential diagnosis Clinically, the lesions resemble erythema elevatum diutinum but a biopsy should differentiate erythema elevatum diutinum by demonstrating a leukocytoclastic vasculitis and an absence of both eosinophils and a Grenz zone in erythema elevatum diutinum. The histiocytes lack Langerhans granules, which distinguishes this disease from Langerhans cell histiocytosis. Sarcoidosis, lymphocytic infiltrate of Jessner, fixed drug eruption, urticaria pigmentosa, juvenile xanthogranuloma, leprosy, Langerhans cell histiocytosis, and allergic vasculitis can all resemble granuloma faciale clinically. A biopsy helps distinguish among these entities.

CUTANEOUS LYMPHOID HYPERPLASIA (PSEUDOLYMPHOMA)

face although rarely, they may be seen on other parts of the body.311,312 The surrounding skin is normal. They vary in size from a few millimeters to several centimeters and do not ulcerate.307 Hair, nails, and teeth are not affected. A case of intranasal granuloma faciale has been reported.313 Angiocentric eosino­ philic fibrosis of the larynx which has similar histology may accompany granuloma faciale.314 There is no other associated internal organ involvement.306,307

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Therapy and prognosis Granuloma faciale is extremely resistant to treatment. The most effective therapies include dapsone,301,320 or psoralen plus longwave ultraviolet light (PUVA).321 Use of the pulsed dye laser has given excellent results.322,323 A recent report shows the effectiveness of topical tacrolimus ointment in clearing lesions.324 Other therapies that have occasionally been effective include cryotherapy,325 intralesional steroids, dermabrasion, surgical excision, radiation, oral steroids, antimalarials, and the carbon dioxide laser.326,327 Lesions rarely involute spontaneously. Granuloma faciale is seen most commonly in middle-aged adults. It has been reported in children and should be considered in a differential diagnosis of persistent plaques on the face. It is primarily a cosmetic problem.

CUTANEOUS LYMPHOID HYPERPLASIA (PSEUDOLYMPHOMA) Cutaneous pseudolymphomas are a group of benign diseases that can be difficult to distinguish from true lymphomas. A classification of this group (Box 17.2) has been proposed by Brodell and Santa Cruz.328 Pseudolymphomatous angiokeratoma (previously termed ‘acral pseudolymphomatous angiokeratoma

320. Goldner R, Sina B. Granuloma faciale; the role of dapsone and prior irradiation on the cause of the disease. Cutis. 1984;33:478. 321. Hudson LD. Granuloma faciale: treatment with topical psoralen and UVA. J Am Acad Dermatol. 1983;9:559. 322. Hall Welsh J, Schroeder TL, Levy ML. Granuloma faciale in a child successfully treated with the pulsed dye laser. J Am Acad Dermatol. 1999;41(2):351–353. 323. Ammirati, CT, Hruza GJ. Treatment of granuloma faciale with the 585-nm pulsed dye laser. Arch Dermatol. 1999;135:903–905. 324. Tomason N, Sterling JC, Salvary I. Granuloma faciale treated successfully with topical tacrolimus. Clin Exp Dermatol. 2008;34:424–425. 325. Zacarian SA. Cryosurgery effective for granuloma faciale. J Dermatol Surg Oncol. 1985;11:11. 326. Wheeland RG, Ashley JR, Smith DA, et al. Carbon dioxide laser treatment of granuloma faciale. J Dermatol Surg Oncol. 1984;10:730. 327. Dinehart SM, Gross DJ, Davis CM, et al. Granuloma faciale. Comparison of different treatment modalities. Arch Otolaryngol Head Neck Surg. 1990;116:849. 328. Brodell RT, Santa Cruz DJ. Cutaneous pseudolymphomas. Dermatol Clin. 1985;3:719.

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BOX 17.2 BENIGN AND MALIGNANT CUTANEOUS LYMPHOID INFILTRATES IN CHILDREN Perivascular lymphocytic infiltrates

>> Erythema annulare centrifugum >> Lymphocytic infiltrates with mucinosis >> Lymphocytic infiltrate of Jessner-Kanof Cutaneous lymphoid hyperplasia (CLH pseudolymphoma) Arthropod bites, stings, infestations (nodular scabies), Borrelia burgdorferi, vaccinations ‘Lymphoproliferative’ conditions

>> Drug-induced pseudolymphoma >> Lymphomatoid papulosis CUTANEOUS LYMPHOID HYPERPLASIA (PSEUDOLYMPHOMA)

Lymphomatoid contact dermatitis Cutaneous lymphomas

Figure 17.13  Lymphocytoma cutis on the back of an adolescent.

>> Primary

– T-cell lymphomas – B-cell lymphomas – Histiocytic neoplasms

>> Secondary

of children’, APACHE) is now considered a variant of pseudolymphoma.329 Cutaneous lymphoid hyperplasia (CLH), also called lymphocytoma cutis or pseudolymphoma of Spiegler–Fendt, is a benign skin disorder that presents as persistent red nodules or plaques. Hyperplasia of the reticuloendothelial tissue in the skin is characteristic, with mature germinal centers resembling the architecture in the cortex of lymph nodes.330 Cutaneous lymphoid hyperplasia is usually a B-cell predominant or mixed B-cell/T-cell disorder.331,332

Epidemiology CLH can occur at any age,333 but it usually occurs in the late teenage years and early adult life.334 Females are affected more often than males.

Presenting history The patient usually complains of an asymptomatic nodule or persistent multiple papules on the skin.

329. Murakami T, Ohtsuki M, Nakagawa H. Acral pseudolymphomatous angiokeratoma of children: a pseudolymphoma rather than an angiokeratoma. Br J Dermatol. 2001;145:512–514. 330. Bafverstedt B. Lymphadenosis benigna cutis (LABC): its nature, course and prognosis. Acta Derm Venereol (Stockh). 1960;40:10. 331. Nihal M, Mikkola MS, Horvath N, et al. Cutaneous lymphoid hyperplasia: a lymphoproliferative continuum with lymphomatous potential. Hum Pathology. 2003;34(6):617–622. 332. Leboit P. Cutaneous lymphocytic infiltrates. Am J Dermatopathol. 2005;27(2):182–184. 333. Hurwitz S. Clinical pediatric dermatology. ed 2. Philadelphia: WB Saunders; 1993.

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Physical examination There are two forms of skin lesions. The localized form of CLH (circumscribed lymphocytoma cutis) is more commonly seen in infants and children. Lesions are skin-colored, red, or violaceous and often show a follicular arrangement.330,335 Seventy percent of the lesions occur on the face.336 Other common sites include the extremities, areola, and genitalia. Lesions slowly enlarge and can grow to a diameter of 3–5 cm (Fig. 17.13). The disseminated form is rare and is seen mostly in middleaged adults. Multiple firm papules or small bluish-red nodules are often confined to the face. Sometimes the lesions are large and scattered over the trunk and extremities. Disseminated lesions grow rapidly, tend to recur, and may persist throughout life. There may be temporary loss of hair if the lesions affect a hair-bearing area.335 There are usually no other associated findings on physical examination, except occasional lymphadenopathy.

Laboratory findings No laboratory abnormalities have been noted with lymphocytoma cutis.337

Pathophysiology and histogenesis Although the cause of lymphocytoma cutis is unknown, the lesions are thought to be a reactive hyperplasia of mature lymphocytes. Some cases have followed insect bites, trauma,338 gold

334. Rook A, Wilkinson DS, Ebling FJG, eds. Textbook of dermatology. ed 6. Oxford: Blackwell Scientific; 1998. 335. Bafverstedt B. Unusual forms of lymphadenosis benigna cutis. Acta Derm Venereol (Stockh). 1962;42:3. 336. Moschella SL, Hurley HJ, eds. Dermatology. ed 3. Philadelphia: WB Saunders; 1992. 337. Ralfkiaer E, Wantzin GL, Mason DY, et al. Characterization of benign cutaneous infiltrates by monoclonal antibodies. Br J Dermatol. 1984;111:635. 338. Bafverstedt B. Lymphadenosis benigna cutis. Acta Derm Venereol (Stockh). 1968;48:1.

Diseases of the dermis and subcutaneous tissues

and lymphoma. The disseminated form may resemble polymorphous light eruption, histiocytomas, and lymphocytic infiltrate of Jessner. Histologically, the lesions may resemble insect bites and drug reactions, particularly phenytoin reactions.348 Malignant lymphoreticular disorders, such as non-Hodgkin’s lymphoma, cutaneous T-cell lymphomas, and Langerhans cell histiocytosis, may be difficult to differentiate from lymphocytoma cutis.349 Direct immunofluorescence, monoclonal antibody studies, T-cell receptor gene rearrangement studies, and a history of photosensitivity may help to separate some of these entities.

Therapy and prognosis The course is benign, and treatment should be conservative. Spontaneous regression and recurrences may occur. Topical and intralesional steroids, local excision, cryosurgery,350 or oral hydroxychloroquine351 may have some value. The localized form of lymphocytoma cutis responds rapidly to X-ray therapy (500–1500  cGy), but this modality should be avoided in children.333 There have been a few cases reported that have converted to B-cell lymphoma, although these cases usually show clonality of the infiltrate from the outset.352 Because this entity tends to involve only the skin, and the general health of the patient is good, only the cosmetic appearance and psychological welfare of the child need to be assessed.

LYMPHOCYTIC INFILTRATE OF JESSNER

A clinical differential diagnosis of the solitary form includes histiocytoma, mastocytoma, granuloma faciale, sarcoidosis, DLE,

In 1953, Jessner and Kanof353 described a clinical condition manifested by a lymphocytic infiltrate of the skin with a benign and variable course. The lesions were asymptomatic, erythematous papules or plaques that were associated with spontaneous relapses and recurrences. There is continuing controversy as to whether Jessner’s lymphocytic infiltrate represents a distinct

339. Iwatsuki K, Yamada M, Takigawa M, et al. Benign lymphoplasia of the earlobes induced by gold earrings: immunohistologic study on the cellular infiltrates. J Am Acad Dermatol. 1987;16:83. 340. Braun RP, French LE, Feldmann R, et al. Cutaneous pseudolymphoma, lymphomatoid contact dermatitis type, as an unusual cause of symmetrical upper eyelid nodules. Br J Dermatol. 2000;143(2):411–414. 341. Blumenthal G, Okun MR, Ponitch JA. Pseudolymphomatous reaction to tattoos. J Am Acad Dermatol. 1982;6:485. 342. Sanchez JL, Mendez JA, Palacio R. Cutaneous pseudolymphoma at the site of resolving herpes zoster. Arch Dermatol. 1981;117:377. 343. Albrecht S, Hofstadter S, Artsob H, et al. Lymphadenosis benigna cutis resulting from Borrelia infection (Borrelia lymphocytoma). J Am Acad Dermatol. 1991;24:621. 344. VanHale HM, Winkelmann RK. Nodular lymphoid disease of the head and neck: lymphocytoma cutis, benign lymphocytic infiltrate of Jessner, and their distinction from malignant lymphoma. J Am Acad Dermatol. 1985;12:455. 345. Medeiros LJ, Picker LJ, Abel EA, et al. Cutaneous lymphoid hyperplasia. Immunologic characteristics and assessment of criteria recently proposed as diagnostic of malignant lymphoma. J Am Acad Dermatol. 1989;21:929.

346. Schmid U, Eckert F, Griesser H, et al. Cutaneous follicular lymphoid hyperplasia with monotypic plasma cells. A clinicopathologic study of 18 patients. Am J Surg Pathol. 1995;19(1):12–20. 347. Flaig MJ, Schuhmann K, Sander CA. Impact of molecular analysis in the diagnosis of cutaneous lymphoid infiltrates. Semin Cutan Med Surg. 2000;19(2):87–90. 348. Braddock SW, Harrington D, Vose J. Generalized nodular cutaneous pseudolymphoma associated with phenytoin therapy. J Am Acad Dermatol. 1992;27:337. 349. Heilman E, Ackerman AB. A histological atlas of pseudomalignant and malignant lymphoreticular disorders of the skin. J Dermatol Surg Oncol. 1980;6:646. 350. Cerio R, Oliver BF, Jones EW. The heterogeneity of Jessner’s lymphocytic infiltrate of the skin. J Am Acad Dermatol. 1990;23:63. 351. Stoll DM. Treatment of cutaneous pseudolymphoma with hydroxychloroquine. J Am Acad Dermatol. 1983;8:696. 352. Hammer E, Sangueza O, Suwanjindar P, et al. Immunophenotypic and genotypic analysis in cutaneous lymphoid hyperplasias. J Am Acad Dermatol. 1993;28:426. 353. Jessner M, Kanof NB. Lymphocytic infiltration of the skin. Arch Dermatol Syphilol. 1953;68:447.

Differential diagnosis

LYMPHOCYTIC INFILTRATE OF JESSNER

earring-related dermatitis,339 contact dermatitis from ophthalmological products,340 tattooing,341 herpes zoster,342 and Borrelia infection.343 Histologically, a heavy infiltrate of lymphocytes and histiocytes is present in the dermis.186 Mature lymphoid tissue is seen, which resembles the architecture seen in the cortex of the lymph node, with discrete islands of pale cells surrounded by sheets of dark-staining lymphocytes. A Grenz zone of clear connective tissue between the intense infiltrate and the epidermis, or between the infiltrate and hair follicles, is frequently seen. Differentiation from true lymphoma (particularly well-differentiated lymphocytic lymphoma) is important but may be difficult. The presence of plasma cells or eosinophils, the lack of extension into the deep dermis and subcutaneous fat, and the absence of mitoses and features of atypia indicate a benign disease. Using monoclonal antibody staining, the reactive follicles composed of T cells, polytypic B cells, monotypic plasma cells, macrophages, and Langerhans cells have been found.337,344–346 CLH is generally B-cell rich or a mixed B-cell/Tcell disorder.345 Occasionally, epidermal involvement, adnexal infiltration, vascular invasion, and deep involvement in the dermis may be seen, features commonly seen in cutaneous lymphoma. Clonality of the infiltrate is suggestive but not diagnostic of cutaneous lymphoma. Gene rearrangement of the T-cell receptor gamma chain gene is present in more than 90% of cutaneous T-cell lymphoma and may be helpful in cases that are not obvious.346,347 The demonstration of monoclonal immunoglobulin light chain expression in B cells or aberrant antigen expression on B or T cells suggests a malignant process. Patients with clonal populations of B or T cells (clonal cutaneous lymphoid hyperplasia) should be closely observed for emergence of a lymphoma.331,332 In the skin, T lymphocytes may have proliferative abilities, as is also seen in lupus profundus, lymphocytic vasculitis, and insect bites.344 The lymphoid follicles seen in cutaneous lymphoid hyperplasia may be another example of this phenomenon.

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clinical entity or is a variant of lupus erythematosus, polymorphic light eruption, or lymphocytoma cutis.350

Epidemiology Lymphocytic infiltrate of Jessner is a sporadic disease affecting people from 4 to 68 years of age.354,355 Most cases involve adults.356 Males are affected more often than females, but female carriers of chronic granulomatous disease may have an eruption similar to lymphocytic infiltrate of Jessner.357 It has been seen following exposure to ACE inhibitors358 and glatiramer acetate, an immune modifying drug used to treat multiple sclerosis.359

Presenting history LYMPHOCYTIC INFILTRATE OF JESSNER

Patients present with persistent erythematous discrete papules or plaques. The face, earlobes, and neck are most frequently involved, but lesions may be seen on the upper trunk, extremities, and scrotum. Exacerbations may occur with exposure to sunlight.

Physical examination The lesions start as asymptomatic, well-defined papules that may expand peripherally and clear in the center as they expand, to form annular lesions. The papules or plaques are pink to reddish-brown and are usually smooth, but occasionally may have an uneven surface. Lesions may be solitary or numerous. Most commonly, they affect the face, but other body areas may also be affected. The general health of the individual is unaffected and hair, nails, teeth, and mucous membranes are normal. There is no lymphadenopathy or other associated findings on physical examination.

Laboratory findings

Differential diagnosis

Lymphocytosis of the peripheral blood has been reported in a minority of patients.334,353

The major differential diagnoses are with the other lymphocytic infiltrates of the skin as mentioned above. Drug eruptions and sarcoidosis must also be excluded. Direct immunofluorescence and serologic studies may be helpful to rule out LE. Monoclonal antibody studies may also be useful. Cytologic atypia is not seen in lymphocytic infiltrate of Jessner but is seen in lymphoma cutis and lymphomatoid papulosis.367

Pathophysiology and histogenesis Histologically, there is a well-circumscribed, intense superficial and deep lymphocytic infiltrate in the dermis, predominantly in

354. Ralfkiaer E, Lange Wantzin G, Mason DY, et al. Characterization of benign cutaneous lymphocytic infiltrates by monoclonal antibodies. Br J Dermatol. 1984;111:635. 355. Ashworth J, Morley WN. Jessner and Kanof’s lymphocytic infiltration of the skin: a familial variant. Dermatologica. 1988;177:120. 356. Calnan CD. Lymphocytic infiltration of the skin (Jessner). Br J Dermatol. 1957;69:169. 357. Nelson CE, Dahl MV, Goltz RW. Arcuate dermal erythema in a carrier of granulomatous disease. Arch Dermatol. 1977;113:798. 358. Schepis C, Lentini M, Siragusa M, et al. ACE-inhibitor-induced drug eruption resembling lymphocytic infiltration (of Jessner-Kanof) and lupus erythematosus tumidus. Dermatology. 2004;208:354–355. 359. Nolden S, Casper C, Kuhn A, et al. Jessner-Kanof lymphocytic infiltration of the skin associated with glatiramer acetate. Mult Scler. 2005; 11:245–248. 360. Toonstra J, Wildschut A, Boer J, et al. Jessner’s lymphocytic infiltration of the skin. A clinical study of 100 patients. Arch Dermatol. 1989;125:1525. 361. Abele DC, Anders KH. The many faces and phases of borreliosis II. J Am Acad Dermatol. 1990;23:401.

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the perivascular and periadnexal areas.186 There are no germinal centers, or significant numbers of reticular or histiocytic elements. A few histiocytes and plasma cells may be found. The epidermis is normal. Controversy has surrounded lymphocytic infiltrate of Jessner. Some authors consider it to be a form of lymphocytoma cutis while others classify it as a variant of DLE, polymorphous light eruption, or lymphocytic lymphoma. It may be a heterogeneous group of disorders, but a review of 100 patients found it to be a single entity.360 Some of the patients in this study had coexisting polymorphous light eruption, suggesting sunlight may play a role in the pathogenesis.360 Borrelia burgdorferi serology has been reported to be positive by some authors361 but refuted by others.362 Lever186 suggests that the term lymphocytic infiltrate be used as a preliminary term and not a definitive diagnosis because many cases evolve into DLE, polymorphous light eruption, lymphocytoma cutis, or lymphocytic lymphoma at a later time. Studies using monoclonal antibodies have demonstrated that most of the infiltrating cells are CD4+ T cells.344,363 B lymphocytes are rare or absent.364 This distinguishes lymphocytic infiltrate of Jessner from lymphocytoma cutis, which frequently shows a predominance of B cells in the infiltrate. Circulating immune complexes are increased during active disease and decrease when treatment is effective.365 Natural killer cell function and antibody-dependent cell-mediated cytotoxicity are also decreased, showing that an immune defect may predominate in this disorder. However, T lymphocytes may accumulate from the circulation and not proliferate within the site of inflammation.366 Lymphocytic infiltrate of Jessner is most likely a unique benign immunoreactive process, recognized as a chronic papular lymphocytic dermatosis without associated systemic disease.

362. Guillaume JC, Moulin G, Dieng M, et al. Crossover study of thalidomide vs placebo in Jessner’s lymphocytic infiltration of the skin. Arch Dermatol. 1995;131:1032–1035. 363. Willemze R, Dijkstra A, Meijer CJ. Lymphocytic infiltration of the skin (Jessner): a T-cell lymphoproliferative disease. Br J Dermatol. 1984; 110:523. 364. Kuo T, Lo SK, Chan HL. Immunohistochemical analysis of mononuclear cell infiltrates in cutaneous lupus erythematosus, polymorphous light eruption, lymphocytic infiltration of Jessner, and cutaneous lymphoid hyperplasia. J Cutan Pathol. 1991;21:430–436. 365. Braddock SW, Kay HD, Maennle D, et al. Clinical and immunologic studies in reticular erythematous mucinosis and Jessner’s lymphocytic infiltrate of skin. J Am Acad Dermatol. 1993;28:691. 366. Kon Hinen YT, Bergroth V, Johansson E, et al. A long-term clinicopathologic survey of patients with Jessner’s lymphocytic infiltration of the skin. J Invest Dermatol. 1987;89:205. 367. Mac Donald DM. Histopathological differentiation of benign and malignant cutaneous lymphocytic infiltrates. Br J Dermatol. 1982;107:715.

Diseases of the dermis and subcutaneous tissues

Therapy and prognosis

SWEET SYNDROME Sweet syndrome (acute febrile neutrophilic dermatosis) was first reported by Sweet371 in 1964. The four cardinal features are: fever; neutrophilic leukocytosis in the peripheral blood; raised painful plaques on the limbs, face, and neck; and histological evidence of a dense dermal infiltrate of neutrophils histologically. Diagnostic criteria are listed in Box 17.3. Although most cases in the original series were preceded by infections, chronic inflammatory diseases of various types, particularly inflammatory bowel disease, hemoproliferative disorders especially myeloid malignancies in adolescents and adults, and solid carcinomas have been reported with Sweet syndrome.372–386 Miscellaneous associations include pregnancy, vaccination, Fanconi anemia, and use of granulocyte colony-stimulating factors.387 Patients respond rapidly to systemic corticosteroid therapy.

Epidemiology This entity is rare in children; a recent review included 64 childhood and adolescent cases.373 Affected children as young as 7 weeks old have been described.385,386 Nevertheless, Sweet syn-

368. Gottlieb B, Winkelmann RK. Lymphocytic infiltration of skin. Arch Dermatol. 1962;86:626. 369. Wantzin GL, Hou-Jensen K, Nielsen M, et al. Cutaneous lymphocytomas: clinical and histological aspects. Acta Derm Venereol (Stockh). 1982;62:119. 370. Rupec RA, Petropoulou T, Belohradsky BH, et al. Lupus erythematosus tumidus and chronic discoid lupus erythematosus in carriers of X-linked chronic granulomatous disease. Eur J Dermatol. 2000;10(3):184–189. 371. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. 1964;76:349. 372. Von den Driesch P. Sweet’s syndrome (acute neutrophilic dermatosis). J Am Acad Dermatol. 1994;3:535–556. 373. Hospach T, von den Driesch P, Dannecker GE. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) in childhood and adolescence: two new patients and review of the literature and associated diseases. Eur J Pediatr. 2009;168:1–9. 374. Sedel D, Huguet P, Lebbe C, et al. Sweet syndrome as the presenting manifestation of chronic granulomatous disease in an infant. Pediatr Dermatol. 1994;11(3):237–240. 375. Shimizu T, Yoshida I, Eguchi H, et al. Sweet syndrome in a child with aplastic anemia receiving recombinant granulocyte colony-stimulating factor. J Pediatr Hematol Oncol. 1996;18(3):282–284. 376. Hassouna L, Nabulsi-Khalil M, Mroueh SM, et al. Multiple erythematous tender papules and nodules in an 11-month-old boy. Sweet syndrome (SS) (acute febrile neutrophilic dermatosis). Arch Dermatol. 1996; 132(12):1507–1510. 377. Gray LC, Abele DC. Annular erythematous plaques and tibial pain in a child. Sweet syndrome. Arch Dermatol. 1998;134(5):625–626, 628–629.

BOX 17.3 DIAGNOSTIC CRITERIA FOR SWEET SYNDROMEa Major criteria 1. Abrupt onset of tender or painful erythematous plaques or nodules occasionally with vesicles, pustules, or bullae 2. Predominantly neutrophilic infiltration in the dermis without leukocytoclastic vasculitis Minor criteria 1. Preceded by nonspecific respiratory or gastrointestinal tract infection or vaccination or associated with: – Inflammatory disease such as chronic autoimmune disorders, infections – Hemoproliferative disorders or solid malignant tumors – Pregnancy SWEET SYNDROME

Therapies for Jessner’s lymphocytic infiltrate of the skin include oral antimalarials, topical steroids, X-ray therapy, and cryotherapy.368 Thalidomide given for 2 months has been reported to be effective.362 Although many treatments are associated with a clinical response in some patients, this entity tends to be resistant to most modes of therapy. Lesions persist for weeks to years or even as long as 30 years, with an average length of 5 years. They resolve leaving no residual trace.369 However, lesions may recur either at the same sites or elsewhere. This disease has been reported in the pediatric age group; although it is rare. It is important to differentiate from other lymphocytic infiltrates and in female carriers of chronic granulomatous disease who may present with similar skin lesions.370

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2. Accompanied by periods of general malaise and fever (>38 °C) 3. Laboratory values during onset: ESR >20 mm; C-reactive protein positive; segmented-nuclear neutrophils and bands 0.70% in peripheral blood smear; leukocytosis >8000 (three of four of these values necessary) 4. Excellent response to treatment with systemic corticosteroids or potassium iodide. a

Both major and two minor criteria needed for diagnosis. Initiated by Su and Liu and modified by von den Driesch.372

drome is most commonly seen in patients aged 30–49 years, with a female to male ratio of 3.7 : 1.372 In children, the sex incidence is equal with peaks of occurrence in the first year of life and between 6 and 12 years of age. In adult cases there is an increased incidence in the spring and autumn. A recent review of childhood and adolescent cases noted three broad groups with 42% of patients presenting with classic/idiopathic disease, 58% associated with chronic diseases of which 33% were parainflammatory Sweet’s syndrome, and 25% were paraneoplastic associated with malignant or premalignant disease.373

378. Schneider DT, Schuppe HC, Schwamborn D, et al. Acute febrile neutrophilic dermatosis (Sweet syndrome) as initial presentation in a child with acute myelogenous leukaemia. Med Pediatr Oncol. 1998;31(3):178–181. 379. Tuerlinckx D, Bodart E, Despontin K, et al. Sweet’s syndrome with arthritis in an 8-month-old boy. J Rheumatol. 1999;26(2):440–442. 380. Lipp KE, Shenefelt PD, Nelson Jr RP, et al. Persistent Sweet’s syndrome occurring in a child with a primary immunodeficiency. J Am Acad Dermatol. 1999;40(5 Pt 2):838–841. 381. Guia JM, Frias J, Castro FJ, et al. Cardiovascular involvement in a boy with Sweet’s syndrome. Pediatr Cardiol. 1999;20(4):295–297. 382. Nurre LD, Rabalasi GP, Callen JP. Neutrophilic dermatosis-associated sterile chronic multifocal osteomyelitis in pediatric patients: case report and review. Pediatr Dermatol. 1999;16(3):214–216. 383. Eliott SP, Malloy SB. Sweet syndrome: an unusual presentation of chronic granulomatous disease in a child. Pediatr Infect Dis J. 1999;18(6):568–570. 384. Sirvent N, Olivier V, Benet L, et al. Sweet syndrome in an infant. Arch Pediatr. 2000;7(5):501–504. 385. Itami S, Nishioka K. Sweet’s syndrome in infancy. Br J Dermatol. 1980;103:449. 386. Chatham-Stephens K, Devere T, Guzman-Cottrill J, et al. Metachronous manifestations of Sweet’s syndrome in a neutropenic patient with Fanconi anemia. Pediatr Blood Cancer 2008;51:128–130. 387. Cohen PR. Sweets syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34.

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Presenting history Some 85–90% of patients have a high, persistent fever up to 40°C,388 usually antedating the eruption by several days. Raised, erythematous, painful plaques and nodules appear about 1 week later.389 Many of the patients have had a recent infection or other associated illness.

Physical examination

SWEET SYNDROME

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Elevated tender plaques measuring 0.5–4 cm are most commonly found on the face, neck, and limbs in an asymmetric distribution. Lesions usually spare the trunk but have been described on the palms, soles and mucous membranes.390,391 Palmoplantar lesions may mimic palmoplantar pustulosis.392 Lesions enlarge quickly and develop annular patterns with clearing in the center. Milia may occur.393 The larger plaques have heaped-up mamillated margins and develop vesicles or sterile pustules along their borders (Fig. 17.14); generally, lesions heal without sequelae,390 except for temporary hyperpigmentation due to hemosiderin deposition. Secondary cutis laxa has been described within the areas of involvement in some children,394,395 possibly secondary to the intense inflammatory process. Other associated findings include arthritis and arthralgias in 33–62% of cases, which resolve with treatment.372,389 Sterile osteomyelitis has been observed in some children.234 Conjunctivitis and episcleritis have been described in up to 72% of cases;396 renal involvement including proteinuria, hematuria, and glomerulonephritis also occur.389 Neuro-Sweet disease with aseptic meningitis and encephalitis has mainly been reported in adults.397 Of the childhood cases described in the literature, 25% have had an associated malignancy, particularly acute myelo­genous leukemia.274,373,398,399 This association is mainly in adult males, but has been reported in adolescents and children.373,378 Sterile neutrophilic infiltrates in organs other than skin occur as uncommon manifestations of Sweet syndrome or pyoderma gangrenosum. These infiltrates have been reported in the lungs, bones, joints, central nervous system, liver, gastrointestinal tract, lymph nodes, spleen, cardiovascular system, and eyes.372,382,400,401 One child, who had cutis laxa-like changes following Sweet syndrome, died

suddenly of occlusive coronary artery disease 2 years after the diagnosis of Sweet syndrome.402 A total of five pediatric patients have been described with these residual cutis laxa-like changes following Sweet syndrome with significant vascular disease of the aorta, coronary and pulmonary vessels without signs of occlusion.373,381,403 The phenomenon of pathergy, typical of pyoderma gangrenosum and Behçet syndrome, has been reported in several cases of Sweet syndrome.404 Sweet syndrome has been associated with embryonal carcinoma of the testicle,388 ulcerative colitis,371,405 Crohn’s desease,406 sarcoidosis,407 Sjögren syndrome,389 erythema nodosum,408 chronic granulomatous disease,383 primary immunodeficiency,380 arthritis (rheumatoid and sero-negative),379,409 G-CSF infusion for

388. Shapiro L, Baraf CS, Richheimer LL. Sweet’s syndrome (acute febrile neutrophilic dermatosis). Arch Dermatol. 1971;103:81. 389. Storer JS, Nesbitt LT, Galen WK, DeLeo VA. Sweet’s syndrome. Int J Dermatol. 1983;22:8. 390. Sweet RD. Acute febrile neutrophilic dermatosis. Br J Dermatol. 1979;100:93. 391. Spector JI, Zimbler H, Levine R, et al. Sweet’s syndrome. JAMA. 1980;244:1131. 392. Sommer S, Wilkinson SM, Merchant WJ, et al. Sweet’s syndrome presenting as palmoplantar pustulosis. J Am Acad Dermatol. 2000;42(2 Pt 2):332–334. 393. Kemmett D, Hunter JAA. Sweet’s syndrome: a clinicopathologic review of twenty-nine cases. J Am Acad Dermatol. 1990;23:503. 394. Kibbi AG, Zaynoun ST, Kurban AK, et al. Acute febrile neutrophilic dermatosis (Sweet’s syndrome): case report and review of the literature. Pediatr Dermatol. 1985;3:40. 395. Levin DL, Esterly NB, Herman JJ, et al. The Sweet syndrome in children. J Pediatr. 1981;99:73. 396. Majeed D, Kalaawi M, Mohanty D, et al. Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and in association with Sweet’s syndrome in two siblings. J Pediatr. 1989;115:730–734. 397. Hisanaga K, Iwasaki Y, Itoyama Y, et al. Neuro-Sweet disease. Clinical manifestations and criteria for diagnosis. Neurology. 2005;64:1756–1761. 398. Klock JC, Oken RL. Febrile neutrophilic dermatosis in acute myelogenous leukemia. Cancer. 1976;37:992.

399. Cohen PR, Talpaz M, Kurzrock R. Malignancy-associated Sweet’s syndrome: review of the world literature. J Clin Oncol. 1988;6:1887. 400. Lazarus AA, McMillam M, Miramadi A. Pulmonary involvement in Sweet’s syndrome (acute febrile neutrophilic dermatosis). Preleukemic and leukemic phases of acute myelogenous leukemia. Chest. 1986;90:922. 401. Vignon-Pennamen MD, Wallach D. Neutrophilic disease: a review of extra-cutaneous neutrophilic manifestations. Eur J Dermatol. 1995; 5:449–455. 402. Muster AJ, Bharati S, Herman JJ, et al. Fatal cardiovascular disease and cutis laxa following acute febrile neutrophilic dermatosis. J Pediatr. 1983;102:243. 403. Manohar R. Idiopathic dilatation of pulmonary artery. J Assoc Phys Ind. 1996;44(5):342. 404. Sitjas D, Puig L, Cuatrecasas M, et al. Acute febrile neutrophilic dermatosis (Sweet’s syndrome). Int J Dermatol. 1993;32:261. 405. Benton EC, Rutherford D, Hunter JAA. Sweet’s syndrome and pyoderma gangrenosum associated with ulcerative colitis. Acta Derm Venereol (Stockh). 1985;65:77. 406. Rappaport A, Shaked M, Landau M, Dolev E. Sweet’s syndrome in association with Crohn’s disease: report of a case and review of the literature. Dis Colon Rectum. 2001;44(10):1526–1529. 407. Stuveling EM, Fedder G, Bruns HM, et al. The association of Sweet’s syndrome with sarcoidosis. Neth J Med. 2001;59(1):31–34. 408. Spatz SA. Erythema nodosum in Sweet’s syndrome. Cutis. 1985;35:327. 409. Harary AM. Sweet’s syndrome associated with rheumatoid arthritis. Arch Intern Med. 1983;143:1993.

Figure 17.14  Typical lesions of Sweet syndrome with heaped edges. (Courtesy of Nancy Esterly.)

Diseases of the dermis and subcutaneous tissues

Laboratory findings Leukocytosis ranging from 15 000 to 24 000/mm3 is described in most patients, with 80–90% polymorphonuclear leukocytes.244 An elevated erythrocyte sedimentation rate is common, often as high as 80 mm/h.395 Thrombocytosis was described in one child who died of occlusive coronary artery disease.402 Anemia and urinary abnormalities, including red cells and granular casts in the urinary sediment, can occur. Fever and leukocytosis may be absent when Sweet syndrome occurs in association with immunodeficiency.380 Culture of skin lesions for bacteria and fungi are negative. Circulating antibodies to neutrophil cytoplasm (ANCA) have been demonstrated in some but not all patients with Sweet syndrome.412

Pathophysiology and histogenesis Sweet syndrome forms part of a spectrum of reactive neutrophilic dermatoses including pyoderma gangrenosum, neutrophilic eccrine hidradenitis, subcorneal pustulosis, pustular vasculitis, erythema elevatum diutinum, rheumatoid neutrophilic dermatosis, and erythema nodosum. Two other entities, chronic recurrent multifocal osteomyelitis (CRMO), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) also resemble a reactive neutrophilic dermatoses.382,413 Although the cause of Sweet syndrome remains unclear, studies point to a T-cell dependent cellular immune reaction underlying the disease. CD 251 activated T cells are noted in the inflammatory infiltrate as well as an increased expression of ICAM-1 and IL-8 immunoreactive cells. IL-1 (α and β) and IFNγ levels are increased in serum of patients with Sweet syndrome.414 IL-4 levels in the serum are normal, suggesting the disorder is mediated through helper T cell type 1 cytokines. The ensuing cytokine cascade including IL-1, IL-3, IL-6, IL-8, and G-CSF and GM-CSF may explain the local and systemic activation of neutrophils and histiocytes.372 The trigger to this process may be an antigen or superantigen,372 including bacterial or viral infection,415 an immunologic response to a leukemic or preleukemic state399 or a drug reaction. Because many of the patients have a preceding

410. Bechtel MA, Callen JP. Acute febrile neutrophilic dermatosis, Sweet’s syndrome. Arch Dermatol. 1981;117:664. 411. Brady RC, Morris J, Connelly BL, et al. Sweet’s syndrome as an initial manifestation of pediatric human immunodeficiency virus infection. Pediatrics. 1999;104(5 Pt 1):1142–1144. 412. Kemmett D, Harrison DJ, Hunter JAA. Antibodies to neutrophil cytoplasmic antigens: a serologic marker for Sweet’s syndrome. J Am Acad Dermatol. 1991;24:967. 413. Beretta-Piccoli BC, Sauvain MJ, Gal I, et al. Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in childhood: a report of ten cases and review of the literature. Eur J Pediatr. 2000;159(8):594–601. 414. Giasuddin AS, El-Orfi AH, Ziu MM, et al. Sweet’s syndrome: Is the pathogenesis mediated by helper T cell type 1 cytokines? J Am Acad Dermatol. 1998;39(6):940–943. 415. Collins P, Rogers S, Keenan P, et al. Acute febrile neutrophilic dermatosis in childhood (Sweet’s syndrome). Br J Dermatol. 1991;124:203.

febrile illness,246,397 an immune complex mediated process has been postulated.372 Two groups found no deposition of immune complexes in 35 patients with Sweet syndrome.372 Studies of altered function of neutrophils in Sweet syndrome including chemotaxis have given contradictory results and may represent an epiphenomenon.372 Histologically, a dense perivascular infiltrate of polymorphonuclear leukocytes with leukocytoclasis is found in the dermis and may extend into the subcutis.186 Because in most specimens there are no fibrinoid deposits in the capillaries or extravasated red blood cells, a true vasculitis is not usually present. In some cases however, the changes are consistent with a true vasculitis and a recent review has suggested that Sweet syndrome is a variant of leukocytoclastic vasculitis.416 The histologic appearance varies with the stage of the process. In the later stages, lymphocytes and histiocytes may predominate. ‘Histiocytoid Sweet syndrome’ has been recently described with biopsy specimens showing many histiocyte-like cells that were confirmed to be of myeloid lineage by immuinohistochemistry.417 The dermal papillae may be involved with marked edema, which causes subepidermal blisters. Pulmonary infiltrates, on lung biopsies, reveal extensive neutrophilic infiltrates similar to the findings in cutaneous biopsies.400

SWEET SYNDROME

aplastic anemia,375 immunodeficiency,375,379,380,409 gastrojejuno­ stomy with blind loop syndrome,410 and HIV infection.411 Drug induced Sweet syndrome may occur following GMCS-F or GCS-F, pegfilgrastim, Imatinib mesylate, Bortezomib, all trans retinoic acid, minocycline and trimethoprim –sulfamethoxazole, all with multiple reports cited.387

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Differential diagnosis Clinically, Sweet syndrome must be separated from other reactive neutrophilic dermatoses.418 Pyoderma gangrenosum is usually easy to differentiate but the acute disseminated vesiculopustular forms in association with autoimmune bowel disease and hemoproliferative disorders may be more difficult to distinguish. Simultaneous occurrence of both disorders has been reported.372 Disseminated forms of erythema nodosum may be confusing clinically but histology shows infiltrates predominantly in the septa of the subcutaneous tissue.186 Bowel bypass syndrome may present with fever, arthralgias and papulopustular lesions. The histological changes have been termed ‘Sweetlike vasculitis.’186 Neutrophilic eccrine hidradenitis is associated with chemotherapy of malignant disorders. Clinically identical skin lesions may occur accompanied by drug-induced neutropenia.419 Histology shows dermal infiltration of neutrophils mainly around eccrine sweat glands.420 The differentiation of this entity from Sweet syndrome may be difficult as both are part of a continuous spectrum of neutrophilic dermatoses.421 Idiopathic recurrent palmoplantar hidradenitis (IRPH) is a benign disorder characterized by multiple tender erythematous

416. Ratzinger G, Burgdorf W, Zelger B, et al. Acute febrile neutrophilic dermatosis: a histopathologic study of 31 cases with review of literature. Am J Dermatopathol. 2007;29:125–133. 417. Requena L, Kutzner H, Palmedo G, et al. Histiocytoid Sweet syndrome: a dermal infiltration of immature neutrophilic granulocytes. Arch Dermatol. 2005;141(7):834–842. 418. Wallach D, Vignon-Pennamen M. From acute febrile neutrophilic dermatosis to neutrophil disease: Forty years of clinical research. J am Acad Dermatol. 2006;56:1066–1071. 419. Harris TJ, Fine JD, Berman RS. Neutrophilic eccrine hidradenitis: a distinct type of neutrophilic dermatosis. Arch Dermatol. 1982;118:263–266. 420. Thorisdottir K, Tomecki KJ, Bergfeld WF, et al. Neutrophilic eccrine hidradenitis. J Am Acad Dermatol. 1993;28:775–777. 421. Gross PR, Margolis D, Starobinski M, et al. Neutrophilic dermatosis versus neutrophilic eccrine hidradenitis. N Engl J Med. 1999;340:1371.

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nodules on the soles and in some cases the palms of otherwise healthy young persons.422 Fever is usually absent and the disorder clears spontaneously.422 Mechanical or thermal trauma is thought to lead to rupture of the palmoplantar eccrine glands. The release of eccrine secretions into the surrounding stroma may activate a cytokine cascade including TNFα, IL-8, and G-CSF capable of attracting neutrophils and producing the resultant inflammation. Most cases resolve spontaneously within three weeks without treatment. Pernio (chilblains) may have a similar clinical appearance; however, histology shows a lymphoid infiltrate with endothelial swelling.186 An outbreak of ‘Pseudomonas hot foot syndrome’423 was reported in 40 children who developed acute inflammatory, painful, plantar nodules after contact with pool water contaminated with P. aeruginosa. The floor of the pool had been coated with an abrasive grit to prevent slipping. Culture of skin lesions grew Pseudomonas and biopsy showed a perieccrine neutrophilic infiltrate that extended to the subcutaneous fat. The disorder is self-limited with recovery in 14 days. Lupus erythematosus, erythema elevatum diutinum, Behçet’s disease, granuloma faciale, halogenoderma and other bacterial infections may be excluded by skin biopsy or appropriate cultures.372

Therapy and prognosis Untreated lesions tend to increase in size and persist for 1–12 months, eventually resolving without sequelae. Some children have secondary cutis laxa in the areas of involvement, probably as a result of intense inflammation and degradation of the collagen.402 Sweet syndrome that is associated or resolving with extensive cutis laxa may be a sign of occult cardiac disease or major vessel disruption;402 long-term follow-up with echocardiography is reccomended.373 Lesions respond to oral steroids (prednisone) at a dose of 0.5 1.5 mg/kg per day given for 10 days and then tapered slowly to prevent recurrences.372,398 Kemmett and Hunter,393 in a review of 29 cases, reported 21% of patients had more than one episode and another 10% had relapsing disease for at least 3 years. High potency topical corticosteroids or intralesional triamcinolone may be used for localized disease. Alternatives to corticosteroid treatment include potassium iodide, colchicine, dapsone, doxycycline, clofazimine, indomethacin, and interferon-α.372,424,425

422. Miklos S, Cremer H, Von den Driesch P. Idiopathic recurrent palmoplantar hidradenitis in children. Arch Dermatol. 1998;134:76–79. 423. Fiorillo I, Zucker M, Sawyer D, et al. The Pseudomonas hot foot syndrome. N Engl J Med. 2001;345(5):335–338. 424. Maillard H, Leclech C, Peria P, et al. Colchicine for Sweet’s syndrome. A study of twenty cases. Br J Dermatol. 1999;140(3):565–566. 425. Bianchi L, Masi M, Hagman JH, et al. Systemic interferon-alpha treatment for idiopathic Sweet’s syndrome. Clin Exp Dermatol. 1999;24(6):443–445. 426. Wilson DM, John GR, Callen JP. Peripheral ulcerative keratitis—an extracutaneous neutrophilic disorder: report of a patient with rheumatoid arthritis, pustular vasculitis, pyoderma gangrenosum, and Sweet’s syndrome with an excellent response to cyclosporine therapy. J Am Acad Dermatol. 1999;40(2 Pt 2):331–334. 427. Delluc A, Limal N, Puechal X, et al. Efficacy of anakinra, an IL-1 receptor antagonist, in refractory Sweet syndrome. Ann Rheum Dis. 2008;67(2):278. 428. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia. J Am Acad Dermatol. 1985;12:781. 429. Blauvelt A, Cobb MW, Turner ML. Widespread cutaneous vascular papules associated with peripheral blood eosinophilia and prominent inguinal lymphadenopathy. J Am Acad Dermatol. 2000;43(4):698–700.

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Resistant cases often respond to cyclosporin,426 Infliximab, etanercept, thalidomide and anakinra.387,427 In view of 16 pediatric patients373,378,398 having an associated malignancy, mainly AML, this eruption should be considered a possible cutaneous sign of malignancy, and appropriate investigations should be performed.373,395 The prognosis depends on the severity of the systemic disease that accompanies the eruption. In children, the serious complication of occlusive coronary artery or other large vessel disease has been reported in three patients.381,402,403 As the disorder is considered to be a hypersensitivity reaction, giving aspirin and/or other nonsteroidal antiinflammatory agents is warranted, particularly if there is thrombocytosis. Because of the possible relationship to malignancy, the eruption should be thoroughly evaluated with this in mind. If cardiovascular symptoms or signs develop in Sweet syndrome, a thorough investigation of the cardiac status is mandatory to avoid potentially fatal coronary artery disease.381

ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA AND KIMURA DISEASE The term angiolymphoid hyperplasia with eosinophilia (ALHE) is used for a group of vascular tumor-like lesions of the skin, which have characteristic, nonspecific histiocytoid endothelial cells on histology.428,429 In 1969, Wells and Whimster430 reported their findings on patients with subcutaneous nodules on the head and neck who showed a distinctive vascular proliferation with inflammatory infiltrates containing eosinophils and numerous lymphoid follicles. They termed this disease ALHE, and considered it to be a distinct clinical and pathologic entity that occurred most often in young adults. Kimura disease was originally described by Kim and Szeto in 1937 in a Chinese journal and is uncommon in Western countries.431 It has been reported mainly in the Asian literature and is a similar but distinct entity from ALHE; it occurs more commonly in Asian male children. Many authors consider these entities to be the same disease because of their clinical and pathologic similarities.430,432 Others contend that the clinical differences and the histiocytoid endothelial cells seen in ALHE are not consistently found in Kimura disease433 and that they are two separate unrelated disorders.434–436 A comparison of the two disorders is found in Table 17.2.

430. Wells GC, Whimster IW. Subcutaneous angiolymphoid hyperplasia with eosinophilia. Br J Dermatol. 1969;81:1. 431. Allen PW, Ramakrishna B, MacCormac LB. The histiocytoid hemangiomas and other controversies. Path Annu. 1992;2:51. 432. Reed RJ, Terazakis N. Subcutaneous angioblastic lymphoid hyperplasia with eosinophilia (Kimura’s disease). Cancer. 1972;29:489. 433. Rossai J. Angiolymphoid hyperplasia with eosinophilia of the skin. Am J Dermatopathol. 1982;4:175. 434. Helander SD, Peters MS, Kuo TT, et al. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: new observations from immunohistochemical studies of lymphocyte markers, endothelial antigens and granulocyte proteins. J Cutan Path. 1995;22:319–326. 435. Requena L, Sangueza OP. Cutaneous vascular proliferation. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol. 1997;37:887–919. 436. Chen H, Thompson LD, Ives Aguilera NS, et al. Kimura disease. A clinicopathologic study of 21 cases. Am J Surg Pathol. 2004;28: 505–513.

Diseases of the dermis and subcutaneous tissues

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ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA

KIMURA’S DISEASE

Distribution

Worldwide

Asia

Age

13–67 years

7–50 years

Sex

Males = females

Males > females

Location

Head and neck

Head and neck

Appearance

Superficial papules and nodules usually unilateral

Tumor-like mass with deep soft tissues involved, sometimes bilateral

Size

0.8 cm to massive

3–10 cm

Lymphadenopathy

No

Yes

Blood findings

Serum IgE normal

Serum IgE usually elevated

Blood eosinophilia sometimes

Blood eosinophilia usual

Proliferating vessels with histiocytoid endothelial cells,   eosinophils, lymphocytes often with follicles, plasma cells

Vessels not prominent

Fibrosis absent or minimal

Fibrosis prominent surrounding lymphoid follicles, lymphocytes, plasma cells, mast cells with IgE, eosinophils, and eosinophilic microabscesses

Mast cells commonly increased

Mast cells rarely increased

Associated in one case

Associated

Histologic results

Nephrotic syndrome

Epidemiology ALHE most commonly occurs sporadically in young adults, with equal sex distribution. Asians, whites, blacks, Native Americans, and Middle Eastern patients all have been reported.437 Kimura disease occurs most commonly in young Asian boys and men.

ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA AND KIMURA DISEASE

Table 17.2  Comparison of angiolymphoid hyperplasia with eosinophilia and Kimura’s disease

subcutaneous masses with normal overlying skin.439 Oral lesions have been reported.440,441 Lymphadenopathy is common in Asian children with Kimura disease.437 Associated conditions include atopic dermatitis438 and lichen amyloidosis.442

Laboratory findings Presenting history The patient usually complains of a growing erythematous nodule, usually in the pre-auricular area, scalp, or forehead. Onethird of the patients have pain,428 and there may be spontaneous bleeding or throbbing in the lesion. Diagnosis before biopsy is unlikely because of the nonspecific morphologic features.

Blood eosinophilia is seen in both diseases and may be as high as 75% in patients with Kimura disease;442 serum IgE levels may also be elevated.438 Kimura’s disease may be complicated by proteinuria and nephrotic syndrome.443

Pathophysiology and histogenesis

Pruritus is a feature in most, but 21% of patients are totally asymptomatic.428 Lesions are usually single but may be multiple428 and appear as dusky, erythematous, or purplish plaques or nodules, measuring 1–2 cm in diameter, but may be as large as 10 cm.430 They are occasionally covered with a central crust or scale and occur principally on the head and neck with a predilection for the face and ears (Fig. 17.15). Although many lesions have been reported to be painless,438 pressure may elicit pain in one-third of patients.428 In Kimura disease the lesions are bulky

Histologically, the lesions of ALHE are characterized by vascular proliferations and a lymphocytic infiltration, with eosinophils within the dermis and subcutaneous tissue.428 Both mature and immature blood vessels are lined by several layers of thick, plump, rounded endothelial cells. The intense infiltrate consists of eosinophils, lymphocytes, mast cells, histiocytes, and lymphoid follicles with germinal centers in many cases. Early lesions show more vascular proliferation than older lesions, which demonstrate more prominent lymphoid tissue with flatter vascular endothelium.430 Direct immunofluorescence testing demonstrates granular deposits of IgA, IgM, and C3 around small blood

437. Henry PG, Burnett JW. Angiolymphoid hyperplasia with eosinophilia. Arch Dermatol. 1978;11:1168. 438. Hamrick HJ, Jennette JC, LaForce CF. Kimura’s disease: report of a pediatric case in the United States. J Allergy Clin Immunol. 1984;73:561. 439. Zhang JZ, Zhang CG, Chen JM. Thirty-five cases of Kimura’s disease. Br J Dermatol. 1998;139(3):542–543. 440. Buckerfield JB, Edwards MB. Angiolymphoid hyperplasia with eosinophils in oral mucosa. Oral Surg Oral Med Oral Pathol. 1979;47:539.

441. Massa MC, Fretzin DF, Chowdhury L, et al. Angiolymphoid hyperplasia demonstrating extensive skin and mucosal lesions controlled with vinblastine therapy. J Am Acad Dermatol. 1984;11:333. 442. Danno K, Horio T, Miyachi Y, et al. Coexistence of Kimura’s disease and lichen amyloidosis in three patients. Arch Dermatol. 1982;118:976. 443. Atar S, Oberman AS, Ben-Izhak O., et al. Recurrent nephrotic syndrome associated with Kimura’s disease in a young non-Oriental male. Nephron. 1994;68:259–261.

Physical examination

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ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA AND KIMURA DISEASE

may be a benign or low grade malignant lymphoproliferative disorder. ALHE has been reported in a patient with peripheral T-cell lymphoma.450 Histologically, Kimura disease shows fibrosis, lymphocytes, plasma cells, eosinophils, mast cells, and eosinophilic microabscesses. Blood vessels are not prominent. The cause of ALHE is unknown, and opinions are divided on whether the lesions represent a true neoplasm of vascular tissue or a reactive healing process after trauma, infection, or injury.428 Olsen and Helwig428 believe that, in a susceptible individual, a traumatic event, immunization451 or altered estrogen state (such as pregnancy)445 serves as a stimulus for vascular endothelial proliferation, particularly in exposed areas such as the scalp and ears where the blood supply is abundant. Arteriovenous shunts may result directly from the injury itself or indirectly from release of vasoactive metabolites such as tumor angiogenic factor. Fetsch and Weiss452 recognized that 63% of cases were associated with an artery or vein, many of which were damaged, and they suggest a reparative, reactive process. The cause of Kimura disease is unknown. Figure 17.15  Angiolymphoid hyperplasia with eosinophilia. Typical lesions of the ear.

vessels in the center of the lesion.444 Olsen and Helwig428 showed arterial structures with an internal elastic lamina among the venules and endothelial cell proliferations and suggested that these may be arteriovenous shunts. Renin production by nonendothelial perivascular cells has been demonstrated and may stimulate the vascular proliferation seen in ALHE. Immunohistochemical markers such as cytokeratins, vimentin, factor VIII-related antigen, collagen type IV, estrogen and progesterone receptors,445 and adhesion molecule markers have been used to evaluate the pathogenesis of AHLE.446 The intensity of marker reaction suggests an immunologic activation of proliferating endothelial cells.446 Gyulai et al. reported the presence of DNA of human herpesvirus type 8 (HHV8) in the lesions of angiolymphoid hyperplasia suggesting a possible infectious cause.447 However, a more recent study of both Kimura disease and ALHE using heteroduplex PCR showed no evidence of HHV8 in the lesions.448 Five of seven patients with ALHE showed a lesional clonal T-cell population,449 suggesting that the process

444. Grimwood R, Swinehart JM, Aeling JL. Angiolymphoid hyperplasia with eosinophilia. Arch Dermatol. 1979;115:205. 445. Moy RL, Luftman DB, Nguyen QH, et al. Estrogen receptors and the response to sex hormones in angiolymphoid hyperplasia with eosinophilia. Arch Dermatol. 1992;128:825. 446. von den Driesch P, Gruschwitz M, Schell H, et al. Distribution of adhesion molecules, IgE, and CD23 in a case of angiolymphoid hyperplasia with eosinophilia. J Am Acad Dermatol. 1992;26:799. 447. Gyulai R, Kemeny L, Adam E, et al. HHV8 DNA in angiolymphoid hyperplasia of the skin. Lancet. 1996;347:1837. 448. Jang KA, Ahn SJ, Choi JH, et al. Polymerase chain reaction (PCR) for human herpesvirus 8 and heteroduplex PCR for clonality assessment in angiolymphoid hyperplasia with eosinophilia in Kimura’s disease. J Cutan Pathol. 2001;28(7):363–367. 449. Kempf W, Haeffner AC, Zepter K, et al. Angiolymphoid hyperplasia with eosinophilia: evidence for a T-cell lymphoproliferative origin. Hum Pathol. 2002;33(10):1023–1029.

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Differential diagnosis Clinically, the lesions do not have a characteristic morphology other than a vascular background. Therefore, diverse lesions such as epidermoid cysts, angiomas, angiosarcomas, Kaposi’s sarcoma, bacillary angiomatosis, pseudo-Kaposi’s sarcoma, pseudoangio­ sarcoma, and pyogenic granulomas may be confused with ALHE. Biopsy of the lesion is necessary to rule out these other entities. Histologically, ALHE can resemble angiosarcoma.

Therapy and prognosis The process is benign, and the general health of the patient is unaffected. Plaques may resolve spontaneously within a few months or may remain active for years with indolent enlargement, persistent eosinophilia, and pruritus.438 Rarely, lesions can be locally destructive. When lesions are few and persistent, excision is the treatment of choice for both AHLE and Kimura disease, but recurrences may still occur.444,453 Intralesional corticosteroids and topical tacrolimus have been helpful, especially in early lesions,454–456 and oral prednisone may induce regression.431 Pentoxifylline has

450. Gonzalez-Cuyar L, Tavora F, Zhao XF, et al. Angiolymphoid hyperplasia with eosinophilia developing in a patient with history of peripheral T-cell lymphoma: evidence for multicentric T-cell lymphoproliferative process. Diagn Pathol. 2008;3:22. 451. Akosa AB, Ali MH, Khoo CTK, et al. Angiolymphoid hyperplasia with eosinophilia associated with tetanus toxoid vaccination. Histopathology. 1990;16:589. 452. Fetsch JF, Weiss SW. Observations concerning the pathogenesis of epithelioid hemangioma (angiolymphoid hyperplasia). Modern Pathol. 1991;4:449. 453. Bendl BJ, Asano K, Lewis RJ. Nodular angioblastic hyperplasia with eosinophilia and lymphofolliculosis. Cutis. 1977;19:327. 454. Bonnetblanc JM, Bernard P, Malinvaud G. Treatment of angiolymphoid hyperplasia with eosinophilia. J Am Acad Dermatol. 1985;13:668. 455. Nelson DA, Jarratt M. Angiolymphoid hyperplasia with eosinophilia. Pediatr Dermatol. 1984;1:210. 456. Mashiko M, Yokata K, Yamanka Y, et al. A case of angiolymphoid hyperplasia with eosinophilia successfully treated with tacrolimus ointment. Br J Dermatol. 2006;154:803–804.

Diseases of the dermis and subcutaneous tissues

FOREIGN BODY REACTIONS Foreign body granulomas are caused by a myriad of exogenous materials that have been accidentally or factitiously implanted or injected into the skin. These sometimes persist indefinitely. Examples of common exogenous materials are vegetable spines, cactus bristles,466 metals, tick parts, wooden splinters,467 silk or nylon sutures, paraffin, silicone, silica, starch powder, broken thermometers,468 acrylic or nylon fibers acquired while walking barefoot on acrylic carpets,469 and acrylic fibers implanted into the scalp for male-pattern baldness and reactions to implantable dermal fillers.470,471 Rare causes include spurs from rooster attacks,472 silver,473 self-sticking bindi disks placed on the glabellar region,474 and moth cocoon spines.475 Injections with pentazocine476 or diphtheria, pertussis, and tetanus vaccine (DPT) secondarily contaminated with aluminum hydroxide have also 457. Hongcharu W, Baldassano M, Taylor CR. Kimura’s disease with oral ulcers: response to pentoxifylline. J Am Acad Dermatol. 2000;43:905–907. 458. Person J. Angiolymphoid hyperplasia with eosinophilia may respond to pentoxifylline. J Am Acad Dermatol. 1994;31:117–118. 459. Fosko SW, Glaser DA, Rogers CJ. Eradication of angiolymphoid hyperplasia with eosinophilia by copper vapor laser. Arch Dermatol. 2001;137(7):863–865. 460. Gupta G, Munro CS. Angiolymphoid hyperplasia with eosinophilia: successful treatment with pulsed dye laser using the double pulse technique. Br J Dermatol. 2000;143(1):214–215. 461. Rampini P, Semino M, Drago F, et al. Angiolymphoid hyperplasia with eosinophilia: successful treatment with interferon alpha 2b. Dermatol. 2001;202(4):343. 462. Shenefelt PD, Rinker M, Caradonna S. A case of angiolymphoid hyperplasia with eosinophilia treated with intralesional interferon alfa-2a. Arch Dermatol. 2000;136(7):837–839. 463. Rajpoot D, Pahl M, Clark J. Nephrotic syndrome associated with Kimura’s disease. Pediatr Nephrol. 2000;14:486–488. 464. Horigome H, Sekijima T, Ohtsuka S, et al. Life threatening coronary artery spasm in childhood Kimura’s disease. Heart. 2000;84(2):E5. 465. Hallam LA, Mackinlay GA, Wright AMA. Angiolymphoid hyperplasia with eosinophilia: possible aetiological role for immunization. J Clin Pathol. 1989;42:944. 466. Synder RA, Schwartz RA. Cactus bristle implantation. Arch Dermatol. 1983;119:152. 467. Tschen JA, Knox JM, McGavran MH, et al. Chromomycosis. The association of fungal elements and wood splinters. Arch Dermatol. 1984;120:107. 468. Sau P, Solivan G, Johnson FB. Cutaneous reaction from a broken thermometer. J Am Acad Dermatol. 1991;25:915.

been reported to cause a foreign body reaction.477 Erythematous plaques with possible progression to sclerodermatous plaques have been reported with vitamin K injections.478 Patients with psychiatric illnesses may inject materials into their skin causing foreign body granulomas.479 Endogenous materials may also elicit a foreign body reaction. Examples include keratinous material from ruptured epidermal, pilar, or acne cysts, urates (gout), and human hair causing interdigital sinuses on barbers’ hands.480

Epidemiology Any age group or sex may be affected. This entity is relatively frequently encountered by dermatologists, pediatricians, family practitioners, and internists. FOREIGN BODY REACTIONS

been used to treat AHLE and two patients with Kimura disease.457,458 Withdrawal of birth control pills may be warranted.445 Vinblastine may be effective for treating the disfiguring lesion of AHLE,441 as is radiation or carbon dioxide laser therapy. Both pulse dye and copper vapor laser have eradicated lesions of ALHE459,460 Interferon-α 2a and 2b have both been used successfully to treat AHLE in areas not amenable to surgical removal.461,462 Liquid nitrogen has also been used when the lesions are extensive. These entities occur in both children and adults. The general health of the patient is usually unaffected. Large lesions may be cosmetically unsightly, but ALHE and Kimura disease do not interfere with school or physical activities. Kimura disease has been reported with nephrotic syndrome and nephritis; however only three of the 14 cases were children.463 A 13-year-old male with Kimura’s disease, coronary spasm, and coronary aneurysms has been described.464 As several children have been reported to develop ALHE after immunization,451,465 time relationship with vaccination should be considered.

17

Presenting history The patient usually complains of a persistent nodule or papule that may be painful. If located on the plantar surface of the foot, the lesion is especially painful during walking. Lesions usually appear weeks to months after the initial inoculation, so that the cause is often not suspected by the patient or the physician.

Physical examination Lesions appear as firm or fluctuant erythematous papules or nodules, usually on exposed areas. Most often they are single and are localized. Hair, nails, teeth, and mucous membranes are not usually involved. A patient with widespread foreign body granulomas caused by talc application on a chronic generalized dermatitis has been described.481 Silica may cause a nonallergic granulomatous reaction in exposed subjects and, years later, a delayed hypersensitivity granulomatous response may take place.482 Lesions appear in exposed 469. Pimentel JC. Sarcoid granulomas of the skin produced by acrylic and nylon fibers. Br J Dermatol. 1977;96:673. 470. Hanke CW, Norins AL, Pantzer JG, et al. Hair implant complications. JAMA. 1981;245:1344. 471. Del Rosario RN, Barr RJ, Graham BS, et al. Exogenous and endogenous cutaneous anomalies and curiosities. Am J Dermatopathol. 2005;27(3):259–267. 472. Cooler JO, Kleiman MB, West K, et al. Retained spur following a rooster attack. Pediatrics. 1992;90:106. 473. Rongioletti F, Robert E, Buffa P, et al. Blue nevi-like dotted occupational argyria. J Am Acad Dermatol. 1992;27:1015. 474. Ramesh V. Foreign-body granuloma of the forehead: reaction to bindi. Arch Dermatol. 1991;127:424. 475. Shenefelt PD. Moth cocoon dermatitis. Arch Dermatol. 1991;127:424. 476. Jackson RM, Tucker SB, Abraham JL, et al. Factitial cutaneous ulcers and nodules: the use of electron-probe microanalysis in diagnosis. J Am Acad Dermatol. 1984;11:1065. 477. Slater DN, Underwood JCE, Durrant TE, et al. Aluminium hydroxide granulomas: light and electron microscopic studies and X-ray microanalysis. Br J Dermatol. 1982;107:103. 478. Lemlich G, Green M, Phelps R, et al. Cutaneous reactions to vitamin K1 injections. J Am Acad Dermatol. 1993;28:345. 479. Allen CC, Lund KA, Treadwell PA. Elemental mercury foreign body granulomas. Int J Dermatol. 1992;31:353. 480. Joseph HL, Gifford H. Barber’s interdigital pilonidal sinus. Arch Dermatol. 1954;70:616. 481. Pucevich MV, Rosenberg EW, Bale GF, et al. Widespread foreign-body granulomas and elevated serum angiotensin-converting enzyme. Arch Dermatol. 1983;119:229. 482. Mowry RG, Sams WM, Caulfield JB. Cutaneous silica granuloma. Arch Dermatol. 1991;127:692.

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areas, frequently arranged in parallel streaks, and they may be firm or become fluctuant and ulcerate. Beryllium granulomas result from cuts by fluorescent lamps coated with a beryllium mixture.483 These lacerations heal incompletely and tend to persist with swelling, induration, tenderness, and ulceration. They often discharge material for months to years. Zirconium granulomas are often found in the axilla as 1–4 mm discrete soft reddish-brown papules.

Laboratory findings

FOREIGN BODY REACTIONS

Serum angiotensin-converting enzyme levels may be elevated. Studies show that this laboratory test does not differentiate one granulomatous disease from another and thus cannot separate foreign body granulomas from other granulomatous processes such as sarcoidosis.481 Eosinophilia may occur if lesions are extensive.481

Pathophysiology and histogenesis Two major histological types of foreign body reactions are described by Lever.186 The first type is the allergic granuloma, which may be caused by zirconium, beryllium, silica, and certain tattoo dyes. It occurs only in sensitized individuals and is a manifestation of a delayed-type hypersensitivity reaction.484,485 Histologically, epithelioid cells, giant cells, and caseation necrosis are present in varying degrees. There are usually fewer giant cells than are seen in nonallergic granulomas. Phagocytosis of the foreign substance may be slight or even absent. It may be difficult to distinguish these granulomatous reactions from sarcoidosis. The epidermis may show acanthosis with ulceration. Beryllium granulomas often show pronounced caseation necrosis.483 Zirconium granulomas used to appear in the axilla when sodium zirconium lactate was commonly found in deodorants.486 It is still available in underarm deodorants but is thought to be safer in a combined weight of less than 20% in an aluminum salt.487 Topical lotions for treatment of poison ivy dermatitis may contain zirconium; these are still available over the counter, and may also cause a foreign body reaction in skin damaged by the dermatitis.488,489 Silica granulomas can be caused by silicon dioxide found in soil (quartz), talc (magnesium silicate) that is deposited into surgical wounds or used as a dusting powder,490,491 asbestos (complex polysilicates), sea urchin spines, and coral polyps.336

483. Neave HJ, Frank SB, Tolmach JA. Cutaneous granuloma following laceration by fluorescent light bulbs. Arch Dermatol Syphilol. 1950;61:401. 484. Hanifin JM, Epstein WL, Cline MJ. In vitro studies of granulomatous hypersensitivity to beryllium. J Invest Dermatol. 1970;55:284. 485. Henderson WR, Fukuyama K, Epstein WL, et al. In patients with berylliosis. J Invest Dermatol. 1972;58:5. 486. Shelley WB, Hurley HJ. The allergic origin of zirconium deodorant granulomas. Br J Dermatol. 1958;70:75. 487. Lisi DM. Availability of zirconium in topical antiperspirants. Arch Intern Med. 1992;152:421. 488. Baler GR. Granulomas from topical zirconium in poison ivy dermatitis. Arch Dermatol. 1965;91:145. 489. LoPresti PJ, Hambrick GW. Zirconium granuloma following treatment of Rhus dermatitis. Arch Dermatol. 1965;92:188.

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Injection of silicone (polydimethylsiloxane) used for cosmetic purposes (artificial implants), or as prosthetic devices, can result in siliconomas,490 which are soft tissue masses caused by granulomatous reactions to the silicone. Silicone can migrate in soft tissues and should be considered when evaluating new masses in patients who have received silicone prostheses. Tattoo granulomas occur most commonly from the red pigment, cinnabar (mercuric sulfide). However, chromium oxide (chrome green),492 cobalt blue, and cadmium sulfide (yellow) may also be implicated. Such allergic foreign body granulomas may appear years after the acquisition of a tattoo. Tattoo granulomas reveal scattered granules of dye located within macrophages and extracellularly in the dermis. Zirconium and beryllium particles cannot be detected by polarized light, and thus electron probe X-ray microanalysis must be used to identify beryllium and zirconium within tissue. Some foreign body substances are doubly refractile with a polarizing microscope, and this property can be helpful in localizing and determining the foreign substance. The second type of foreign body granulomatous reaction is non-allergic and is caused by silk and nylon sutures, paraffin, wood, talc, surgical glove starch powder,493 cactus spines, silicone gel, and imbedded hairs. Typically, a non-allergic foreign body reaction shows macrophages and many giant cells surrounding the foreign material. Paraffinomas are produced when oily substances such as mineral oil (paraffin), cottonseed oil, sesame seed oil, or camphor oil are injected into the skin494 or applied topically in the nasal cavity.495 Irregular plaques form and may ulcerate to discharge an oily substance.186 These may develop years after injection of paraffin. Paraffinomas cause a ‘Swiss cheese’ appearance in the tissue with numerous ovoid or round cavities that represent spaces occupied by the oil. Macrophages may have the appearance of foam cells. Multinucleated giant cells are commonly seen. Osmic acid, bromine-silver stains, oil Red-O, and Sudan IV stains may be helpful in distinguishing these exogenous materials from one another.186 Histologic features of foreign body reactions may be different in patients infected with the human immunodeficiency virus type 1,496 where abundant macrophages and a lack of giant cells may be seen.

Differential diagnosis Electron probe microanalysis of tissue blocks is very helpful in determining the cause of foreign body reactions when the substance cannot be seen on routine histochemical stains or

490. Travis WD, Balogh K, Abraham JL. Silicone granulomas: report of three cases and review of the literature. Hum Pathol. 1985;16:19. 491. Kaya TI, Kokturk A, Polat A, et al. Cutaneous silica granuloma in a child. Pediatr Dermatol. 2003;20(1):40–43. 492. Epstein WL, Skahen JR, Krasnobrod H. The organized epithelioid cell granuloma: differentiation of allergic (zirconium) from colloidal (silica) types. Am J Pathol. 1963;43:391. 493. Leonard DD. Starch granulomas. Arch Dermatol. 1973;107:101. 494. Urbach F, Wine SS, Johnson WC, et al. Generalized paraffinoma (sclerosing lipogranuloma). Arch Dermatol. 1971;103:277. 495. Feldmann R, Harms M, Chavaz P. Orbital and palpebral paraffinoma. J Am Acad Dermatol. 1992;26:833. 496. Smith KJ, Skelton HG, Yeager J. Histologic features of foreign body reactions in patients infected with human immunodeficiency virus type 1. J Am Acad Dermatol. 1993;28:470.

Diseases of the dermis and subcutaneous tissues

Therapy and prognosis Removal of the foreign body is the treatment of choice. Tweezers, adhesive tape stripping, wax stripping, or glue with gauze may aid in the removal of large quantities of foreign bodies.498 Topical, intralesional, or systemic steroids inhibit an inflammatory reaction if present. Lesions may persist indefinitely if the foreign material is not removed and may continue to ulcerate and extrude material. With the introduction of foreign material into the body, infection may be introduced, especially bacterial Gram-positive organisms, fungal infections (chromomycosis),467 syphilis, hepatitis, leprosy, warts, and vaccinia. Because children commonly walk with bare feet, they are more likely to pick up foreign material on their exposed parts. Solitary foreign body granuloma on the foot in a child may mimic a solitary wart. DPT immunizations are generally given only to children and produce their intended effect by a foreign body reaction and an allied immune response. A foreign body granuloma of the tissues may occasionally result at the site of the immunization.

HALOGENODERMAS Halogenodermas are drug eruptions caused by the ingestion or absorption of bromide, iodide, or fluoride, probably representing an idiosyncratic response.499 The reactions usually occur after a prolonged period of use, but signs may be seen as early as eight days after initial administration. Manifestations include acneiform papules and pustules, vesicles, granulomatous nodules, vegetating plaques, and urticarial lesions. The lesions tend to affect areas of the skin with the highest concentration of sebaceous glands, such as the face, neck, and upper back. Despite the withdrawal of bromide from prescription medications,500 these lesions are still occasionally caused by over-the-counter hypnotics such as propantheline bromide.501,502 Iodides can be found in cough medicines, expectorants, and dyes used in radiogra-

497. Andres TL, Vallyathan NV, Madison JF. Electron-probe microanalysis: aid in the study of skin granulomas. Arch Dermatol. 1980;116:1272. 498. Martinez TT, Jerome M, Barry RC, et al. Removal of cactus spines from the skin. Am J Dis Child. 1987;141:1291. 499. Soria C, Allegue F, Espana A, et al. Vegetating iododerma with underlying systemic disease: report of three cases. J Am Acad Dermatol. 1990;22:418. 500. Smith SZ, Scheen SR. Bromoderma. Arch Dermatol. 1978;114:458. 501. Ewing JA, Grant WJ. The bromide hazard. South Med J. 1965;58:148. 502. May SB. Ingestion of halogens. Arch Dermatol. 1972;106:599. 503. Boudoulas O, Siegle RJ, Grimwood RE. Iododerma occurring after orally administered iopanoic acid. Arch Dermatol. 1987;123:387. 504. Bishop ME, Garcia RL. Iododerma from wound irrigation with povidoneiodine. JAMA. 1978;240:249. 505. Yeung GTC. Skin eruption in newborn due to bromism derived from mother’s milk. BMJ. 1950;1:769.

phy.503 Iododerma has been described with the use of povidoneiodine.504 Patients with monoclonal gammopathy or other underlying diseases may be more susceptible to developing these lesions.499,503

Epidemiology Halogenodermas are acquired disorders that can occur at any age, including the neonatal period, from the mother’s taking bromides during breast-feeding.505 Because of an increased incidence of exposure to drugs, they most commonly affect adults. Potassium bromide is still in use for multidrug resistant seizures and other sources include ingestion of large quantities of soft drinks containing brominated vegetable oil (ruby red and cola) and exposure to brominated pool disinfectants.506–508 Methyl bromide used in fumigation can cause urticaria and blisters after exposure but not the typical vegetating plaques seen in typical halogenodermas.509 Topical povidone-iodine used chronically as an antiseptic or following repeated use in sitz baths may cause iododerma.510,511

HALOGENODERMAS

polarized light.476,477,497 Talc, silica, zirconium, and aluminum can all be determined by this method, as can the elements from sodium (atomic number 11) to uranium (atomic number 92). Clinically, lesions can resemble sarcoidosis, pyogenic granuloma, normal granulation tissue, and neurofibromas. Biopsy of such lesions aids in the diagnosis. The Köbner phenomenon may occur at the site of inoculation if the patient has lichen planus, psoriasis, or LE, which may result in further delay of the diagnosis.

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Presenting history Acneiform eruptions occur on the face and upper trunk with the sudden onset of papules and pustules without comedones. Iododermas and bromodermas usually begin as multiple pustules or ‘boils’ that quickly coalesce into vegetating plaques with pustules along the periphery. The lesions may ulcerate and form central crusts. Fluorodermas manifest as scattered papules and nodules on the neck and pre-auricular area.512

Physical examination There are two major types of clinical presentation. The first is with an acute acneiform eruption with papules and pustules, usually on the face, neck, back, and upper extremities. In the second type, a more chronic eruption evolves into vegetating plaques with central ulceration and a pustular border (Fig. 17.16). These pustular plaques are seen most commonly on the lower legs. The hair, nails, teeth, and mucous membranes are not usually affected. Fever may accompany the eruption.

Laboratory findings Halogen levels in the blood do not necessarily correlate with clinical findings but may be helpful if elevated.512 Elevation of the leukocyte count may occur, with eosinophilia as high as

506. Maffeis L, Musolino MC, Cambiaghi S. Single-plaque vegetating bromoderma. J Am Acad Dermatol. 2008;58:682–684. 507. Hafiji J, Majmudar V, Mathews S., et al. A case of bromoderma and bromism. Br J Dermatol. 2007;158:427–429. 508. Jih DM, Khanna V. Bromoderma after excessive ingestion of Ruby Red Squirt. N Engl J Med. 2003;348(19):1932–1934. 509. Hezemans-Boer M, Toonstra J, Meulenbelt J, et al. Skin lesions due to exposure to methyl bromide. Arch Dermatol. 1988;124:917. 510. Masse M, Falanga V, Zhou L. Use of topical povidone-iodine resulting in an iododerma like eruption. J Dermatol. 2008;35:744–747; 2008. 511. Aydmgoz IE, Goktay F, Serdar ZA, et al. Iododerma following sitz bath with povidone-iodine. Austral J Dermatol. 2007;48:102–104. 512. Blasic LG, Spencer SK. Fluoroderma. Arch Dermatol. 1979;115: 1134.

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as blastomycosis. However, fungal elements are not found, and cultures are negative. Folliculitis and other bacterial infections grow organisms on culture. Pemphigus vegetans can be ruled out if there is no acantholysis on biopsy. Mycosis fungoides, syphilis, tuberculosis, anthrax, and pyoderma gangrenosum should be excluded by histologic examination and culture.

Therapy and prognosis

CALCINOSIS CUTIS

Topical therapy with Burow’s solution and topical steroids may be helpful with hastening the resolution of the lesion.503 Once the offending agent is removed, lesions resolve, leaving residual hyperpigmentation. Usually, there is little scarring,499 but if lesions remain untreated, there may be disfigurement and other serious or fatal sequelae.517 Chronic iodine ingestion may affect the thyroid gland in children and cause a goiter; this requires investigation. Halogenodermas are mainly a cosmetic problem, and once treated, there should be little cosmetic disfigurement.

Figure 17.16  Plaques of bromoderma. 513

85%. Elevation of the erythrocyte sedimentation rate may also be found. In patients with suspected iododerma, levels of total iodine and inorganic iodine may be elevated. Triiodothyronine and T4 levels may be low, indicating thyroid dysfunction, compounding the problem. Impaired renal function increases toxicity by decreasing excretion of iodine.504

CALCINOSIS CUTIS Calcinosis cutis is the precipitation or deposition of hydroxyapatite, crystals of calcium phosphate, within cutaneous tissues. Normally, calcification occurs only in bone and teeth within the body,336 but under pathologic circumstances, it may occur in other tissues. Cutaneous calcification may be focal or widespread and symptomatic or asymptomatic. Most forms of calcinosis cutis can be divided into dystrophic, idiopathic, metastatic, and iatrogenic calcinosis.186,518

Pathophysiology and histogenesis The histologic appearance of a lesion is not diagnostic but may be suggestive.186 The epidermis shows papillomatosis with downward proliferation (pseudoepitheliomatous hyperplasia). Intraepidermal abscesses filled with neutrophils, eosinophils, and keratinocytes are characteristic. Epidermal changes may be more pronounced in bromoderma than iododerma. The pathogenesis is not well understood. Rosenberg et al.514 hypothesized a delayed-type hypersensitivity reaction based on lymphocyte transformation studies. Iodides may act as haptens by combining with serum protein. Once a patient is sensitized, a similar eruption may occur within a few days on readministration of the offending agent.504,515 Iodides are known to increase movement of polymorphonuclear leukocytes into inflamed tissues.516

Pustular lesions may resemble acne or drug-induced acneiform eruptions. Fungating lesions may resemble deep mycoses, such

Dystrophic calcinosis cutis, the most common form of cutaneous calcification, is caused by deposition of calcium salts within previously damaged tissues; there are no metabolic abnormalities of the calcium or phosphorus. Internal organ involvement is not found except within the muscles in the rare situation of calcinosis universalis. Localized dystrophic forms of calcinosis cutis arise in inflammatory lesions such as acne, ulcers, foreign body granulomas, traumatic lesions, and subcutaneous fat necrosis of the newborn. Calcinosis has also been noted after heel sticks performed for drawing blood in neonates.519 Degenerative lesions, such as vascular infarcts and parasitic infections, may also give rise to dystrophic calcinosis cutis. Neoplasms, such as epidermal cysts, lipomas, pilomatricomas, and basal cell carcinomas, can show areas of calcification. Widespread calcification (calcinosis cutis universalis) is seen in association with systemic sclerosis, CRST syndrome (calcinosis cutis, Raynaud’s phenomenon, sclerodactyly, telangiectasias), dermatomyositis, Werner syndrome,520 pseudoxanthoma elasticum, Ehlers–

513. Jacob HS, Sidd JJ, Greenberg BH, et al. Extreme eosinophilia with iodide hypersensitivity. A report of a case with observations on the cellular composition of inflammatory exudates. N Engl J Med. 1964;271:1138. 514. Rosenberg FR, Einbinder J, Walzer RA, et al. Vegetating iododerma. Arch Dermatol. 1972;105:900. 515. Jones LE, Pariser H, Murray PF. Recurrent iododerma. Arch Dermatol. 1958;78:353. 516. Stone OJ. Proliferative iododerma. Int J Dermatol. 1985;24:565.

517. Hollander L, Fetterman GH. Fatal iododerma: eleventh case reported in the literature. Arch Dermatol. 1936;34:228. 518. Orlow SJ, Watsky KL, Bolognia JL. Cutaneous deposition diseases: skin and bone, part 2. J Am Acad Dermatol. 1991;25:445–462. 519. Sell EJ, Hansen RC, Struck-Pierce S. Calcified nodules on the heel: a complication of neonatal intensive care. J Pediatr. 1980;96:473. 520. Lucke T, Fallowfield M, McHenry P. Idiopathic calcinosis cutis of the penis. Br J Dermatol. 1997;137:1011–1013.

Differential diagnosis

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Diseases of the dermis and subcutaneous tissues

17

CALCINOSIS CUTIS

Danlos syndrome, DLE,521 SLE, and following resolution of skin lesions of congenital acute monocytic leukemia.522–524 Calcinosis cutis in dermatomyositis tends to develop 2–3 years after the onset of disease.525 Ten to twenty percent of adults and 30% of children with dermatomyositis have calcinosis.526 Deposits may be large and develop slowly, accompanied by healing ulcers and draining sinuses; calcium deposits are often extruded from the skin. Increased staphylococcal infections and elevated IgE levels have been associated with the calcinosis in childhood dermatomyositis. The staphylococcal infections can occur before the onset of calcinosis, and an intermittent defect in granulocyte chemotaxis may lead to the areas of calcinosis.527 Calcinosis universalis, with sheet-like calcified deposits in the intermuscular fascial planes, causing an exoskeleton, forms in a small subgroup of patients with dermatomyositis and portends a poor outcome.525 These patients tend to have a severe cutaneous vasculitis and the widespread calcinosis limits their physical function. Hypercalcemia may occur during resolution.528 Calcinosis cutis in scleroderma usually occurs 10–12 years after the onset of disease, and is rarely seen in childhood.529 The calcium deposits in scleroderma tend to be smaller than in dermatomyositis, commonly occurring on the fingers and hands but also on the feet, elbows, knees, and hips. Secondary hyperparathyroidism has been reported in patients who had systemic sclerosis and aberrant calcifications, prompting some authors to consider prophylactic treatment with vitamin D to prevent calcinosis.530

IDIOPATHIC CALCINOSIS CUTIS Idiopathic calcification occurs without evidence of local tissue injury or a systemic metabolic defect. Lesions can be localized (Fig. 17.17) or generalized. One localized form of calcinosis cutis is the subepidermal calcified nodule, which is a solitary, hard lesion or lesions usually seen on the face, particularly the helix of the ear, of infants or small children; it may be congenital (Fig. 17.18).531 Lesions are usually 3–11 mm in size and histologically demonstrate globules of calcified material in the uppermost dermis.186 The origin of the homogeneous calcified masses is obscure. Another localized form is calcinosis of the scrotum, which is characterized by calcified nodules limited to the scrotum or penis.520,532 Vulvar lesions may occur in females.533 Lesions begin in childhood or early adult life, increase in size and number, and sometimes break down and discharge chalky material. They are

usually asymptomatic, but patients may have itching, tenderness, or a feeling of heaviness of the scrotum. Radiographic examination reveals radio-opaque densities in areas of calcification. Generalized milia-like idiopathic calcinosis cutis has been described in Down syndrome,534 where in some instances it may represent calcification of syringomas.535 Rarely the milia-like variety may present as a perforating form with transepidermal elimination.536

521. Ueki H, Takei Y, Nakagawa S. Cutaneous calcinosis in localized discoid lupus erythematosus. Arch Dermatol. 1980;116:196. 522. Nomura M, Okada N, Okada M, et al. Large subcutaneous calcification in systemic lupus erythematosus. Arch Dermatol. 1990;126:1057. 523. Carette S, Urowitz MB. Systemic lupus erythematosus and diffuse soft tissue calcifications. Int J Dermatol. 1983;22:416. 524. Satter EK, Maari CH, Morel KD, et al. Disseminated linear calcinosis cutis associated with the Koebner phenomenon in an infant with congenital acute monocytic leukemia. Br J Dermatol. 2004;150:753–756. 525. Rider LG. Calcinosis in JDM. Pathogenesis and current therapies. Pediatric Rheumatol Online J. 2003;1:119–133. 526. Huber AM, Lang B, Leblanc CN, et al. Medium and long term functional outcomes in a multicenter cohort of children with juvenile dermatomyositis. Arthritis and Rheum. 2000;43:541–549. 527. Moore EC, Cohen F, Douglas SD, et al. Staphylococcal infections in childhood dermatomyositis—association with the development of calcinosis, raised IgE concentrations and granulocyte chemotactic defect. Ann Rheum Dis. 1992;51:378.

528. Ostrov BE, Goldsmith DP, Eichenfield AH, et al. Hypercalcemia during the resolution of calcinosis universalis in juvenile dermatomyositis. J Rheumatol. 1991;18:1730. 529. Raimer SS. Calcinosis cutis. Curr Concepts Skin Disord. 1985;6:9. 530. Serup J, Hagdrup HK. Parathyroid hormone and calcium metabolism in generalized scleroderma. Arch Dermatol Res. 1984;276:91. 531. Nico MM, Bergonse FN. Subepidermal calcified nodule: report of two cases and review of the literature. Pediatr Dermatol. 2001;18:227–229. 532. Wright S, Navsaria H, Leigh IM. Idiopathic scrotal calcinosis is idiopathic. J Am Acad Dermatol. 1991;24:727. 533. Jamaleddine FN, Salman SM, Shbaklo Z, et al. Idiopathic vulvar calcinosis: the counterpart of idiopathic scrotal calcinosis. Cutis. 1988;4:273. 534. Smith ML, Golitz LE, Morelli JG, et al. Milialike idiopathic calcinosis cutis in Down’s syndrome. Arch Dermatol. 1989;125:1586. 535. Kanzaki T, Nakajima M. Milia-like idiopathic calcinosis cutis and syringoma in Down’s syndrome. J Dermatol. 1991;18:616–618. 536. Mehta JN, Berk DR, Hanson S, et al. Generalized Milia-like idiopathic calcinosis cutis. Arch Dermatol. 2006;142:1238–1239.

Figure 17.17  Solitary rock-hard papule of calcinosis cutis on the ankle.

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in 60% of children with uremia, but calciphylaxis is extremely rare in children.538

IATROGENIC CALCINOSIS CUTIS Inadvertent extravasation of intravenous calcium salts into subcutaneous tissue may give rise to dystrophic calcinosis cutis,539,540 which can break down, causing swelling and induration that may be mistaken for an abscess or cellulitis. Cutaneous lesions develop a few hours to 3 weeks after injection. Radiographic changes may be seen within five days but become maximal at 2 weeks.541 Calcinosis cutis has been reported after electroencephalographic examination and electromyographic examination when there is prolonged contact with calcium-containing electrode paste.542 CALCINOSIS CUTIS

Presenting history There is usually a complaint of firm, stony papules or plaques, which may have an erythematous or purplish border. The lesions may be tender and ulcerate. Figure 17.18  Congenital subepidermal calcified nodule of the ear.

Physical examination

METASTATIC CALCINOSIS CUTIS

The papules and plaques are firm or rock hard and may be located anywhere on the body. They are found most commonly on the extremities, face, or scrotum. The size of the papules ranges from 1 to 30 mm. Plaques may ulcerate and discharge a chalky, creamy material or gritty particles that can be demonstrated histologically to be calcium deposits. Secondary infection is common within areas of calcinosis cutis. Metastatic calcinosis cutis occurs more commonly around joints or in areas of increased trauma.

Metastatic calcinosis cutis is caused by the precipitation of calcium salts in undamaged tissue and occurs in disorders associated with abnormal metabolism of calcium and/or phosphorus.537 Chronic renal failure, vitamin D intoxication, milk-alkali syndrome, sarcoidosis, parathyroid neoplasms, bony destruction from malignant tumors, and tumor-related calcinosis are conditions in which metastatic calcinosis cutis may be seen. In chronic renal failure, decreased renal clearance of phosphate results in supersaturation of the serum with phosphate, causing a compensatory drop in the serum calcium level. This stimulates parathyroid hormone, which in turn mobilizes calcium from bone, with the subsequent release of more phosphorus into the serum. Calcium deposits may occur in various organs including the kidney, lung, gastric mucosa, eyes, and arteries. These deposits are not commonly seen in the skin but, when present, usually occur within the dermis and subcutaneous tissue overlying large joints. Calciphylaxis, a rare, life-threatening complication of chronic renal failure, is manifest by rapidly progressive calcification of small and medium-sized blood vessels.538 Calciphylaxis presents with livedo reticularis-like changes of the skin which develop overlying subcutaneous plaques. Ultimately, necrosis and deep subcutaneous ulceration develop. Soft tissue calcifications occur

537. Raimer SS, Archer ME, Jorizzo JL. Metastatic calcinosis cutis. Cutis. 1983;32:463. 538. Zouboulis CC, Blumepeytavi U, Lennert T, et al. Fulminant metastatic calcinosis with cutaneous necrosis in a child with end stage renal disease and tertiary hypoparathyroidism. Br J Dermatol. 1996;135:617–622. 539. Speer ME, Rudolph AJ. Calcification of superficial scalp veins secondary to intravenous infusion of sodium bicarbonate and calcium chloride. Cutis. 1983;32:65.

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Laboratory findings Radiographs of the skin in calcinosis cutis reveal radio-opaque deposits within the dermis and subcutaneous tissues. Technetium-99m-methylene diphosphonate scans show a high affinity for the surface of hydroxyapatite crystals and are extremely helpful in picking up small asymptomatic nodules.529 Laboratory abnormalities are not found in the dystrophic and idiopathic forms of calcinosis cutis. In metastatic calcinosis cutis, however, the chronic elevation of either the serum calcium or phosphorus level or both can cause precipitation within tissues.

Pathophysiology and histogenesis Histologically, calcium deposits may be easily recognized in the dermis or subcutaneous tissues with hematoxylin and eosin stain, which stains calcium a deep blue color.186 Globules of calcium stain black with von Kossa’s stain. Calcified lesions may

540. Hironaga M, Fujigaki T, Tanaka S. Cutaneous calcinosis in a neonate following extravasation of calcium gluconate. J Am Acad Dermatol. 1982;6:392. 541. Rodgríguez-Cano L, García-Patos V, Creus, M, et al. Childhood calcinosis cutis. Pediatr Dermatol. 1996;13(2):114–117. 542. Johnson RC, Fitzpatrick JE, Hahn DE. Calcinosis cutis following electromyographic examination. Cutis. 1993;52:161.

Diseases of the dermis and subcutaneous tissues

Differential diagnosis Calcinosis cutis is characteristic in forming rock-hard, white nodules in the skin, particularly when seen in areas of dystrophy. Other entities that may be confused with calcinosis cutis include osteoma cutis and myositis ossificans.

Therapy and prognosis When a metabolic disorder, such as hyperparathyroidism, hypervitaminosis D, chronic renal failure, milk-alkali syndrome, or tumor-related calcinosis occurs, correction of the underlying disorder aids in resolution of the calcinosis. Idiopathic and dystrophic calcinosis cutis may be resistant to therapy and incision and drainage547 and surgical excision for painful deposits may be necessary.548 Oral phosphate binding agents, such as magnesium hydroxide, or oral aluminum hydroxide antacids, such as aluminum carbonate gel, may decrease the serum phosphate level and thus decrease deposits of calcinosis. Lowering the dietary calcium intake to 250–300 mg/day and decreasing vitamin D intake may also be helpful. Calcium chelating agents, such as edetate trisodium and polyphosphates, have been helpful in treating some patients.549 Other reported therapies include furosemide, colchicine,550 diltiazem,551 monthly injections of intralesional steroid,552 warfarin,553 magnesium sulfate, and

543. Cochran RJ, Wilkin JK. An unusual case of calcinosis cutis. J Am Acad Dermatol. 1983;8:103. 544. Richens G, Piepkorn MW, Krueger GG. Calcifying panniculitis associated with renal failure. J Am Acad Dermatol. 1982;6:537. 545. Rivet J, Lebbe C, Urena P, et al. Cutaneous calcification in patients with end-stage renal disease. Arch Dermatol. 2006;142:900–906. 546. Johnson WC, Forbes PD, Graham JH, et al. Experimental cutaneous calcinosis: a histopathologic and histochemical study. J Invest Dermatol. 1964;43:453. 547. Wu JJ, Metz BJ. Calcinosis cutis of juvenile dermatomyositis treated with incision and drainage. Dermatol Surg. 2008;34:575–577. 548. Shearin JC, Pickrell K. Surgical treatment of subcutaneous calcifications of polymyositis or dermatomyositis. Ann Plast Surg. 1980;5:381. 549. Rabens SF, Bethune JE. Disodium etidronate therapy for dystrophic cutaneous calcification. Arch Dermatol. 1975;111:357. 550. Taborn J, Bole GG, Thompson GR. Colchicine suppression of local and systemic inflammation due to calcinosis universalis in chronic dermatomyositis. Ann Intern Med. 1978;89:648. 551. Palmieri GMA, Sebes JI, Aelion JA, et al. Treatment of calcinosis with diltiazem. Arthritis Rheum. 1995;38:1646–1654. 552. Hazen PG, Walker AE, Carney JF, et al. Cutaneous calcinosis of scleroderma. Arch Dermatol. 1982;118:366.

magnesium lactate554 and electroshock wave lithotripsy.555 Intravenous immunoglobulin infusion has shown mixed results in treatment of calcinosis secondary to connective tissue diseases.556,557 Sodium thiosulfate infusions have been used in the treatment of calciphylaxis with variable results.558 For ulcerations, compresses of 1 : 40 aluminum acetate, solution may be used to dry the area. Some forms of calcinosis cutis are seen more commonly in children. These include calcinosis cutis associated with dermatomyositis, subepidermal calcified nodules, solitary congenital calcified nodule of the ear, and calcifications secondary to heel sticks in neonates. With extensive calcinosis, complications of contractures, pain, and suppuration with or without superinfection may occur.

CUTANEOUS OSSIFICATION

CUTANEOUS OSSIFICATION

be present with massive deposits in the subcutaneous tissue or may form tiny granules with small deposits in the dermis. A foreign body reaction with giant cells, inflammation, and fibrosis may be seen surrounding the area of calcification. The pathogenesis of calcinosis cutis is unexplained. It tends to occur in areas of damaged tissue or increased trauma,529 such as the damaged elastic fibers of pseudoxanthoma elasticum.520,543 In cases of idiopathic calcinosis cutis, there may be unidentified local factors that promote calcification within tissue. Calciphylaxis (soft tissue calcification and necrosis) can be induced experimentally in appropriately sensitized animals and may play a role in human calcinosis cutis.544 Osteopontin dysregulation with defective inhibition of calcification has been reported in patients with end stage renal disease.545 Johnson et al.546 suggested that sulfated mucopolysaccharides and/or collagen may act as a template for initial crystal formation. Once started, calcification continues unimpeded.

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Primary dermal ossification (heterotopic ossification, HO) is rarely seen in childhood.559 Osteoma cutis is spontaneous new bone formation within the skin. Calcification, lamellae, lacunae, and bone marrow may all be seen within the dermis or in the subcutaneous tissue. Osteoma cutis may be primary, in which there are no preceding cutaneous lesions, or secondary, in which there has been tissue trauma or inflammation with secondary bone formation. Neither the type of ossification (endochondral or intramembranous) nor the number of sites of HO is helpful in distinguishing these disorders. The majority of patients have associated GNAS mutations or epigenetic regulatory factors affecting GNAS function and that phenotype is related to parental imprinting and whether the gene is maternal (resulting in Albright’s hereditary osteodystrophy (AHO) or paternal (resulting in progressive osseous heteroplasia (POH).560 In a review of 111 patients with non-traumatic heterotopic ossification, 26 had osteoma cutis without evidence of AHO; 10 had AHO; 52 had POH without AHO features; six had PHO//AHO; five had POH with associated pseudohyperparathyroidism; and 12 had pseudohyperparathyroidism 1a/1c.560

PRIMARY OSTEOMA CUTIS Primary osteoma cutis is a congenital, benign growth of bone with no invasion of surrounding tissues or tendency to metastasize.561 There are four types of primary osteoma cutis: Albright

553. Martinez-Cordero E, Lopez-Zepeda J, Choza-Tomero F. Calcinosis in childhood dermatomyositis. Clin Exp Rheumatol. 1990;8:198. 554. Steidl L, Ditmar R. Soft tissue calcification treated with local and oral magnesium therapy. Magnes Res. 1990;3:113. 555. Chan AYK, Li E. Electric shock wave lithotripsy (ESWL) as a pain control measure in dermatomyositis with calcinosis cutis – old method, new discovery. Clin Rheumatol. 2005;24:172–173. 556. Schanz S, Ulmer A, Fierlbeck G, et al. Response of dystrophic calcification to intravenous immunoglobulin. Arch Dermatol. 2008;144(5):585–587. 557. Kalajian A, Perryman J, Callen J. Intravenous immunoglobulin therapy for dystrophic calcinosis cutis: unreliable in our hands. Arch Dermatol. 2009;145(3):334–335. 558. O’Neill WC. Treatment of vascular calcification. Kidney Int. 2008;74: 1376–1378. 559. Roth SI, Stowell RE, Helwig EB. Cutaneous ossification. Arch Pathol. 1963;76:44. 560. Lui J, Nealon JG, Weinstein LS. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohyperparathyroidism type 1B. Hum Mol Genet. 2005;14:95–102. 561. O’Donnell TF, Geller SA. Primary osteoma cutis. Arch Dermatol. 1971;104:325.

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CUTANEOUS OSSIFICATION

Figure 17.19  Osteoma cutis in a child with Albright’s osteodystrophy.

hereditary osteodystrophy (AHO), progressive osseous heteroplasia (POH), plate-like osteoma cutis (POC) and a miscellaneous group of other primary osteomas.

Albright hereditary osteodystrophy Albright hereditary osteodystrophy562 (AHO) was described in 1952 and includes both pseudohypoparathyroidism and pseudopseudohypoparathyroidism. This is a disorder in which multiple areas of subcutaneous or intracutaneous ossification arise at birth, or in early infancy and early childhood. Lesions may be located anywhere on the body, including the trunk, extremities, and scalp, and range in size from pinpoint to 5 cm (Fig. 17.19). Associated abnormalities include short stature, round facies, multiple skeletal abnormalities, short broad nails, basal ganglia calcification, hypothyroidism, mental retardation, defective teeth, and cataracts.563,564 Skeletal abnormalities seen in AHO include curvature of the radius and shortened metacarpals and metatarsals. A characteristic dimpling sign, particularly over the fourth and fifth metacarpals, results from these shortened bones.562 AHO is thought to be inherited as an autosomal-dominant trait.564 Pseudohypoparathyroidism is characterized by a low serum calcium level, hyperphosphatemia, and no response to parathyroid hormone (PTH), with no evidence of renal disease, steatorrhea, or generalized osteomalacia. Circulating concentrations of PTH are normal or even increased; there is end-organ resistance to the action of PTH. Patients with pseudopseudohypoparathyroidism have all the other congenital abnor-

562. Albright F, Forbes AP, Henneman PH. Pseudo-pseudohypoparathyroidism. Trans Assoc Am Physicians. 1952;65:337. 563. Eyre WG, Reed WB. Albright’s hereditary osteodystrophy with cutaneous bone formation. Arch Dermatol. 1971;104:636. 564. Brook CGD, Valman HB. Osteoma cutis and Albright’s hereditary osteodystrophy. Br J Dermatol. 1971;85:471. 565. Prendiville JS, Lucky AW, Mallory SB, et al. Osteoma cutis as a presenting sign of pseudohypoparathyroidism. Pediatr Dermatol. 1992;9:11. 566. Izraeli S, Metzker A, Horev G, et al. Albright hereditary osteodystrophy with hypothyroidism, normocalcemia, and normal Gs protein activity: a family presenting with congenital osteoma cutis. Am J Med Genet. 1992;43:764.

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malities of pseudohypoparathyroidism but have normal serum calcium and phosphorus levels. Osteoma cutis is found in both.563 Thyroid abnormalities frequently occur in these patients. Progression to pseudohypoparathyroidism with hypocalcemia and seizures has been documented in patients who present in infancy with only osteoma cutis (pseudopseudohypoparathyroidism) and clinical features of AHO; these patients need to be monitored closely.565 Both types of pseudohypoparathyroidism are recognized as variable expressions of the same disease and may be seen in pedigrees or even in the same individual at different periods. Most of the actions of PTH are mediated by cyclic adenosine monophosphate. In most patients with AHO the disease is caused by heterozygous mutations in GNASI, a gene on chromosome 20 encoding the α-subunit of the stimulatory G protein of adenyl cyclase (Gsα). Patients with AHO have a 50% reduction in the expression or activity of Gsα in multiple cell types. This results in poor coupling of hormone receptors to stimulate adenylate cyclase leading to multiple-organ hormone resistance.566,567

Progressive osseous heteroplasia Progressive osseous heteroplasia (POH) is an autosomaldominant disorder characterized by dermal ossification during infancy and progressive heterotopic ossification of cutaneous, subcutaneous, and deep connective tissues during childhood.568 The disorder is rare with 52 cases published in a recent review; sex ratio is equal.568 The initial lesions appear in the reticular dermis and subcutaneous fat. The progression of the lesions into deeper tissue should alert the clinician to the diagnosis of POH or other progressive HO syndrome.568 Over time, the islands of heterotopic bone coalesce into plaques with involvement of the deeper connective tissues including fascia, muscle, tendon and ligaments. Skin lesions appear as small hard papules resembling grains of rice, or larger plaques with a gritty consistency.569 Extensive ossification eventually results in ankylosis of affected joints and focal growth retardation of affected limbs.570 The head, face, and extraocular muscles are characteristically spared. There may be mild clinical and biochemical features that overlap with AHO in a minority of patients including short stature, brachydactyly and evidence of pseudohypoparathyroidism 1a/1c.571 The distribution of lesions is random and asymmetrical, unlike the typical progressive pattern of ossification seen in fibrodysplasia ossificans progressive (myositis ossificans). Pathology shows ossification. X-ray shows a cocoon-like web of heterotopic bone entangling the soft tissue from the dermis to skeletal muscle and independent of muscle planes.570 Routine laboratory studies are normal; however, elevated alkaline

567. Pattern JL, Johns DR, Valle D, et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med. 1990;322:1412. 568. Adegbite NS, Xu M, Kaplan FS, et al. Diagnostic and mutational spectrum of progressive osseus heteroplasia (POH) and other forms of GNAS-based heterotopic ossification. Am J Med Genet, Part A. 2008;146A:1788–1796. 569. Miller ES, Esterly NB, Fairley JA. Progressive osseous heteroplasia. Arch Dermatol. 1996;132:787–791. 570. Urtizberea JA, Testart H, Cartault F, et al. Progressive osseous heteroplasia. Report of a family. Br J Bone Joint Surg. 1998;80(5):768–771. 571. Gelfand IM, Hub RS, Shore EM, et al. Progressive osseous heteroplasia-like heterotopic ossification in a male infant with pseudohyperparathyroidism type 1a: A case report. Bone. 2007;40:1425–1428.

phosphatase levels may be seen during active phases of osteogenesis. GNAS mutation analysis has revealed mutations in the majority of patients with POH which are paternally derived.568 Treatment is unsatisfactory, with surgical removal often leading to recurrence except when totally removed.572 Pamidronate has been reported to control progression of the disease in one report.573 The long-term prognosis is uncertain; surgical removal may lead to recurrence.

The most common type of secondary osteoma cutis is that seen in patients with acne who have taken tetracycline or minocycline.581,582 Lesions appear as 1–2 mm blue-black papules on the face. Tetracycline is known to form a complex with calcium orthophosphate that is deposited in developing teeth and bone and can cause a characteristic blue-black discoloration within osteoma cutis of acne lesions.583

Plate-like osteoma cutis

Epidemiology

Plate-like osteoma cutis (POC) presents as hard plaques with a gritty consistency one to several centimeters in size. POC is used to describe lesions present at birth or within the first year of life in infants without evidence of abnormal calcium or phosphate metabolism, absence of trauma, and the presence of at least one bony plate with or without other cutaneous osteomas.574 The lesions are more common on the scalp and extremities.575 It is likely that most reports of widespread POC represent a limited form of progressive osseous heteroplasia (POH)568 as progressive ossification may occur independently of AHO characteristics.572 Surgical excision is the treatment of choice except in patients with POH where recurrence is common.

Cutaneous ossification can occur at any age, even at birth.584 Albright hereditary osteodystrophy and progressive osseous heteroplasia (POH) are inherited as an autosomal-dominant disease. POC is usually sporadic but familial cases have been reported.584,585

Other forms of primary osteoma cutis

Physical examination

Several forms of primary osteoma cutis are not easily categorized,576 including single small osteomas that arise later in life and may show transepidermal elimination and multiple miliary osteomas of the face, which are seen in women with or without a history of acne vulgaris.577 It has been proposed that these miliary lesions represent a hamartoma, where ectopic rests of mesenchymal cells differentiate into osteoclasts for unknown reasons.578 Primary osteoma cutis has been reported in an adult with unilateral basal cell nevus syndrome with anodontia.579

Lesions are common on the trunk or face, particularly the forehead, cheeks, and chin, and tend to be hard, raised, and well defined. The overlying skin may be normal, erythematous, blue pigmented, ulcerated, or atrophic. Superficial lesions sometimes become inflamed and extrude bony particles. When associated with long-standing acne, lesions appear as small blue-gray, hard papules or nodules.582 The hair, nails, teeth, and mucous membranes are not involved.

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CUTANEOUS OSSIFICATION

Diseases of the dermis and subcutaneous tissues

Presenting history The patient or parent usually complains of asymptomatic, solitary or multiple hard, raised 1–5 mm nodules with normal or erythematous surrounding skin.

Laboratory findings SECONDARY OSTEOMA CUTIS Secondary osteoma cutis, also called metaplastic osteoma cutis, arises in tumors or in areas of inflammation. Tumors that can show osteoma cutis include pilomatricoma (calcifying epithelioma), basal cell carcinoma, nevus sebaceus of Jadassohn, nevus cell nevi, chondroid syringomas, and mixed tumors of the skin. Lesions caused by trauma or injections, acne vulgaris, folliculitis, stasis dermatitis, scars, dermatomyositis, scleroderma and nephrogenic systemic sclerosis336,580 are inflammatory processes that may all have an associated osteoma cutis.

572. Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Min Res. 2000;15(11):2084–2092. 573. Hou JW. Progressive osseous heteroplasia controlled by intravenous administration of pamidronate. Am J Med Genet. 2006;140A:910–913. 574. Worret WI, Burgdorf W. Congenital plaque-like osteoma of the skin in an infant. Hautarzt. 1978;29:590–596. 575. Sanmartin O, Alegre V, Martinez-Aparicio A, et al. Congenital platelike osteoma cutis: case report and review of the literature. Pediatr Dermatol. 1993;10:182. 576. Burgdorf W, Naseman T. Cutaneous osteomas: a clinical and histopathological review. Arch Dermatol Res. 1977;260:121. 577. Levell NJ, Lawrence CM. Multiple papules on the face. Multiple miliary osteoma cutis. Arch Dermatol. 1994;130:370–374. 578. Gfeser M, Worret W, Hein R, et al. Multiple primary miliary osteoma cutis. Arch Dermatol. 1998;134:641–643.

Patients with pseudohypoparathyroidism have decreased serum calcium and high serum phosphorus levels. In other forms of osteoma cutis, levels of calcium, phosphorus, and alkaline phosphatase are normal. In AHO, low thyroid levels may be found.

Pathophysiology and histogenesis Histologically, there is proliferation of bony tissue with spicules of bone within the dermis and subcutaneous tissue.186 Osteo­ blasts, osteocytes, osteoclasts, and mature fat cells are commonly

579. Aloi FG, Tomasini CF, Isaia G, et al. Unilateral linear basal cell nevus associated with diffuse osteoma cutis, unilateral anodontia, and abnormal bone mineralization. J Am Acad Dermatol. 1989;20:973. 580. Nagai Y, Hasegawa M, Shinmi K, et al. Nephrogenic systemic fibrosis with multiple calcification and osseous metaplasia. Acta Derm Venereol. 2008;88(6):597–600. 581. Basler RS, Taylor WB, Peacor DR. Postacne osteoma cutis, X-ray diffraction analysis. Arch Dermatol. 1974;110:113. 582. Moritz DL, Elewski B. Pigmented postacne osteoma cutis in a patient treated with minocycline: report and review of the literature. J Am Acad Dermatol. 1991;24:851. 583. Walter JF, Macknet KD. Pigmentation of osteoma cutis caused by tetracycline. Arch Dermatol. 1979;115:1087. 584. Peterson WC, Mandel SL. Primary osteomas of the skin. Arch Dermatol Syphilol. 1963;87:626. 585. Maclean GD, Main RA, Anderson TE, et al. Connective tissue ossification presenting in the skin. Arch Dermatol. 1966;94:168.

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seen within the bone, but only rarely are hematopoietic elements seen. Transepidermal elimination of bone with fragments of bone within channels lined by epidermis leading to the skin surface may be seen. Osteoblasts and osteocytes in primary cutaneous ossification originate from mesenchymal cells186 and usually form membranous bone but occasionally enchondral bone.559

Differential diagnosis

MYOSITIS OSSIFICANS

Subungual exostosis of the finger or toe may resemble osteoma cutis. These lesions are solitary fibrous nodules on the terminal phalynx, most commonly seen on the great toe, and may develop secondary to trauma, originating from the underlying bone. They commonly project from underneath the nail. Calcification in the skin may be difficult to distinguish from osteoma cutis.

Therapy and prognosis The treatment of choice for most forms of osteoma cutis is surgical excision. Small lesions may not require treatment. Dermabrasion plus excision of individual lesions has been successful for multiple lesions of the face.586 Isotretinoin may aggravate osteoma formation.587 Pseudopseudohypoparathyroidism should be closely monitored by a renal or endocrine consultant to prevent severe hypocalcemia and seizures. Vitamin D and calcium supplements are the mainstay of therapy when necessary. Mental retardation may be related to the hypocalcemia. Patients should be screened periodically for hypo­ thyroidism because of its frequent association with pseudohypoparathyroidism. AHO, POH and plate-like osteoma cutis all appear in the pediatric age group, presenting with multiple areas of intracutaneous ossification and/or skeletal abnormalities. Calcifying epithelioma (pilomatricoma) is a disease of childhood.

Traumatic myositis ossificans circumscripta develops in a traumatized muscle, often after minor repetitive trauma or an infectious event. It most commonly affects the flexor muscles of the upper arms and thighs,589 presenting about 1 month after injury as a solitary 3–6  cm localized, well-circumscribed tender soft tissue swelling. In the head and neck it often affects the masseter muscle.588 It has been reported in an infant 5 months of age.590 Patients usually present with pain or tenderness in subcutaneous tissues, which lasts for 2–3 weeks, and then progressively becomes indurated, and stony hard to palpation. Diagnostic difficulties may arise in early lesions as the imaging, both ultrasound and radiographic features, is nonspecific or confusing.588

ATRAUMATIC MYOSITIS OSSIFICANS CIRCUMSCRIPTA Atraumatic myositis ossificans circumscripta is a localized lesion that appears without apparent cause and is sometimes referred to as pseudomalignant myositis ossificans. Included in this group is myositis ossificans related to systemic conditions such as paraplegia, poliomyelitis, burns, and hemophilia.591

MYOSITIS OSSIFICANS PROGRESSIVA (FIBRODYSPLASIA OSSIFICANS PROGRESSIVA, FOP)

Myositis ossificans is a rare, benign, non-neoplastic disorder in which there is formation of true bone, and less frequently cartilage, within muscles.588 Although uncommon, it has well-described radiologic, pathologic, and clinical features. There are three clinical varieties: traumatic myositis ossificans circumscripta, atraumatic myositis ossificans circumscripta, and myositis ossificans progressiva.

Fibrodysplasia ossificans progressiva is an autosomal-dominant inherited disorder with varied expressivity, the main feature of which is progressive extraskeletal ossification. It is associated with several congenital abnormalities, particularly microdactylia or adactylia of the thumbs and consistent presence of hallux valgus of the great toes. Progressive muscle ossification occurs, usually within the first few years of life. The disease has recently been shown to be due to a mutation in activin receptor 1A/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type 1 receptor, which is a member of the TGF-β gene family.592 The bone morphogenetic proteins appear to induce ossification of cartilage in vivo.593 The disease progresses in a characteristic anatomic pattern – dorsal to ventral, axial to appendicular, cranial to caudal, and proximal to distal.594 Young children present with lumps or bruises over the back or nuchal area and may be febrile and irritable. Calcium turnover is elevated, which reflects a large load of extraskeletal bone.595

586. Fulton JE. Dermabrasion-Loo-punch-excision technique for the treatment of acne-induced oesteoma cutis. J Dermatol Surg Oncol. 1987;13:6. 587. Brodkin RH, Abbey AA. Osteoma cutis: a case of probable exacerbation following treatment of severe acne with isotretinoin. Dermatologica. 1985;170:210. 588. Gindele A, Schwamborn D, Tsironis K, et al. Myositis ossificans traumatica in young children: report of three cases and a review of the literature. Pediatr Radiol. 2000;30: 451–459. 589. Ackerman LV. Extra-osseous localized non-neoplastic bone and cartilage formation (so-called myositis ossificans): clinical and pathologic confusion with malignant neoplasms. J Bone Joint Surg [Am]. 1958;40A:279. 590. Heifetz SA, Galliani CA, DeRosa GP. Myositis (fasciitis) ossificans in an infant. Pediatr Pathol. 1992;12:233.

591. Micheli A, Trapani S, Brizzi I, et al. Myositis ossificans circumscripta: a pediatric case and review of the literature. Eur J Pediatr. 2009;168:523–529. 592. Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type 1 receptor ACVR 1 causes in herited and sporadic fibrodysplasia ossificans progressiva. Nature Genetics. 2006;38:525–527. 593. Shafritz AB, Shore EM, Gannon FH, et al. Overexpression of an osteogenic morphogen in fibrodysplasia ossificans progressiva. N Engl J Med. 1996;335:555–561. 594. Kaplan FS, Merrer M, Glaser D, et al. Fibrodysplasia ossificans progressiva. Best practice and research. Clin Rheumatol. 2008;22(1):191–205. 595. Lutwak L. Myositis ossificans progressiva: mineral, metabolic and radioactive calcium studies of the effects of hormones. Am J Med. 1964;37:269.

MYOSITIS OSSIFICANS

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TRAUMATIC MYOSITIS OSSIFICANS CIRCUMSCRIPTA

Diseases of the dermis and subcutaneous tissues

Physical examination Clinically, acute lesions of myositis ossificans appear as hard swellings, which can be either localized or generalized. The nodules are warm, red, and painful. There is stiffness and lack of mobility in the areas involved. The acute changes usually subside over a few weeks but intermittent relapses of myositis may occur. This inflammatory stage is followed by fixation of the major joints involved, particularly the hips. Chronic stable lesions may be nontender and manifest as discrete mobile masses. Skeletal muscle involvement is variable.599

Pathophysiology and histogenesis The histological appearance is determined by the age of the lesion. Biopsy may not always show inflammation but this is more likely to occur in early lesions. Traumatic myositis ossificans demonstrates a zonal pattern, which shows a central undifferentiated area surrounded by osteoid material and this is encapsulated by true bone formation.589 This zone phenomenon helps distinguish myositis ossificans as a benign process, differentiating it from osteogenic sarcoma. The basic mechanism of ectopic bone formation is unknown. It has been assumed that tissue necrosis, with or without hemorrhage, leads to fibroblastic proliferation and eventual ossification. Once bone matrix is laid down, the area is readily calcified.600 A metabolic disorder of calcium or phosphorus is not necessary for bone formation, nor is it usually found. Radiographs of the involved areas show multiple exostoses of bone, and ankylosis, and deformities of the cervical vertebrae. Traumatic myositis ossificans typically shows a soft tissue mass that develops irregular, downy opacities, which as it matures develops a radiolucent center encircled by a well-defined densely calcified periphery.601 In fibrodysplasia ossificans progressiva, radiographs show distinct, well-circumscribed areas of deep heterotopic ossification that often correspond to a distinct skeletal muscle.602 Radiographs of the feet show classic hallux valgus

596. Kaplan FS. Fibrodysplasia ossificans progressiva. Clin Orthop. 1998;346:1–140. 597. Kitterman JA, Kantanie S, Rocke DM, et al. Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics. 2005;116(5):e654. 598. Kaplan FS, Glaser DL. Thoracic insufficiency syndrome in patients with fibrodysplasia ossificans progressiva. Clin Rev Bone Mineral Metab. 2005;3:213–216. 599. Kaplan FS, Tabas JA, Gannon FH, et al. The histopathology of fibrodysplasia ossificans progressiva. An endochondral process. J Bone Joint Surg [Am]. 1993;75:220–230. 600. Smith R. Myositis ossificans progressiva: a review of current problems. Semin Arthritis Rheum. 1975;4:369. 601. Nuovo MA, Norman A, Chumas J, et al. Myositis ossificans with a typical clinical, radiographic, and pathologic findings: a review of 23 cases. Skeletal Radiol. 1992;21:87. 602. Kaplan FS, Strear CM, Zasloff MA. Radiographic and scintigraphic features of modeling and remodeling in the heterotopic skeleton of patients who have fibrodysplasia ossificans progressiva. Clin Orthop. 1994;304:238–247.

deformity of the great toes. MRI may be very useful in differentiating these lesions from osteosarcomas because they show characteristic distribution of abnormal signal intensity in the muscles with no abnormality in the adjacent bone marrow or cortex.603 Calcium and phosphorus levels are usually normal, and there may be a slight elevation of the alkaline phosphatase level600 and the erythrocyte sedimentation rate. Electromyographic studies suggest a primary myopathy but nerve conduction studies are normal.

Differential diagnosis The differential diagnosis includes nodular fasciitis, traumatic fibrosis, battered child syndrome, the major forms of osteoma cutis, osteomyelitis, osteochondroma, osteogenic sarcoma, subcutaneous fat necrosis, and morphea. The definitive diagnosis of FOP can be made by simple clinical evaluation that associates progressively ossifying soft tissue lesions with malformations of the great toes.604 Treatment is aimed at alleviating or preventing myositis with systemic steroids.605

MASTOCYTOSIS

Diagnosis is often delayed or erroneously made because the significance of the skeletal abnormalities is not recognized.596,597 The prognosis is poor with relentless ossification causing severe incapacitation and eventual death from respiratory failure.598 Conductive hearing loss appears in 25% of patients.

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Treatment and prognosis Preventing mineralization by decreasing dietary calcium and using calcium-binding agents (diphosphonates) may reduce ectopic calcification.600 Surgical excision for painful lesions must be attempted cautiously because of recurrence. The benign nature of the localized form of this nonneoplastic process requires a conservative approach.601 Acetic acid 2% was administered by iontophoresis into an area of traumatic myositis ossificans on the thigh of a 16 year old, with 98.9% decrease in the size of the ossified mass after 3 weeks.606 In another case, surgery plus isotretinoin at a dose of 2–5 mg/kg per day did not prevent ectopic ossification.607 Treatment of FOP is mainly suppurative and avoiding surgical intervention.608

MASTOCYTOSIS Mastocytosis is the broad term used for a group of disorders characterized by the accumulation of mast cells in the skin with or without other organ system involvement609 (Box 17.4). The most common site of mast cell accumulation is the skin.610 Nettleship and Tay first described mastocytosis in a 2-year-old girl

603. Ehara S, Nakasato T, Tamakawa Y, et al. MRI of myositis ossificans circumscripta. Clin Imaging. 1991;15:130. 604. Kaplan FS, Meiqi X, Glaser D, et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008;121(5):e1295–e1300. 605. Illingworth RS. Myositis ossificans progressiva (Munchmeyer’s disease). Arch Dis Child. 1971;46:264. 606. Wieder DL. Treatment of traumatic myositis ossificans with acetic acid iontophoresis. Phys Ther. 1992;72:133. 607. Crofford LJ, Brahim JS, Zasloff MA, et al. Failure of surgery and isotretinoin to relieve jaw immobilization in fibrodysplasia ossificans progressiva: report of two cases. J Oral Maxillofac Surg. 1990;48:204. 608. Glaser DL, Kaplan FS. Treatment considerations for the management of fibrodysplasia ossificans progressiva. Clin Rev Bone Mineral Metab. 2005;3:243–250. 609. Valenta P, Cem A, Sperra WR, et al. Mastocytosis: Pathology, genetics and current options for therapy. Leukemia & Lymphoma. 2005;46(1):35–48. 610. Soter NA. Mast cell disorders. Mastocytosis and the skin. Hematol/oncol Clin North Am. 2000;14(3):537–555.

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BOX 17.4 CLASSIFICATION OF MASTOCYTOSIS Cutaneous mastocytosis 1. Urticaria pigmentosa 2. Diffuse cutaneous mastocytosis 3. Mastocytoma of the skin 4. TMEP Systemic mastocytosis (without AHNMD or leukemic mast cell disease) 1. Systemic indolent mastocytosis 2. Systemic smouldering mastocytosis Systemic mastocytosis with an AHNMD 1. Myeloproliferative syndrome MASTOCYTOSIS

2. Myelodysplastic syndrome 3. Acute myeloid leukemia 4. Non-Hodgkin’s lymphoma Systemic aggressive mastocytosis 1. Mast cell leukemia 2. Mast cell sarcoma 3. Extracutaneous mastocytoma. Classification adopted from the WHO Classification (AHNMD, Associated hematological non-mast cell disorder). Modified from Carter MC, Metcalfe DD. Paediatric mastocytosis. Arch Dis Child 2002; 86:315–319, with permission.

in 1869.611 Ehrlich discovered the mast cell in 1877.612 Mast cells are derived from pluripotent CD34+ precursors in bone marrow and assume their typical granular morphology after migrating into tissue.613,614 When bridging of IgE bound to FcεRI receptors on mast cells by specific antigens occurs, mast cells undergo degranulation and release biologically active preformed mediators and newly formed mediators characteristic of stimulated mast cells. Mast cells are naturally distributed within the dermis, the respiratory system, gastrointestinal tract, genitourinary tract, adjacent to blood and lymphatic vessels, and near peripheral nerves. They act as surveillance cells that can respond to environmental antigens that come in contact with the skin or mucosal surfaces. Symptoms can be isolated to the organ system involved or may be systemic; they are caused by the release of

611. Nettleship E, Tay W. Rare forms of urticaria. BMJ. 1869;2:323–324. 612. Ehrlich P. Beiträge zur Kenntnis der Anilinfarbungen und ihrer Verwendurg in der Mikroskopischen Technik. Arch Mikros Anat. 1877;13:263–277. 613. Kirshenbaum AS, Goff JP, Kessler SW, et al. Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol. 1991;46:1410–1415. 614. Kirshenbaum AS, Metcalf DD. Growth of human mast cells from bone marrow and peripheral blood derived CD34+ pluripotent progenitor cells. Methods Mol Biol. 2006;315:105–112. 615. Kneilling M, Röcken M. Mast cells: novel clinical perspectives from recent insights. Exp Dermatol. 2009;18(5):488–496. 616. De Paulis A, Minopoli G, Arbustini E, et al. Stem cell factor is localized in, released from, and cleaved by human mast cells. J Immunol. 1999;163:2799–2808.

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histamine, cytokines, and other mast-cell mediators such as prostaglandins, leukotrienes, and platelet-activating factor, and TNF-α.615 Stimulated mast cells store and release stem cell factor indicating the potential for autocrine growth.616

Epidemiology Cutaneous mastocytosis is a relatively frequent condition in pediatric dermatology. Prevalence ranges from 1 in 200 to 1 in 800 first time patients presenting to a pediatric dermatology clinic.617 The disease appears to be sporadic, but there are more than 57 case reports of familial occurrence.617–619 There is some evidence of an autosomal-dominant pattern in the diffuse cutaneous form.620 Most studies show a slight male preponderance and the majority of reported patients are white.617,621 Mastocytosis limited to the skin is primarily a disease of children. It can be accompanied by systemic symptoms without systemic infiltration. On the other hand, systemic internal mastocytosis is more common in adults with infiltration of mast cells in other organs. It may be progressive, relenting, debilitating, and fatal. In two large reviews of pediatric mast cell disease, over 90% of pediatric cases presented by 2 years of age.622,623 However, the disease may appear at any time from birth to middle age.

Presenting history In infants, the parent usually seeks attention for a pruritic lesion or multiple lesions that recurrently urticate or blister, usually after a hot bath or rubbing of the lesion (Fig. 17.20). These lesions are commonly mistaken for bullous impetigo. Less commonly, flushing, gastrointestinal complaints such as vomiting, colicky pain, and diarrhea or headaches may be the initial problems.

Physical examination Mastocytosis exhibits a wide spectrum of manifestations. Cutaneous forms include a solitary mastocytoma, urticaria pigmentosa (several lesions), diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans (TMEP).610 Systemic forms may or may not be associated with malignancy but rarely occur in childhood. Darier’s sign is a pathognomic sign of mastocytosis. It is defined as the urtication of a lesion after firm stroking. In a young child, the lesion may become bullous. Darier’s sign is caused by the release of histamine from

617. Kiszewski AE, Duran-Mckinster C, Orozco-Covarrubias L, et al. Cutaneous mastocytosis in children: a clinical analysis of 71 cases. JEADV. 2004;18:285–290. 618. Jappe U, Aumann V, Mittler U, et al. Familial urticaria pigmentosa associated with thrombocytosis as the initial symptom of systemic mastocytosis and Down’s syndrome. JEADV. 2003;17:718–722. 619. Anstey A, Lowe DG, Kirby JD. Familial mastocytosis: a clinical, immunophenotypic, light and electron microscopic study. Br J Dermatol. 1991;125:583. 620. Oku T, Hashizume H, Yokote R, et al. The familial occurrence of bullous mastocytosis (diffuse cutaneous mastocytosis). Arch Dermatol. 1990;126:1478. 621. Fine JD. Mastocytosis. Int J Dermatol. 1980;19:117. 622. Ben-Amitai D, Metzker A, Cohen HA. Pediatric cutaneous mastocytosis: a review of 180 patients. Isr Med Assoc J. 2005;7(5):320–322. 623. Hannaford R, Rogers M. Presentation of cutaneous mastocytosis in 173 children. Australas J Dermatol. 2001;42:15–21.

Diseases of the dermis and subcutaneous tissues

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MASTOCYTOSIS

A

C

B

Figure 17.20  (A) Solitary mastocytoma that has urticated after being rubbed (Darier’s sign). (B,C) Mastocytoma.

degranulation of mast cells secondary to mechanical trauma. The wheal and flare response persists for 30 min to several hours and may be intensely pruritic. Other signs of mast cell degranulation include flushing, particularly marked on the upper body and usually lasting 10–30 min, dermographism on clinically uninvolved skin, and, rarely, telangiectasias (seen in TMEP). A mastocytoma is a reddish-brown, pink, or yellow nodule that is usually solitary. The surface is usually smooth but may rarely have the appearance of orange peel (peau d’orange). Lesions are round or oval, vary in size from 1 to 5 cm, and may have a thick or rubbery quality. The lesions usually occur at birth or in infancy and account for 15–50% of the cases of cutaneous mastocytosis.617,623 Symptoms associated with single mastocytomas are usually few, but generalized pruritus, urticaria, and bullae formation over the lesion and systemic symptoms such as flushing may occur. It is unusual for children who present with a solitary lesion to acquire additional lesions more than 2 months after the initial lesion. Urticaria pigmentosa, the commonest form of mastocytosis, usually begins between 3 and 9 months of age but may be present at birth.623 Lesions are usually numerous, red-brown macules, papules, and sometimes nodules and plaques mainly

distributed over the trunk (Fig. 17.21). The number of lesions ranges from several to hundreds. Individual lesions are round to oval and vary in size from 1 mm to several centimeters. The numbers of lesions may increase for several years after diagnosis. Urticaria pigmentosa may rarely be associated with systemic involvement, particularly if lesions appear after 10 years of age. Infrequently, hepatosplenomegaly or skeletal lesions may be found that are due to mast cell hyperplasia in these organs. Diffuse cutaneous mastocytosis is a rare type of mastocytosis that involves skin with an infiltration of mast cells without discrete lesions. The skin is usually thickened, lichenified, and doughy (Figs 17.22, 17.23), with numerous tiny papules, which have a yellowish tint. Initial manifestations often occur at 3 months of age with the sudden appearance of sero-sanguineous bullae (Fig. 17.24). Systemic symptoms including flushing, hemorrhage, hypotension, diarrhea, dyspnea, or overt shock may occur.624 When the bullae subside the thickened skin is evident. TMEP is a term used to describe telangiectatic hyperpigmented macules that are usually extensive and located mainly on the trunk. The lesions do not typically urticate when stroked. They are seen more commonly in teenagers and adults and are rarely reported in children.625

624. Golitz LE, Weston WL, Lane AT. Bullous mastocytosis with extensive blisters mimicking scalded skin syndrome or erythema multiforme. Pediatr Dermatol. 1984;1(4):288–294.

625. Gibbs NF, Friedlander SF, Harpster EF. Telangiectasia macularis eruptive perstans. Pediatr Dermatol. 2000;17:194–197.

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MASTOCYTOSIS

Figure 17.21  Numerous lesions of urticaria pigmentosa on the abdomen and chest of a child.

Figure 17.22  Pebbly changes of diffuse cutaneous mastocytosis in a 12-month-old infant.

Systemic infiltration with mastocytosis is more common in adults and older children but has been reported rarely in infants.626 The gastrointestinal and skeletal systems are most commonly involved, but mast cell infiltration can be found in the lung, kidney, myocardium, pericardium, omentum, and other tissues. The mastocytosis syndrome results from the massive release of vasodepressor mast cell products with a resultant shock state.627 It can last from several minutes to several hours. It occurs most commonly in neonates or young children with diffuse cutaneous mastocytosis. Pruritus, headache, bronchospasm, rhinorrhea, flushing, diarrhea, hypotension, tachycardia, dyspnea, and syncope may all result. Occasionally the reaction is so severe that death may result.624,628 In a review of 95 children, 14 showed radiographic bone lesions thought to be related to their mastocytosis.629 None of these children had an aggressive course, and in three children follow-up radiographs were normal. Skeletal lesions may therefore be transitory and do not correlate with systemic involvement.630 Obvious radiographic findings include discrete lytic, cystic, or sclerotic lesions and osteoporosis or osteosclerosis; these are most often seen in the axial skeleton.621 Diffuse bone involvement occurs almost solely in adult-onset disease.631 Gastrointestinal symptoms are not common in children632 but, when present, are usually seen with systemic disease. They may result from direct infiltration of mast cells into the mucosa

626. Hartmann K, Metcalfe DD. Pediatric mastocytosis. Hematol/oncol Clinics North Am. 2000;14(3):625–640. 627. Turk J, Oates JA, Roberts LJ. Intervention with epinephrine in hypotension associated with mastocytosis. J Allergy Clin Immunol. 1983;71:189. 628. Murphy M, Walsh D, Drumm B, Watson R. Bullous mastocytosis: a fatal outcome. Pediatr Dermatol. 1999;16:452–455. 629. Lucaya J, Perez-Candela V, Aso C, et al. Mastocytosis with skeletal and gastrointestinal involvement in infancy: two case reports and review of the literature. Radiology. 1979;131:363.

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Figure 17.23  Nodular lesions of mastocytosis. (courtesy of Dr A. Torrelo).

or from increased tissue levels of histamine, which results in symptoms such as nausea, vomiting, abdominal pain, gastrointestinal hemorrhage, diarrhea, steatorrhea, and malabsorption.633 Hepatomegaly or splenomegaly occurs in about 12% of cases of urticaria pigmentosa.634,617

630. Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. Ann Allergy. 1994;73:197–202. 631. Travis W, Li C-Y, Bergstrahl E, et al. Systemic mast cell disease. Medicine. 1988;67:345–368. 632. Stein DH. Mastocytosis: a review. Pediatr Dermatol. 1986;3:365. 633. Lewis RA. Mastocytosis. J Allergy Clin Immunol. 1984;74:755. 634. Soter NA, Austen KF, Wasserman SI. Oral disodium cromoglycate in the treatment of systemic mastocytosis. N Engl J Med. 1979;301:465.

Diseases of the dermis and subcutaneous tissues

Figure 17.24  Bullae in a 3-month-old infant with diffuse cutaneous mastocytosis.

The hematopoietic and reticuloendothelial systems are seldom involved in children. Urticaria pigmentosa has been associated with an increased number of hematologic malignancies, including Hodgkin’s disease, lymphocytic lymphoma, and leukemia.635 Diffuse cutaneous mastocytosis has been associated with a myelo­ proliferative disorder presenting in utero or shortly after birth.636,637 Familial forms of urticaria pigmentosa have been associated with gastrointestinal stromal tumors in other family members.638

MASTOCYTOSIS

mine are metabolized rapidly and the major metabolites (N-methylhistamine and N-methylimidazylacetic acid), when elevated, are a sensitive test for the diagnosis of mastocytosis.640,641 Elevation of mast cell secretory products (prostaglandin D2, α-tryptase, and heparin) can be measured in an attempt to demonstrate systemic mast cell activation.642–644 Prostaglandin D2 elevation in the urine suggests that mast cell-derived mediators cause vasodepression and other symptoms.645 Serum α-tryptase levels when elevated in urine or blood of patients with mastocytosis may be useful in assessing totalbody mast cell burden. Serum levels above 20  ng/mL are seen in 80% of patients with systemic mastocytosis while 87% of patients with cutaneous mastocytosis will have levels less than 20  ng/mL.646 Assay of bone marrow tryptase may have a higher sensitivity than bone marrow examination alone for assessing systemic mastocytosis due to the focal distribution of increased mast cells in bone marrow.647 Elevated IL-6 levels are a useful marker of severity in patients with systemic disease and bone marrow involvement.648 A skeletal radiographic survey or a technetium bone scan is indicated only if the patient has bone pain, hepato­ splenomegaly, anemia, or failure to thrive. The usefulness of routine skeletal surveys is doubtful.649 Examination of the gastrointestinal tract or bone marrow should be reserved for those instances where clinical evidence suggests organ system involvement. Patients may have hypocholesterolemia secondary to the effects of mast cell heparin on lipoprotein metabolism. Hematologic abnormalities, including anemia, thrombocy­ topenia, and eosinophilia, may also occur with systemic involvement.

Pathophysiology and histogenesis

Elevated urinary or plasma histamine levels may be helpful in making a diagnosis in patients with diffuse involvement, especially with gastrointestinal symptoms.639 Urinary levels of hista-

Urticaria pigmentosa and mastocytoma lesions have an infiltration of mast cells in the upper third of the dermis with occasional perivascular aggregates.186 These aggregates may be so extensive that they obliterate all the cutaneous architecture. Mast cells are difficult to demonstrate by routine hematoxylin and eosin staining. Giemsa stain, toluidine blue or Leder’s method (naphthol AS-D chloracetate esterase) identify the characteristic metachro-

635. McElroy EA, Phyliky RL, Li CY. Systemic mast cell disease associated with the hypereosinophilic syndrome. Mayo Clin Proc. 1998;73:47–50. 636. Kuint J, Bielorai B, Gilat D, et al. C-kit activating mutation in a neonate with in-utero presentation of systemic mastocytosis associated with myeloproliferative disorder. Br J Haematol. 1999;106:833–839. 637. Shah PY, Sharma V, Worobec AS, et al. Congenital bullous mastocytosis with myeloproliferative disorder and c-kit mutation. J Am Acad Dermatol. 1998;39:119–121. 638. Hartmann K, Wardelmann E, Yongsheng MA, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology. 2005;129:1042–1046. 639. Kendall ME, Fields JP, King LE. Cutaneous mastocytosis without clinically obvious skin lesions. J Am Acad Dermatol. 1984;10:903. 640. Granerus G, Olafasson JH, Roupe G. Studies on histamine metabolism in mastocytosis. J Invest Dermatol. 1983;80:410–416. 641. Keyzer JJ, deMonchy JGR, van Doormaal JJ, et al. Improved diagnosis of mastocytosis by measurement of urinary histamine metabolites. N Engl J Med. 1983;309:1603. 642. Roberts LJ, Oates JA. Biochemical diagnosis of systemic mast cell disorders. J Invest Dermatol. 1991;96:19S.

643. Roberts LJ, Sweetman BJ, Lewis RA, et al. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med. 1980;303:1400. 644. Morrow J, Guzo C, Lazarus G, et al. Improved diagnosis of mastocytosis by measurement of the major urinary metabolite of prostaglandin D2. J Invest Dermatol. 1995;104:937–940. 645. Kawai S, Okamoto H. Giant mast cell granules in a solitary mastocytoma. Pediatr Dermatol. 1993;10:12. 646. Sperr WR, Jordan JH, Fiegl M, et al. Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease. Int Arch Allergy Immunol. 2002;128:136–141. 647. Proelss J, Wenzel J, Ko J, et al. Tryptase detection in bone marrow blood: A new diagnostic tool in systemic mastocytosis. J Am Acad Dermatol. 2007;56:453–457. 648. Brockow K, Akin C, Huber M, et al. IL-6 levels predict disease variant and extent of organ involvement in patients with mastocytosis. Clin Immunol. 2005;115:216–223. 649. Cooper AJ, Winkelmann RK, Wiltsie JC. Hematologic malignancies occurring in patients with urticaria pigmentosa. J Am Acad Dermatol. 1982;7:215.

Laboratory findings

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matic cytoplasmic granules and should be requested if indicated. It is important to choose a biopsy site that has not been recently traumatized. When the lesion has recently been urticated, the mast cells may be degranulated and not evident. Eosinophils, edema, and subepidermal bullae may be seen in some biopsy specimens. TMEP demonstrates a subtle increase in the number of mast cells, usually around capillary venules, along with vascular ectasia. Pigmentation in urticaria pigmentosa is secondary to the presence of increased melanin in the basal cell layer and melanophages in the upper dermis. Electron microscopy demonstrates typical mast cell morphology with rare reports of giant mast cell granules.645 The cause of mastocytosis is unknown. Mast cells can be found in the connective tissue of most organs and originate from bone marrow CD34+ precursors. Their granular morphology is only assumed after migrating into tissues. The precursor cells in peripheral blood also express the protein kinase KIT (CD117), which is the receptor ligand for stem cell factor (SCF) and FcγRII but not the high-affinity IgE receptors.650 KIT is the product of the proto-oncogene c-kit located on chromosome 4q12 and belongs to the family of tyrosine kinase receptors. It is expressed on numerous cells other than mast cells including melanocytes, primitive hematopoietic stem cells, germ cell lines, and the intestinal cells of Cajal. Abnormalities of the c-kit receptor have been described in mastocytosis and piebaldism.651–653 Alterations in SCF and KIT are seen in mastocytosis patients. More than 80% of adult-onset cases and up to 40% of adults with disease onset in childhood with systemic mast cell disease are associated with the c-kit point mutation D816V.653 This results in activation of KIT, which induces cellular proliferation and decreased apoptosis of mast cells.654 These mutations are uncommon in sporadic childhood mastocytosis but when present may indicate atypical or prolonged disease.653 Longley et al.655 investigated c-kit autoactivating mutations in 11 adults and 11 children with sporadic mastocytosis. All the adults displayed the codon 816 mutations and all pediatric patients tested negative. Four other pediatric patients with extensive skin involvement, two of whom eventually developed systemic disease, proved positive for the codon 816 mutation.655 A recent study of 12 patients with nonfamilial childhood onset mastocytosis showed c-kit mutations were present in 10 patients, the majority showing the D816V mutation, while three showed D816P.656 Familial mastocytosis families have shown mutations in exon 8 and 11 of c-kit.638 Taken together, it is likely that in pediatric patients other mutations either in c-kit or its activation pathways which are as yet undefined may be present.

A classification of mastocytosis based on the molecular defect has recently been proposed, as patients who express these mutations regardless of their age appear to have persistent disease with increased risk of systemic involvement and non-mast cell hematologic disorders.609,657 Increased soluble stem cell factor has been reported in skin lesions of patients with both adult and pediatric mastocytosis and may contribute to mast cell growth and survival as well as to the hyperpigmentation seen clinically.658–660 Mast cells are paracrine cells that store products within granules and release them directly into the surrounding tissue fluid. Histamine, a major component of the granules, can alter vascular permeability, increase airway resistance, stimulate cardiac and gastric secretory systems, and mediate T-lymphocyte suppression by acting on specific membrane receptors. Other mediators released include cytokines, TNF-α, IL-4–5–6, and -8. Once stimulated, mast cells may also generate newly formed PGD-2, leukotrienes, platelet activating factor (PAF), and SCF.616 Disease results either from the local effects of infiltration of mast cells that interfere with normal organ function or from the pharmacologic effects of chemicals generated by mast cell activation. Immediate type 1 hypersensitivity reactions may occur secondary to chemical mediators, such as histamine and prostaglandin D2 which causes injury to tissue, increased vascular permeability, constriction of smooth muscles, enhanced leukocyte migration, and increased platelet activation.

650. Rottem M, Okada T, Goff JP, et al. Mast cells cultured from the peripheral blood of normal donors and patients with mastocytosis originate from CD341 /Fcε/RI-cell population. Blood. 1994;84:2489–2496. 651. Lev S, Blechman JM, Givol D, et al. Steel factor and c-kit proto-oncogene: Genetic lessons in signal transduction. Crit Rev Oncog. 1994;5:141–168. 652. Longley BJ, Tyrell L, Lu SZ, et al. Somatic c-kit activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. Nat Genet. 1996;12:312–314. 653. Lanternier F, Cohen-Akenine A, Palmerini F, et al. Phenotypic and genotypic characteristics of mastocytosis according to the age of onset. PloS ONE. 2008;3(4):e1906. 654. Boissan M, Fegr F, Guillosson JJ, et al. c-Kit and c-Kit mutation in mastocytosis and other hematological diseases. J Leukoc Biol. 2000;67:135–148. 655. Longley BJ, Metcalfe DD, Tharp MD, et al. Activating and dominant inactivating c-kit catalytic domain mutations in distinct forms of human mastocytosis. Proc Natl Acad Sci USA. 1999;96:1609–1614.

656. Yanagihori H, Oyama N, Nakamura K, et al. c-kit Mutations in patients with childhood-onset mastocytosis and genotype-phenotype correlation. J Mol Diagn. 2005;7(2):252–257. 657. Longley BJ, Metcalfe D. A proposed classification system of mastocytosis incorporating molecular genetics. Hematol/oncol Clin North Am. 2000;14(3):697–701. 658. Longley BJ, Morganroth GS, Tyrrell L, et al. Altered metabolism of mast cell growth factor (c-kit ligand) in cutaneous mastocytosis. N Engl J Med. 1993;328:1302–1307. 659. Halaban R, Tyrrell L, Longley J, et al. Pigmentation and proliferation of human melanocytes and the effect of melanocyte-stimulating hormone and ultraviolet B light. Ann NY Acad Sci. 1993;680:290–301. 660. Geissler EN, Ryan MA, Housman DE. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell. 1988; 55:185–192.

Differential diagnosis A solitary lesion of mastocytosis may be misdiagnosed as bullous impetigo because of the blistering. Other lesions confused with mastocytomas are juvenile xanthogranulomas, nevocellular nevi, connective tissue nevi, bullous insect bites, bullous urticaria, and the nodular lesions of scabies. Darier’s sign is helpful in distinguishing these entities. The macular form of mastocytosis may be confused with multiple lentigines, pigmented nevi, eruptive xanthomas, and neurofibromatosis. TMEP may be mistaken for hereditary hemorrhagic telangiectasia. The diffuse or erythrodermic form may be mistaken for Langerhans histiocytosis, bullous erythema multiforme, or other bullous diseases. Biopsy is essential for diagnosis in such cases. Cutaneous mastocytosis beginning in an older child or adult, or extensive cutaneous lesions associated with symptoms such as episodic flushing, palpitations, or syncope, should alert the physician to evaluate for systemic involvement. Carcinoid

The patient should avoid precipitating causes for mast cell degranulation (Box 17.5), and a list of medications to avoid should be given to the parent and/or patient. Over-the-counter cough preparations may contain dextromethorphan or codeine which may induce significant histamine release and blistering.615 Propofol, vecuronium, and fentanyl are safe to use in mastocytosis patients undergoing surgery.661

General anesthesia in children with mastocytosis can be safely carried out by a pediatric anesthetist who has a thorough understanding of the disease, its anesthetic implications and adverse events.661,662 Various medications have been used to treat mastocytosis. Antihistamines such as hydroxyzine may help alleviate symptoms and are usually given four times a day if symptoms occur. H1- and H2-receptor antagonists either alone or together may be of some benefit. Non-sedative H1 antihistamines such as cetirizine, loratadine, and fexofenadine, have the advantage of not causing drowsiness. Cyproheptadine (0.25 mg/kg per day) plus cimetidine (30 mg/kg per day) have reduced the bullae in two cases of congenital bullous urticaria pigmentosa.663 Cromolyn sodium (200–800 mg/day) has been effective in reducing symptoms of pruritus, dermographism, and blister formation in a number of studies.664,665 The urinary histamine levels are usually unaffected by cromolyn sodium. Recommendations are 20 mg/ kg per day in four divided doses up to age 2 years; for children 2–12 years, 100 mg qid can be given. Ketotifen, which has both antihistamine and mast cell stabilizing properties, has been used in both childhood and adult forms of mastocytosis alone or combined with ranitidine.666,667 One study suggested no advantage over conventional H1 antihistamines.666 Dosage of ketotifen is 1–2 mg twice daily, and is well tolerated in infants although it may stimulate appetite and weight gain. Aspirin inhibits prostaglandin synthesis643 but caution should be used in prescribing this, as fatal histamine shock may be precipitated. Potent topical steroids under occlusion (betamethasone dipropionate 0.05%, clobetasol propionate 0.05%) may improve the clinical appearance and reduce the number of mast cells in the skin.668 Occasional prolonged remission of treated areas has been described.669–672 Intralesional steroids (triamcinolone acetonide 5–10 mg/mL) may be used for individual lesions.670 Adults with mastocytosis have been reported to have severe anaphylaxis after insect stings.671 An EpiPen or ANA-Kit may be considered for selected children,628 and a medical alert bracelet may also be suggested. In the diffuse cutaneous form, PUVA may cause relief of pruritus and symptoms and improve the patient’s appearance.672,673 Caution should be used when starting treatment to prevent massive mast cell degranulation. Bath PUVA was not effective in four patients.674 Cyclical use (2 weeks on and 2 weeks off) of potent topical steroids may be beneficial for skin lesions and symptoms in patients with diffuse cutaneous mastocytosis but these children must be closely monitored for systemic side

661. Ahmad N, Evans P, Lloyd-Thomas A. Anesthesia in children with mastocytosis – a case-based review. Pediatr Anesth. 2009;19:97–107. 662. Carter MC, Uzzaman A, Scott LM, et al. Pediatric mastocytosis: routine anesthetic management for a complex disease. Anesth Analg. 2008;107:422–427. 663. Horan RF, Sheffer AL, Austen KF, et al. Cromolyn sodium in the management of systemic mastocytosis. J Allergy Clin Immunol. 1990;25:852–855. 664. Frieri M, Alling DW, Metcalfe DD. Comparison of the therapeutic efficacy of cromolyn sodium with that of combined chlorpheniramine and cimetidine in systemic mastocytosis: results of a double-blind clinical trial. Am J Med. 1985;78:9. 665. Welch EA, Alper JC, Gogaars H, et al. Treatment of bullous mastocytosis with disodium cromoglycate. J Am Acad Dermatol. 1983;9:349. 666. Czarnetzki BM. A double-blind cross-over study of the effect of ketotifen in urticaria pigmentosa. Dermatologica. 1983;166:44. 667. Kurosawa M, Amano H, Kanbe N, et al. Heterogeneity of mast cells in mastocytosis and inhibitory effect of ketotifen and ranitidine on indolent systemic mastocytosis. J Allergy Clin Immunol. 1997;100:S25–S32.

668. Guzzo C, Lavker R, Roberts LJ, et al. Urticaria pigmentosa. Systemic evaluation and successful treatment with topical steroids. Arch Dermatol. 1991;127:191. 669. Sidhu S, Wakelin SH, Wojnarowska F. Prolonged remission of urticaria pigmentosa following topical steroid therapy under hydrocolloid occlusion. Clin and Experiment Dermatol. 1997;22:300–304. 670. Barton J, Lavker RM, Schechter NM, et al. Treatment of urticaria pigmentosa with corticosteroids. Arch Dermatol. 1985;121:1516–1523. 671. Fricker M, Helbling A, Schwartz L, et al. Hymenoptera sting anaphylaxis and urticaria pigmentosa: clinical findings and results of venom immunotherapy in 10 patients. J Allergy Clin Immunol. 1997; 100(1):11–15. 672. Mackey S, Pride HB, Tyler WB. Diffuse cutaneous mastocytosis. Arch Dermatol. 1996;132:1429–1430. 673. Smith ML, Orton PW, Chu H, et al. Photochemotherapy of dominant, diffuse, cutaneous mastocytosis. Pediatr Dermatol. 1991;7:251. 674. Godt D, Proksch E, Streit V, et al. Short and long term effectiveness of oral and bath PUVA therapy in urticaria pigmentosa and systemic mastocytosis. Dermatology. 1997;195:35–39.

BOX 17.5 MAST CELL DEGRANULATORS Physical stimuli

>> Fever >> Pressure or friction >> Skin temperature changes (especially with bathing) >> Sunlight Drugs

>> Aspirin and related analgesics such as non-steroidal antiinflammatory agents

>> Alcohol >> Narcotics (opiates): codeine, meperidine, morphine, dextromethorphan

>> Polymyxin B >> Thiamine >> d-Tubocurarine >> Iodine containing radiocontrast dyes >> Cholinergic medications (scopolamine, etc.) Other

>> Intravenous high molecular weight polymers (dextran) >> Venoms (Hymenoptera and other stinging insects) >> Bacterial toxins >> Snake venoms >> Biologic peptides (substance P. somatostatin) >> Polypeptides released by Ascaris >> Emotional stress

syndrome may show similar symptoms, but these patients do not have telangiectasias.

Therapy and prognosis

17

MASTOCYTOSIS

Diseases of the dermis and subcutaneous tissues

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Reaction Patterns

HYPERLIPIDEMIAS AND XANTHOMAS

effects. The combination of interferon-α 2b and prednisone may be effective in systemic mast cell disease.675 Symptoms improve but tissue mast cells, particularly bone marrow involvement persists.676 Interferon has not been adequately studied in pediatric mastocytosis.610 Oral prednisone is the mainstay of treatment in severe cases of systemic mastocytosis in adults associated with malabsorption.677,678 In the future, agents which inhibit KIT kinase may be useful in patients with documented activating c-kit mutations. Successful treatment of progressive cutaneous mastocytosis with imatinib in a 2-year-old boy has been reported. Imatinib stopped symptoms and disease progression and was well tolerated. Of note, he did not have the common D816V mutation but a somatic deletion of codon 419 in exon 8 of c-kit.679 The common D816V mutation activates the serine/threonine kinase mammalian target of rapamycin (mTOR) pathway downstream suggesting that rapamycin may inhibit proliferation and survival of mast cells bearing the D816V c-kit mutation and prove a useful treatment in future for severely affected patients.680 Surgical excision of isolated persistent lesions may occasionally be appropriate if other treatments have failed and the lesions are symptomatic. Episodes of profound hypotension and shock in systemic mastocytosis may require intravenous saline, corticosteroids, pressor agents, epinephrine (adrenaline),627 and both H1 and H2 antihistamines. Treatment of bullae requires local care and prevention of infection. Because many over-the-counter antibiotics contain polymyxin B, a degranulator of mast cells, mupirocin may be a good choice for local wound care. Blisters generally heal without scarring but may leave residual hyperpigmentation. The course of an isolated mastocytoma is usually spontaneous regression over several years. Childhood urticaria pigmentosa also has a favorable outcome with lesions regressing by puberty.681 The prognosis in the very young with diffuse cutaneous mastocytosis depends on systemic involvement. Death is usually related to hemorrhage, leukemia, myelofibrosis, or cachexia. Infants who present with bullae are more likely to have systemic involvement. Children whose mastocytosis persists into adulthood typically demonstrate a course similar to adult-onset disease in which 5–10% have systemic involvement.622 Older children and adults who have serious systemic involvement have a guarded prognosis, as do neonates with massive diffuse cutaneous involvement. Type I allergies may be more severe in mast cell disease than normal because of profound mast cell degranulation.671 Rarely, a child may have aggressive mastocytosis with bone marrow and other organ involvement. In these cases, mast cells infiltrate the organs, or circulating mast cells may be seen resembling leukemia. These children have a more guarded prognosis.

675. Kluin-Nelemans HC, Jansen JH, Bruekelman H, et al. Response to interferon alfa-2b in a patient with systemic mastocytosis. N Engl J Med. 1992;326:619. 676. Worobec A, Kirshenbaum A, Schwartz L, et al. Treatment of three patients with systemic mastocytosis with interferon alpha-2b. Leukemia & Lymphoma. 1996;22:501–508. 677. Metcalfe DD. The treatment of mastocytosis: an overview. J Invest Dermatol. 1991;96:55S–59S. 678. Worobec AS. Treatment of systemic mast cell disorders. Hematol/oncol Clin North Am. 2000;14:659–687. 679. Hoffman K, Moser A, Lohse P, et al. Successful treatment of progressive cutaneous mastocytosis with imatinib in a 2 yr old boy carrying a somatic KIT mutation. Blood. 2008;112(5):1655–1657.

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BOX 17.6 TYPES OF XANTHOMAS Tendinous Planar

>> Xanthelasma palpebrarum >> Corneal arcus >> Xanthoma striatum palmare >> Diffuse infiltrative plaques Tuberous Eruptive Other

>> Xanthoma disseminatum >> Cerebrotendinous xanthomatosis >> Phytosterolemia >> Tangier disease

Solitary mastocytomas and urticaria pigmentosa are common in children and have a favorable outlook. Diffuse infiltrative mastocytosis is rare in childhood and has a more guarded prognosis. TMEP rarely occurs in childhood, may be familial, and has a benign prognosis.682 Systemic mastocytosis and mastocytosis with malignancy are very rare in childhood.

HYPERLIPIDEMIAS AND XANTHOMAS Xanthomas are localized infiltrates of histiocytic foam cells that contain lipid.683 They are commonly caused by a disturbance of lipoprotein metabolism. In general, five major clinical forms of cutaneous xanthomas exist: tendinous, planar, tuberous, eruptive, and other (Box 17.6). Xanthomas on the skin may lead to the detection of an associated underlying metabolic lipoprotein abnormality. The number of xanthomas is dependent on the duration and severity of the hyperlipoproteinemia; thus lesions occur more commonly in adults. When they do occur in children and adolescents, it is an indicator of greater severity. Although a specific diagnosis cannot be made solely on the basis of clinical signs, certain types of xanthomas are more characteristic of specific types of hyperlipidemias. In adults, lipoprotein disturbances may be early clues to other conditions such as diabetes mellitus, thyroid disease, or early atherosclerotic cardiovascular disease. Prompt diagnosis and treatment may help prevent complications such as pancreatitis and early coronary artery disease.684

680. Gabillot-Carre M, Lepelletier Y, Humbert M, et al. Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells. Blood. 2006;108:1065–1072. 681. Klaus SN, Winkelmann RK. Course of urticaria pigmentosa in children. Arch Dermatol. 1962;86:116. 682. Neri I, Guareschi E, Guerrini V, et al. Familial telangiectasia macularis eruptiva perstans. Pediatr Dermatol. 2005;22(5):488–489. 683. Parker F. Xanthomas and hyperlipidemias. J Am Acad Dermatol. 1985;13:1. 684. Maher-Wiese VL, Marmer EL, Grant-Kels JM. Xanthomas and the inherited hyperlipoproteinemias in children and adolescents. Pediatr Dermatol. 1990;7:166.

Diseases of the dermis and subcutaneous tissues

17

BOX 17.7 DISORDERS ASSOCIATED WITH XANTHOMAS

>> Lipoprotein lipase deficiency >> Type I glycogen storage disease (von Gierke’s disease) >> Familial hyperlipoproteinemia (type V) >> Diabetes mellitus >> Alcohol ingestion >> Retinoid-induced >> Estrogen-induced >> Familial hypertriglyceridemia (type IV) >> Hypothyroidism >> Nephrotic syndrome Tuberous

>> Familial dysbetalipoproteinemia (type III) >> Familial hypercholesterolemia >> Cerebrotendinous xanthomatosis >> β-sitosterolemia >> Hepatic cholestasis >> Normocholesterolemic dysbetalipoproteinemia Tuberoeruptive

>> Familial dysbetalipoproteinemia (type III) >> Hypothyroidism >> Secondary hyperlipoproteinemias Tendinous (seen with elevated LDL or altered LDL)

>> Familial hypercholesterolemia (heterozygous)

Epidemiology The epidemiology of xanthomas varies with the lipoprotein abnormality (Box 17.7).

Presenting history Patients or parents complain of yellow, soft, macular or slightly raised plaques located on characteristic areas of the body.685,686

Physical examination Tendinous xanthomas arise in tendons, ligaments, and fascia and present as deep smooth, nontender, firm nodules of various sizes that move with the affected tendon. The lesions are usually 1 cm or larger in size and are most frequently located on the Achilles tendons and the extensor tendons of the hands, knees, and elbows. They are seen with other forms of xanthomas and almost always indicate a disturbance of cholesterol metabolism.685

685. Cruz PD, East C, Bergstresser PR. Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol. 1988;19:95. 686. Haber C, Kwiterovich PO. Dyslipoproteinemia and xanthomatosis. Pediatr Dermatol. 1984;1:261.

>> Cerebrotendinous xanthomatosis >> β-sitosterolemia >> Hyperapobetalipoproteinemia >> Familial dysbetalipoproteinemia (type III) Planar

>> Homozygous familial hypercholesterolemia (especially intertriginous)

>> Familial dysbetalipoproteinemia (type III) (especially palmar creases)

>> Severe hepatic cholestasis >> Dysglobulinemias >> Paraproteinemias >> Leukemia >> Lymphoma >> Eosinophilic granulomatosis >> Rheumatoid arthritis

HYPERLIPIDEMIAS AND XANTHOMAS

Eruptive (seen with chylomicronemia)

Xanthelasmas

>> Familial dysbetalipoproteinemia (type III) >> Hypercholesterolemia >> Hepatic cholestasis >> Cerebrotendinous xanthomatosis >> β-sitosterolemia >> Hyperapobetalipoproteinemia >> Normolipemic states

Planar xanthomas present as soft yellow macules and slightly elevated papules and plaques located anywhere on the body, with a predilection for surgical or acne scars.244 There are several subtypes of planar xanthomas. The most common type, xanthelasma palpebrarum, occurs on the eyelids. Most patients with xanthelasmas are normolipemic, but abnormal lipoprotein levels may account for the appearance of these lesions and correspond to an increased tendency to develop atherosclerosis.687 When these do rarely occur in a child, diabetes mellitus, Langerhans cell histiocytosis, multiple myeloma, hepatic disorders, especially Alagille syndrome, or familial hyperlipidemia should be suspected. Corneal arcus is a translucent yellow infiltrate at the peripheral limbus of the cornea. The lesions begin in the lower or upper cornea and then become circumferential. Deposits consist of cholesterol, triglycerides, and phospholipids. Corneal arcus is associated with an increased incidence of atherosclerosis, especially when seen in patients younger than 50 years of age.688 Xanthoma striatum palmare lesions are flat, yellow to orange linear lesions in the creases of the palms and fingers. They are

687. Douste-Blazy P, Marcel YL, Cohen L, et al. Increased frequency of apo E-ND phenotype and hyperapobetalipoproteinemia in normolipidemic subjects with xanthelasmas of the eyelids. Ann Intern Med. 1982;96:164. 688. Rosenman RH, Brand RJ, Sholtz RI, et al. Relation of corneal arcus to cardiovascular risk factors and the incidence of coronary disease. N Engl J Med. 1974;291:1322.

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HYPERLIPIDEMIAS AND XANTHOMAS

1048

Reaction Patterns

Figure 17.25  Tuberous xanthomas on the elbow.

Figure 17.26  Plaques of xanthomas in a teenager with biliary atresia.

most commonly seen with type III hyperlipidemia, where an increase in cholesterol and triglyceride levels causes the deposition in these specific tissues. Tuberous xanthomas present as yellow or red nodules located mainly on the extensor surfaces of the extremities, buttocks, and palms (Fig. 17.25). They begin as small, soft papules, which may be confused with eruptive xanthomas; they enlarge and become coalescent and firm, but are not attached to underlying structures like tendinous xanthomas. They indicate an alteration of cholesterol and/or triglyceride metabolism. Atherosclerosis is more common in these patients. Eruptive xanthomas are small, yellow papules that frequently have an erythematous halo around the base. They range in size from 1 to 4 mm and erupt suddenly in crops over the extensor surfaces of the arms, legs, buttocks, and pressure points (Fig. 17.26). They may be associated with the chylomicronemia syndrome, lipemia retinalis (where the fundus appears pale pink secondary to large quantities of light-scattering chylomicrons coursing through the retinal vasculature), recent memory loss, abdominal pain, and occasionally acute pancreatitis.689 Eruptive xanthomas develop in patients who have markedly elevated tri­ glyceride levels, especially those with uncontrolled diabetes, in patients with type I, III, IV, and V hyperlipidemias, and in patients with the nephrotic syndrome.690 Xanthoma disseminatum is rare and usually occurs in adults.691 Distinctive papulonodular red-yellow lesions appear slowly and develop a dark mahogany hue with age. There is a predilection for the flexural creases, mucous membranes, central nervous system, corneas, conjunctivae, and occasionally bone. Lesions may be seen in the pharynx, larynx, and the bronchi. They may cause dysphagia, laryngeal obstruction, hoarseness, and dyspnea. When lesions are located in the central nervous system, they can

cause diabetes insipidus. Serum lipid concentrations are normal. This disorder is considered part of the spectrum of nonLangerhans cell histiocytosis. Cerebrotendinous xanthomatosis is a rare autosomal-recessive syndrome consisting of progressive mental retardation, cataracts, and cerebellar ataxia caused by mutations in the sterol-27 hydroxylase gene that results in a disturbance in the lipid storage process of cholestanol.692,693 The lipid accumulates in the skin, tendons, lungs, and cerebellar white matter. Early manifestations include chronic neonatal diarrhea and juvenile cataracts. Plasma cholesterol levels are usually normal, but blood cholestanol levels are increased. Phytosterolemia is a rare disorder in which tissue accumulation of plant sterols (β-sitosterol, campesterol, and stigmasterol) is caused by an increased absorption of plant sterols from the diet.694,695 It is caused by mutations in the ABCG5 or ABCG8 genes which are adjacent to each other on the short arm of chromosome 2. Cholesterol levels are either normal or slightly elevated, and tuberous and tendinous xanthomas are seen.

689. Brunzell JD, Bierman EL. Chylomicronemia syndrome. Med Clin North Am. 1982;66:455. 690. Teltscher J, Silverman RA, Stork J. Eruptive xanthomas in a child with the nephrotic syndrome. J Am Acad Dermatol. 1989;21:1147. 691. Mishkel MA, Cockshott P, Nazir DJ, et al. Xanthomas disseminatum. Arch Dermatol. 1977;113:1094. 692. Berginer VM, Gross B, Morad K, et al. Chronic diarrhea and juvenile cataracts: think cerebrotendinous xanthomatosis and treat. Pediatrics. 2009;123:143–147.

693. Bel S, Garcia-Patos V, Rodriguez L, et al. Cerebrotendinous xanthomatosis. J Am Acad Dermatol. 2001;45(2):292–295. 694. Lee MH, Lu K, Hazard S. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 2001; 2779–2783. 695. Sehayek E, Yu HJ, von Bergmann K, et al. Phytosterolemia on the island of Kosrae: founder effect for a novel ABCG8 mutation results in high carrier rate and increased plasma sterol levels. J Lipid Res. 2004;45:1608–1613.

Laboratory findings Cholesterol and triglyceride levels should be measured after having the patient fast for 14 h. Lipoprotein electrophoresis separates lipoproteins according to density; those with the greatest portion of protein have the highest density (e.g., high-density lipoproteins [HDL]). Specific patterns are used to classify the type of hyperlipidemia. To determine whether xanthomas are primary or secondary, ancillary tests for the evaluation of thyroid, liver, renal diseases, and diabetes should be performed. Plasma lipoproteins are composed of lipids (cholesterol, triglycerides, and phospholipids) and proteins called

Diseases of the dermis and subcutaneous tissues

Pathophysiology and histogenesis The histologic appearance of xanthomas is characterized by macrophages with foamy cytoplasm filled with lipid droplets.186 Lipoproteins permeate the walls of cutaneous capillaries and are phagocytized by histiocytes, where the lipids accumulate, and result in typical foam cells. Fat stains, such as scarlet red or Sudan red, demonstrate the lipids. Xanthoma cells usually have one nucleus but may have several. Multinucleated xanthoma cells have their nuclei arranged in a wreath-like pattern, or they may look like foreign body giant cells in which the nuclei are randomly scattered. Lymphocytes, histiocytes, and neutrophils may be seen. Accumulations of lipoproteins in the plasma can result from: (1) excessive endogenous production; (2) defective removal; (3) 696. Valente AM, Newburger JW, Lauer RM. Hyperlipidemia in children and adolescents. Am Heart J. 2001;142:433–439. 697. Thiers BH, Dobson RL. Pathogenesis of skin disease. ed 1. New York: Churchill Livingstone; 1986. 698. Parker F. Normocholesterolemic xanthomatosis. Arch Dermatol. 1986;122:1253. 699. Goldstein HL, Kita T, Brown MS. Defective lipoprotein receptors and atherosclerosis. N Engl J Med. 1983;309:288. 700. Kwiterovich PO. Recognition and management of dyslipidemia in children and adolescents. J Clin Endocrinol Metab. 2008;93(11):4200–4209. 701. Haney EM, Huffman LH, Bougatsos C, et al. Screening and treatment of lipid disorders in children and adolescents: systematic evidence review for the US Preventative Services Task Force. Pediatrics. 2007;120:e189–e214. 702. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34.

decreased lipoprotein breakdown; or (4) a combination of these mechanisms.699,700 Metabolic aberrations in lipoprotein metabolism may be seen as a primary manifestation of a specific genetic disorder, such as lipoprotein lipase deficiency, or as a secondary phenomenon associated with an underlying disease, such as diabetes mellitus, cholestatic liver disease, nephrosis, hypothyroidism, or pancreatitis. In addition, drugs such as estrogens, corticosteroids, isotretinoin, cyclosporine, and protease inhibitors used in HIV may cause lipoprotein abnormalities.701 The two sources of lipids from which circulating lipoproteins may be formed are exogenous dietary fats and endogenous fats synthesized by the liver. Reviews of lipid metabolism can be found in the literature and are recommended for in-depth probing into the pathogenesis of lipid disorders.683,700–703 Primary hyperlipoproteinemias have been classified into various types, based on specific lipoprotein patterns by paper electrophoretic separation and inheritance (Table 17.3).683,704 Familial hypercholesterolemia, lipoprotein lipase deficiency, and familial combined hyperlipidemia rarely present in childhood. Lipoprotein lipase deficiency is a rare recessively inherited disorder. Because of the absence of enzyme activity, there is defective removal of chylomicrons with resultant marked hypertriglyceridemia and either a type I or V pattern on electrophoresis, and hyperchylomicronemia. Clinically it presents before puberty with eruptive xanthomas, hepatosplenomegaly, lipemia retinalis, and pancreatitis.689,705 Apoprotein CII deficiency (lipoprotein lipase activator) presents in adolescence with a type I or V pattern. Xanthomas are not usually present. The deficiency results in the inability of lipoprotein lipase recognition, with subsequent nonclearing of chylomicrons from the circulation. Familial combined hyperlipidemia is responsible for 10% of premature coronary artery disease and reveals patterns of type IIa, IIb, IV, or V. It represents 30% of all genetic lipoproteinemias. Although seldom seen in childhood, it is associated with early coronary atherosclerosis and myocardial infarction and should be screened for in families who have early atherosclerosis.706 Childhood xanthomas associated with Alagille syndrome may be either the planar or eruptive type and may improve with time or treatment such as biliary diversion or liver transplant.707,708 This syndrome consists of a distinctive type of congenital cholestasis with intrahepatic ductular hypoplasia, pruritus, cardiac and major structural vessel anomalies, and a characteristic face with a prominent forehead, deep-set eyes, straight nose, and small pointed chin. Butterfly shaped vertebral defects, growth retardation, mental retardation, and hypogonadism have

HYPERLIPIDEMIAS AND XANTHOMAS

apolipoproteins. They are divided into five major classes based on physical and chemical properties. Lipoproteins transport fats in the blood by providing emulsifying properties, which help solubilize the hydrophobic lipids. Chylomicrons are the largest, least dense lipoproteins and contain mostly triglycerides (85%). Very low-density lipoproteins (VLDL) (pre-β-lipoproteins) are not as dense and carry 30% cholesterol and 50% triglyceride. Intermediate-density lipoproteins (IDL) (remnant lipoproteins) carry half cholesterol and half triglyceride. Low-density lipoproteins (LDL) (β-lipoproteins) are the major carriers of cholesterol (50%),696 and elevated levels of LDL can be correlated with premature development of atherosclerosis. HDL (α-lipoproteins) are very dense and contain half apoprotein. They have very little relevance to xanthomas but do play a role in atherosclerosis with increased levels of HDLs protecting against atherosclerosis. In addition to lipoproteins, 12 apoproteins have been identified in humans, and their deficiencies affect lipoprotein metabolism. In many cases, xanthomas are related directly to the degree of elevation in lipoprotein levels and can wax and wane in parallel to fluctuations in serum lipoprotein concentrations. For example, tendinous xanthomas arise when cholesterol levels reach >500 mg/dL.697 Planar xanthomas in obstructive liver disease are seen when plasma cholesterol exceeds 1800 mg/dL, and eruptive xanthomas require triglyceride levels to be >1000 mg/dL to manifest clinically. In rare instances, xanthomas can be seen with normal levels of cholesterol,698 in which case other disorders may be implicated, including the accumulation of plant sterols, cerebrotendinous xanthomatosis, and paraproteinemias or systemic diseases predisposing to the development of lesions, including local factors such as previously inflamed skin.

17

703. Acton S, Rigott A, Landschulz KT, et al. Identification of scavenger receptor SR-B1 as a high density lipoprotein receptor. Science. 1996;271:518–520. 704. Fredrickson DS, Lees RS. A system for phenotyping hyperlipoproteinemia. Circulation. 1965;31:321. 705. Eckel RH. Lipoprotein lipase. N Engl J Med. 1989;320:1060. 706. Cortner JA, Coates PM, Liacouras CA, et al. Familial combined hyperlipidemia in children: clinical expression, metabolic defects, and management. J Pediatr. 1993;123:177. 707. Weston CFM, Burton JL. Xanthomas in the Watson–Alagille syndrome. J Am Acad Dermatol. 1987;16:1117. 708. Schwartz Rehder K, Parsons DJ. et al. Intense pruritus and failure to thrive in Alagille syndrome. J Am Acad Dermatol. 2008;58:S9–11.

1049

1050

Eruptive

None reported

Uncommon

Eruptive

Eruptive

Palmar creases, tuberoeruptive, tuberous xanthelasma

Tendinous, tuberous, xanthelasma

Intertriginous, tendinous, tuberous, xanthelasma

Lipoprotein lipase deficiency

Apolipoprotein CII

Familial combined hyperlipidemia (type IIb and other patterns)

Familial hypertri-glyceridermia

Familial hyperlipoproteinemia (type V)

Familial dysbetalipoproteinemia (type III)

Familial hypercholesterolemia, heterozygous

Familial hypercholesterolemia, (type IIa), homozygous

50% of LDL receptors non-functional

No functional LDL receptors

LDL

Homozygous apolipoprotein E2 results in decreased remnant clearance; combined with overproduction of VLDL

Overproduction of VLDL and defect in catabolism of VLDL

Probably defect in catabolism of VLDL

Overproduction of VLDL

Absence of apolipoprotein CII

Deficiency of lipoprotein lipase

METABOLIC DEFECT

LDL

Chylomicrons and VLDL remnants (IDL)

VLDL and chylomicrons

VLDL

VLDL with or without LDL

Chylomicrons with or without VLDL

Chylomicrons

MAJOR LIPOPROTEINS

Autosomal dominant

Autosomal deficient

Autosomal dominant or genetically complex

Probably autosomal dominant

Autosomal dominant

Autosomal dominant

Autosomal recessive

Autosomal recessive

INHERITANCE

VLDL, very low-density lipoprotein; LDL, low-density lipoprotein; IDL, intermediate-density lipoprotein; chol, cholesterol; TG, triglyceride.

XANTHOMAS

DISORDER

Atherosclerosis; onset in first or second decade

Atherosclerosis; onset in males, fourth or fifth decade, in females, fifth or sixth decade

Premature atherosclerosis, especially peripheral vascular disease

Abdominal pain, pancreatitis, associated with diabetes, mellitus, hypertension, hyperuricemia, and polyneuropathy; cardiovascular

Possible premature atherosclerosis, occasional pancreatitis

Premature coronary artery disease with onset in males, in fifth or sixth decade; in females, later; teenagers may show evidence of atherosclerosis

Abdominal pain and pancreatitis

Hepatosplenomegaly, abdominal pain, pancreatitis, lipemia retinalis usually before puberty and lipemia

CLINICAL FEATURES

HYPERLIPIDEMIAS AND XANTHOMAS

Table 17.3  Primary hyperlipoproteinemias

Serum: clear Plasma chol >600 mg/dL Electrophoresis: type 2a

Serum: clear Plasma chol = 300–5000 mg/dL Electrophoresis: type 2a

Serum: usually clear Plasma TG >250 mg/dL and chol >250 mg/dL Electrophoresis: type 3

Serum: creamy supernatant, turbid infranatant Plasma TG >500 mg/dL Electrophoresis: type 5

Serum: may be tubed

Serum: usually clear Plasma TG >250 mg/dL and chol >250 mg/dL Electrophoresis: type 2a, type 2b, or type 4

Serum: creamy supernatant, with or without turbid infranatant Plasma TG >500 mg/dL Electrophoresis: type 1 or type 5

Serum: creamy supernatant Plasma TG >1000 mg/dL Electrophoresis: type 1

LABORATORY FEATURES

iv Reaction Patterns

Diseases of the dermis and subcutaneous tissues

Differential diagnosis Tendinous xanthomas may be confused with rheumatoid nodules or gouty tophi. Juvenile xanthogranulomas, Langerhans cell histiocytosis, nevus lipomatosis superficialis, and lipoid proteinosis may all have a yellowish nodular appearance, but they may be differentiated by skin biopsy. Tangier disease (familial HDL deficiency) manifests as enlarged tonsils with distinctive alternating bands of red, orange, yellow, and white striations overlying the normal red mucosa. A maculopapular eruption over the trunk, hepatosplenomegaly, lymphadenopathy, corneal arcus, and alterations of intestinal and rectal mucosa are seen. These patients have an abnormal apolipoprotein AI level, which causes an increased catabolism of HDLs and increased storage of cholesterol esters in body tissues.709

Therapy and prognosis The choice of treatment depends on the underlying lipoprotein abnormality. Diet is effective in most primary hyperlipoproteinemias, with the exception of familial hypercholesterolemia in which it is rarely helpful. Both the American Academy of Pediatrics and the American Heart Association have published policy statements on the screening of and drug treatment of lipid abnormalities in children and adolescents.710,711 The American Heart Association and the Department of Health and Human Services publish helpful booklets for patient education.712 Drugs that alter cholesterol and bile salt absorption, such as cholestyramine (cholestyramine) and colestipol, are useful in treating hypercholesterolemia.713 Cholestyramine (8–20 g/day) is given in divided doses bid or tid. These medications are not recommended in patients younger than age 6 years and longterm compliance is limited in many patients by undesirable gastrointestinal side-effects.713–715 Drugs that alter lipoprotein synthesis and metabolism, such as clofibrate (0.5–1.0 g bid), increase the clearance of VLDL and the activity of lipoprotein lipase and are useful in disorders of increased triglyceride production (types IV and V) and increased IDL levels (type III). However, they are less useful in hypercholesterolemia (types IIa and IIb). Nicotinic acid (niacin), given 100 mg tid, and gemfibrozil are useful in treating a wide variety

709. Assman G. Familial high density lipoprotein deficiency: Tangier disease. In: Scriver CR, ed. The metabolic basis of inherited disease. ed 7. New York: McGraw-Hill; 1995. 710. Daniels SR, Greer FR and the Committee on Nutrition. Lipid Screening and Cardiovascular Health in Childhood. Pediatrics. 2008;122:198–208. 711. Mcrindle BW, Urbina EM Dennison BA, et al. Drug therapy of high-risk lipid abnormalities in children and adolescents. Circulation. 2007;115:1948–1967. 712. de Ferranti S, Ludwig DS. Storm over statins – The controversy surrounding pharmacologic treatment of children. N Engl J Med. 2008;359(13):1309–1312. 713. Mabuchi H, Sakai T, Sakai Y, et al. Reduction of serum cholesterol in heterozygous patients with familial hypercholesterolemia. Additive effects of compactin and cholestyramine. N Engl J Med. 1983;308:609. 714. McCrindle BW, O’Neill MB, Cullen-Dean G, et al. Acceptability and compliance with two forms of cholestyramine in the treatment of

of hyperlipidemic disorders, particularly hypertriglyceridemia. They are not recommended for routine use in children because long-term safety and benefit have not been established.696 Nicotinic acid is the least expensive therapy but requires extensive patient education because of flushing, hypotension, and gastrointestinal side-effects. Pharmacologic treatment in children and adolescents with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) is approved for children 8 years of age or older710 with LDL ≥190 mg/dL or >160 mg/dL with a family history of early heart disease and more than two other risk factors. Although short-term trials have been successful and well tolerated in children, there are concerns over long-term safety and potential effects on normal brain development of children from long-term use.712 The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most potent agents for lowering LDL-cholesterol levels. They include lovastatin, pravastatin, simvastatin, and others. Although several small trials have shown efficacy in children similar to that found in adults, no long-term safety studies on prolonged treatment with statins in children have been published.696 Because statins are teratogenic, physicians must ascertain this risk in adolescent girls before commencing therapy. The prognosis depends on the type of hyperlipidemia and the successful management by diet and medication. Eruptive xanthomas tend to respond well to diet and drugs. Tendinous xanthomas and xanthelasmas seldom resolve with treatment. Xanthelasmas may be treated surgically. Certain genetic disorders of lipid metabolism are more common in children. It is important to identify these patients early to institute management of their disease to prevent premature atherosclerosis and coronary artery disease.

SARCOIDOSIS

been reported. The genetic defect is a mutation in Jagged-1 part of the Notch signaling pathway.708

17

SARCOIDOSIS Sarcoidosis is characterized by a T-cell-mediated granulomatous response at specific disease sites in the body.716 It is a common multisystem disorder with the pathologic picture of noncaseating granulomata.717 Sir Jonathan Hutchinson was probably the first physician to record a case of sarcoidosis in 1892.717–719 The first article in English was published by Boeck,720 who described a patient with nodules of the skin and lymphadenopathy in 1899. The histologic appearance of the lesions resembled sarcoma, and he named the disease ‘multiple benign sarcoid.’ In 1934, at the first international conference on sarcoidosis, the

hypercholesterolemia in children: a randomized, crossover trial. J Pediatr. 1997;130:266–273. 715. Tonstad S, Knudtzon J, Sivertsen M, et al. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr. 1996;129:42–49. 716. Iannuzzi MC, Rybicki B, Tierstein AS. Sarcoidosis. N Engl J Med. 2007;357:2153–2165. 717. Nunes H, Bouvry D, Soler P, et al. Sarcoidosis orphanet. J Rare Dis. 2007;2:46. 718. Hutchinson J. Recurring ophthalmitis with opacities in the vitreous Mabey’s malady. Arch Surg (Chicago). 1892;4:361. 719. Hutchinson J. Cases of Mortimer’s malady. Arch Surg (London). 1898;9:307. 720. Boeck C. Multiple benign sarcoid of the skin. J Cutan Genitourinary Dis. 1899;17:543.

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iv

Reaction Patterns

disease was designated a true entity.721 It primarily affects young adults and presents most frequently with bilateral hilar lymphadenopathy, pulmonary infiltration, and skin or eye lesions. The laboratory criteria for diagnosis should include evidence of noncaseating granulomata with negative stains for organisms or foreign bodies and/or a compatible chemical or radiographic picture.

Epidemiology

SARCOIDOSIS

Sarcoidosis is found worldwide but is more prevalent in developed countries.722 A survey of screening chest radiographs in England found an overall prevalence of 20 per 100 000 population.722 The highest incidence is found between ages 20 and 40 years. A Danish study reported a childhood incidence of 0.22–0.27 per 100 000, most commonly from 9 to 15 years of age and it is extremely rare in preschool children.723–725 Women are affected more commonly than men. Although most races are affected, it is more common in Scandinavians and blacks,722,726 and is seen particularly in the south-eastern USA, which is called the ‘sarcoid belt.’727 Although sarcoidosis has been described in families728,729 and in monozygotic twins,716 there is no consistent mode of inheritance.730 Specific HLA genotypes have been reported in patients with sarcoidosis but likely confer a predisposition to the disease phenotype rather than susceptability.731 Two genome-wide scans for loci associated with sarcoidosis have been reported, one in white Germans732 showing the strongest linkage signals at chromosomes 3p and 6p, and the second study in black Americans,730 with linkage signals at chromosomes 5p and 5q.

Presenting history The clinical symptoms of sarcoidosis are often nonspecific and one-third of patients will present with weight loss, fatigue, malaise, anorexia, and fever.723,733 Any organ system may be affected including skin, lungs, eyes, liver, spleen, lymph nodes, bones, muscles, and central nervous system. Extrathoracic

721. Kerdel FA, Moschella SL. Sarcoidosis. J Am Acad Dermatol. 1984;11:1. 722. James DG. Epidemiology of sarcoidosis. Sarcoidosis. 1992;9:79–87. 723. Hoffman AL, Milman N, Byg KE. Childhood sarcoidosis in Denmark 1979–2004; Incidence, clinical features and laboratory results at presentation in 48 children. Acta Paediatr. 1994;93:30–36. 724. Rasmussen JE. Sarcoidosis in young children. J Am Acad Dermatol. 1981;5:566. 725. Shetty AK, Gedalia A. Sarcoidosis in children. Curr Probl Pediatr. 2000;30:149–176. 726. English JC, Patel PJ, Greer KE. Sarcoidosis. J Am Acad Dermatol. 2001;44(5):725–743. 727. Abernathy RS. Childhood sarcoidosis in Arkansas. Southern Med J. 1985;78:435. 728. Rybicki BA, Harrington D, Major M, et al. Heterogeneity of familial risk in sarcoidosis. Genet Epidemiol. 1996;13:23–33. 729. Rybicki BA, Mallarik MJ, Major M, et al. Epidemiology, demographics and genetics of sarcoidosis. Semin Respir Infect. 1998;13:166–173. 730. Iannuzzi MC, Iyengar SK, Gray-McGuire C, et al. Genome-wide search for sarcoidosis susceptibility genes in African Americans. Genes Immun. 2005;6:509–518. 731. Voorter CE, Amicosante M, Berretta F, et al. HLA class II amino acid epitopes as susceptibility markers of sarcoidosis. Tissue Ant. 2007;70:18–27. 732. Schurmann M, Reichel P, Muller-Myhsok B, et al. Results from a genome wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care Med. 2001;164:840–846.

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involvement is more common in African-American patients.734 Twenty-five percent of patients have cutaneous involvement that can occur at any stage of the disease.726 The lung is the most common organ involved in adults.733,734 Pulmonary complaints range from a mild, dry cough to significant dyspnea. Pulmonary fibrosis, when it occurs, and upper respiratory tract involvement tend to correlate with the presence of chronic plaques on the skin, called lupus pernio.735,736 The eye is the second most common organ involved, with ocular findings in 25–80% of patients with systemic disease.737,738 Uveitis (iritis) can range from mild to severe. Conjunctival granulomas can be detected by biopsy in 33–55% of patients with eye involvement.739 Lacrimal gland involvement is also common.738 Keratitis, chorioretinitis, and glaucoma may lead to severe disease, resulting in partial or total blindness. Neurologic or central nervous system involvement is seen in about 5–10% of patients.716,740 Facial nerve paralysis, which is a common neurologic presentation in adults, is rare in children.725 Bone involvement is rare and usually affects the distal bones, such as the metacarpals, metatarsals, or phalanges, with asymptomatic small round lytic lesions found on radiographic examination.722 One-half of patients with osseous sarcoidosis have stiffness and pain. Generalized lymphadenopathy is common, with nontender, freely movable, slightly enlarged lymph nodes.716 Hepatic involvement is clinically apparent in one-third of patients, but granulomas can be detected by liver biopsy in 40–70% of patients.716 Splenic involvement occurs in 53% of patients. Patients may be asymptomatic or have massive splenic enlargement.741 This may be associated with extensive fibrotic changes in other organs and poor outcome.742 Cardiac sarcoidosis can result from either direct granulomatous infiltration, which can cause arrhythmias, or from congestive cardiac failure secondary to lung involvement. While serious cardiac dysfunction is detected in 5–10% of patients, up to 76% of patients will have cardiac involvement at autopsy.716 Sudden death can occur.743 Renal involvement is due to over-production of 1,25-dihydroxyvitamin D leading to increased intestinal absorption of calcium, enhanced bone resorption, and resultant hypercalciuria with or

733. ATS, ERS, WASOG. Statement on sarcoidosis: joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee, February 1999. Am J Respir Crit Care Med. 1999;160:736–755. 734. Johns CJ, Michelle TM. The clinical management of sarcoidosis: a 50-year experience at the Johns Hopkins Hospital. Medicine. 1999;78:65–111. 735. Mana J, Marcoval J, Graelis J, et al. Cutaneous involvement in sarcoidosis: relationship to systemic disease. Arch Dermatol. 1997;133:882–888. 736. Jorizzo JL, Koufman JA, Thompson JN, et al. Sarcoidosis of the upper respiratory tract in patients with nasal rim lesions: a pilot study. J Am Acad Dermatol. 1990;22:439. 737. Smith JA, Foster CS. Sarcoidosis and its ocular manifestations. Int Opthalmol Clin. 1996;36:109–125. 738. Bonfioli AA, Orefice F. Sarcoidosis. Semin Ophtalmol. 2005;20:177–182. 739. Nichols CW, Eagle RC, Yanoff M, et al. Conjunctival biopsy as an aid in the evaluation of the patient with suspected sarcoidosis. Ophthalmology. 1980;87:287. 740. Lower EE, Broderick JP, Brott TG, Baughman RP. Diagnosis and management of neurological sarcoidosis. Arch Intern Med. 1997;157:1864–1868. 741. Selroos O. Sarcoidosis of the spleen. Acta Med Scand. 1976;200:337. 742. Salazar A, Mana J, Corbella X, et al. Splenomegaly in sarcoidosis: a report of sixteen cases. Sarcoidosis. 1995;12:131–134. 743. Shammas RL, Movahed A. Sarcoidosis of the heart. Clin Cariol. 1993;16:462–472.

Diseases of the dermis and subcutaneous tissues

Physical examination Approximately 25% of patients with systemic sarcoidosis have cutaneous lesions.726 Sarcoidosis lesions are both specific, in which granulomas are found, and non-specific, with no granulomas. Although specific lesions may have characteristic features, no lesion is pathognomonic. The most common presentation is with red to yellowish-brown or violaceous flat-topped papules, nodules, and infiltrated plaques, sometimes in an annular configuration. Diascopy (examination with two glass slides pressed against a lesion) often reveals an apple-jelly color, characteristic of granulomata. Scaly, erythematous patches with palpable infiltrations may also be seen. Although lesions have a predilection for the face, nares, lips, and eyelids, any area of the body may be involved, including the mucous membranes, palms and soles.726 Granulomata may develop at the sites of old scars747 and venipuncture sites,748 and they may resemble keloids. Subcutaneous nodules, previously called Darier–Roussy sarcoidosis,749 demonstrate typical sarcoidal granulomas in the subcutaneous tissue on biopsy. This variant presents with painful nodules, usually 5–15 mm in size on the trunk and legs. Ichthyosiform sarcoid is usually seen on the lower extremities.750 Erythrodermic forms with erythema and scaling of the entire skin is an uncommon presentation of sarcoidosis. Hypopigmented lesions that may be localized or generalized have been described mainly in black patients.751,752 Other atypical specific cutaneous presentations of sarcoid include ulcerative, psoriasiform, verrucous, lichenoid and lupus erythematosus-like types.726

744. Nocton JJ, Stork JE, Jacobs G, et al. Sarcoidosis associated with nephrocalcinosis in young children. J Pediatr. 1992;121:937. 745. Lofgren S. Primary pulmonary sarcoidosis: early signs and symptoms. Acta Med Scand. 1953;145:424. 746. Liggett PE. Ocular sarcoidosis. Clin Dermatol. 1986;4:129–135. 747. Manz LA, Rodman OG. Reappearance of quiescent scars: sarcoidosis. Arch Dermatol. 1993;129:105–108. 748. Burgdorf WHC, Hoxtell EO, Bart BJ. Sarcoid granulomas in venipuncture sites. Cutis. 1979;24:52. 749. Vainsencher D, Winkelmann RK. Subcutaneous sarcoidosis. Arch Dermatol. 1984;120:1028. 750. Cather JC, Cohen PR. Ichthyosiform sarcoidosis. J Am Acad Dermatol. 1999;40:862–865. 751. Kouh YG, Goody HE, Luscombe HA. Ichthyosiform sarcoidosis. Arch Dermatol. 1978;114:100. 752. Alexis JB. Sarcoidosis presenting as cutaneous hypopigmentation with repeatedly negative skin biopsies. Int J Dermatol. 1994;33:44–45.

Figure 17.27  Erythematosus papules of juvenile papular sarcoid on the leg of a preschool child.

SARCOIDOSIS

without hypercalcemia.716 Ultimately, the process may result in nephrocalcinosis and renal failure. Renal involvement with nephrocalcinosis has been reported in children who developed symptoms of chronic erythema nodosum and fever in the first 2 years of life, followed by arthritis, iritis, and parotitis years later.744 Granulomas are found in the kidneys in 15–40% of patients but are thought to be less common in children. Sjögren syndrome (keratoconjunctivitis sicca with enlargement of the parotid and lacrimal glands) can be caused by sarcoidosis. Lofgren syndrome,745 consisting of erythema nodosum, uveitis, fever, and bilateral hilar adenopathy, tends to resolve spontaneously over a few weeks and carries a favorable prognosis.746 Heerfordt syndrome (uveoparotid fever) is characterized by uveitis, facial nerve palsy, fever, and parotid gland enlargement and may involve the central nervous system.

17

Non-specific lesions, including erythema nodosum, may be seen in 17% of patients with systemic sarcoidosis and are considered a manifestation of a hypersensitivity reaction. Erythema nodosum is an important favorable prognostic sign, with subsequent resolution of hilar lymphadenopathy in almost all cases.753 The combination of hilar lymphadenopathy and erythema nodosum is named Löfgren syndrome. Lupus pernio presents with chronic infiltrated violaceous plaques most commonly seen on the areas of the body exposed to cold, such as the nose, cheeks, and ears. It is associated with chronic upper respiratory tract involvement with sarcoidosis, and rarely resolves spontaneously.754,755 These lesions can cause marked deformity, with scarring and fibrosis.736

Juvenile papular sarcoid (preschool sarcoidosis, early onset sarcoidosis) Juvenile papular sarcoid is a subgroup of sarcoidosis presenting in children younger than 4 years of age, with a characteristic triad of skin, joint, and eye disease.724,756,757 Pulmonary disease is usually absent initially but may develop over time along with cardiac lesions.757,758 Skin manifestations are often the initial complaint with lesions appearing as typical small red-brown papules (Figs 17.27, 17.28). Frequently the lesions are generalized. The eruption is characterized by exacerbations and remissions but may resolve with scarring. Arthritis affects 60% of patients with non-painful fusiform swelling of the fingers and

753. Maná J, Salazar A, Manresa F. Clinical factors predicting persistence of activity in sarcoidosis: a multivariate analysis of 193 cases. Respiration. 1994;61:219–225. 754. Elgart ML. Cutaneous sarcoidosis: definitions and types of lesions. Clin Dermatol. 1986;4:35–45. 755. Spiteria MA, Matthey F, Gorton T, et al. Lupus pernio: a clinicoradiological study of thirty-five cases. Br J Dermatol. 1985;112:315–322. 756. Mallory SB, Paller AS, Ginsburg BC, et al. Sarcoidosis in children: differentiation from juvenile rheumatoid arthritis. Pediatr Dermatol. 1987;4:313. 757. Shetty AK, Gedalia A. Childhood sarcoidosis: A rare but fascinating disorder. Pediatric Rheumatology. 2008;6:16 doi10.1186/1546–0096–1186/1546–6–16. 758. Hafner R, Vogel P. Sarcoidosis of early onset. A challenge for the pediatric rheumatologist. Clin Exp Rheumatol. 1993;11:685–691.

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Reaction Patterns

15) in 50–90% of cases.760 Pulmonary lesions do not develop. The CARD 15 gene is located on chromosome 16.

Laboratory findings

SARCOIDOSIS

Figure 17.28  Erythematosus grouped papules of sarcoidosis on the face of a 6-year-old boy.

Figure 17.29  Swollen wrists, synovial thickening and fine papular eruption in a 5-year-old with sarcoid.

wrists with boggy synovial thickening (Fig. 17.29).758,759 The range of motion of the joints is usually not impaired, as it is in juvenile rheumatoid arthritis. Granulomatous anterior uveitis is common in this entity and may lead to blindness despite therapy.724 Blau syndrome, a rare autosomal-dominant disorder characterized by arthritis, uveitis, and skin lesions with noncaseating granulomas, may mimic early-onset sarcoidosis. Early onset sarcoidosis and Blau syndrome may represent the same disease since both entities share genetic mutations in the NOD2 (nucleotide binding oligomerization domain 2) gene, also known as caspase recruitment domain family member 15 (CARD

759. Hetherington S. Sarcoidosis in young children. Am J Dis Child. 1982;136:13. 760. Rose CD, Doyle TM, McIlvain-Simpson G, et al. Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis. J Rheumatol. 2005;32:373–375. 761. Sitzbach LE, James DG, Neville E, et al. Course and prognosis of sarcoidosis around the world. Am J Med. 1974;57:847. 762. Siltzbach LE. Qualities and behavior of satisfactory Kveim suspensions. Ann NY Acad Sci. 1976;278:665.

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There are no pathognomonic laboratory tests to substantiate the diagnosis of sarcoidosis. The most convincing diagnostic procedure is the histologic demonstration of non-caseating granulomas in tissue, in association with the clinical picture. Chest radiography reveals bilateral hilar adenopathy in up to 72% of cases and is highly suggestive of sarcoid.761 The Kveim–Siltzbach test is of historical interest as a diagnostic test for sarcoidosis with a reliability of up to 80% of patients with active disease.762 This test is not approved by the Food and Drug Administration and is no longer routinely performed726 A suspension of heat-sterilized human sarcoidal tissue is injected intradermally into the patient. Skin biopsy of a papule formed at the site of injection shows a non-caseating granulomas 4–6 weeks later.762 It is used in patients whose lesions are not easily accessible by biopsy who do not require immunosuppressive treatment in the 4-week waiting period for biopsy.716 Transient hypercalcemia can be seen in 7–24% of patients and may be associated with hypercalciuria.762 If persistent, renal damage may occur. An elevation of angiotensin-converting enzyme (ACE) concentration in two-thirds of patients was once considered to be specific for sarcoidosis.717 It has since been shown to be elevated in many granulomatous diseases.726 Although some studies have suggested the degree of enzyme level elevation may reflect disease activity, this may not always be the case.762,763 Although elevated in 60% of patients with sarcoidosis, ACE levels are generally not a useful guide of disease progression or therapeutic response.726 Chitotriosidase, a protein secreted by activated macrophages, has been reported to be elevated in juvenile sarcoidosis but its specificity is unknown.764 Polyclonal hyperglobulinemia with globulin levels above 3.5 g/100 mL is seen in 22.5–61% of patients, with the highest levels in black patients in the USA.761 Cutaneous anergy, demonstrated by decreased delayed-type hypersensitivity and poor reactivity to tuberculin, mumps, and pertussis antigens,722 is common. Eosinophilia of ≥6% is found in 50% of children with sarcoidosis.765

Pathophysiology and histogenesis Sarcoidosis has been regarded as a reaction pattern to an unknown infectious agent or allergen. Environmental, infectious, genetic, and immunologic hypotheses have been proposed.716 Many infectious agents have been implicated but never conclusively demonstrated. Bacterial infections, systemic fungi, mycobacteria, particularly Mycobacterium tuberculosis;766

763. Callen JP, Hanno R. Serum angiotensin-1-converting enzyme level in patients with cutaneous sarcoidal granulomas. Arch Dermatol. 1982;118:232. 764. Brunner J, Scholl-Bürgi S, Prelog M, et al. Chitotriosidase as a marker of disease activity in sarcoidosis. Rheumatol Int. 2007;27:1185–1186. 765. Di Alberti L, Piattelli A, Artese L, et al. Human herpesvirus 8 in sarcoid tissues. Lancet. 1997;350:1655–1661. 766. Popper HH, Klemen H, Hoefler G, Winter E. Presence of mycobacterial DNA in sarcoidosis. Hum Pathol. 1997;28:796–800.

Diseases of the dermis and subcutaneous tissues

767. Kon OM, du Bois RM. Mycobacteria and sarcoidosis. Thorax. 1997;52(suppl 3):547–551. 768. CDC. Sarcoidosis among US Navy enlisted men 1965–1993. MMWR Morb Mortal Wkly Rep. 1997;46:539–543. 769. Wahlstrom J, Katchar K, Wigzell H, et al. Analysis of intracellular cytokines in CD4+ and CD8+ lung and blood T-cells in sarcoidosis. Am J Respir Crit Care Med. 2001;163:115–121. 770. Zissel G, Prasse A, Muller-Querheim J. Sarcoidosis – immunopathogenetic concepts. Am J Respir Crit Care Med. 2007;28:3–14. 771. Winterbauer RH, Lammert J, Selland M, et al. Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis. Chest. 1993;104:352–361. 772. Bansal AS, Bruce J, Hogan PG, Allen RK. An assessment of peripheral immunity in patients with sarcoidosis using measurements of serum vitamin D3, cytokines and soluble CD23. Clin Exp Immunol. 1997;110:92–97. 773. Crystal RG. Sarcoidosis. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison’s principles of internal medicine. New York: McGraw-Hill; 1998:1922–1928.

Differential diagnosis Sarcoidosis is a diagnosis of exclusion; every patient with suspected sarcoidosis should have a thorough evaluation. Physical examination, a biochemical panel to measure hepatic and renal function, serum calcium, chest radiograph, ophthalmologic evaluation with slit-lamp examination, electrocardiogram, 24-h urine calcium determination, serum protein electrophoresis, and histologic tissue confirmation are useful in confirming the diagnosis. A biopsy should be performed on the most accessible involved tissue, whether it is skin, conjunctivae, lymph nodes, minor salivary glands, or lung. Pulmonary function tests should be performed for baseline measurement when indicated. Gallium scans have been shown to reflect the relative degree of inflammation within the parenchyma of the lungs, but lack specificity for sarcoidosis.716 Angiotensin-converting enzyme (ACE) levels have a false-positive rate of 10% and a false-negative rate of 40%.774 Cutaneous anergy should be evaluated with common recall antigens if indicated. Other diseases that can mimic sarcoidosis histologically are tuberculosis, berylliosis,775 and leprosy. Special stains, cultures, and the use of a polarizing microscope are useful in differentiating among these diseases.

SARCOIDOSIS

viruses;765 and inhaled chemicals or occupational antigens767,768 have all been studied, but none has been confirmed. Whatever the stimulus, the specific reaction pattern is induced in a genetically or otherwise predisposed host, probably to a persistent, poorly degradable antigen. Sarcoid remains a diagnosis of exclusion. The development of non-caseating granulomas occurs after local presentation of an antigen by macrophages to T lymphocytes, CD4 helper T cell type 1 (TH1) phenotype. Once mononuclear inflammatory cells accumulate in the target organ, macrophages aggregate and differentiate into epithelioid and multinucleated giant cells. Abundant CD4 cells are interspersed among these inflammatory cells. Over time, CD4 and CD8 lymphocytes, and to a lesser extent B lymphocytes, form a rim around the granuloma. In all but the earliest stages, a dense band of fibroblasts, mast cells, collagen fibres, and proteoglycans begins to encase the ball-like cluster of cells.716 Once compartmentalized, these CD4+ cells produce cytokines including IL-2, interferon-γ, IL-8, and TNF-α along with other immune effector cells including macrophages, and mast cells, that induce granuloma formation. The granulomas become hyalinized, due to a shift in cytokine profiles to that of TH2 CD4 T cells and produce IL-4,10 and 13 which causes a fibroproliferative response, and ultimate fibrosis.769 This fibrotic response can produce substantial and often irreversible organ dysfunction and destruction. Multiple dysfunctions of the immune system have been elucidated,770 but whether these are primary events or epiphenomena is not known. By biopsy or bronchoalveolar lavage, sarcoidosis in the lung shows an increased ratio of CD4/CD8 cells usually >3.5 to 1.771 The recruitment of CD25 regulatory T cells, a subgroup of CD4+ T cells from the peripheral blood, results in the development of anergy, by abolishing interleukin-2 production and strongly inhibiting T-cell proliferation. Anergy is seen in two-thirds of patients.772 Polyclonal hypergammaglobulinemia results from nonspecific induction of B-cell immunoglobulin production activated by the response of localized T cells.773 The histopathologic findings of the classical chronic cutaneous papules show circumscribed granulomas of epithelioid cells, with little or no caseation necrosis.186 Similar granulomas are seen in the lungs, bones, eyes, and any organ involved with sarcoidosis. Giant cells and inclusion bodies within the giant cells are frequently observed but are not necessary for the diagnosis.

17

Therapy and prognosis Although there is no specific cure for sarcoidosis, systemic corticosteroids help suppress the acute manifestations.776 Ideally, patients should be first observed without therapy due to the potential for spontaneous improvement which occurs in 60% of cases.777 Treatment should be targeted at alleviating symptoms and progressive disease which threatens organ dysfunction.716 A trial of corticosteroids is indicated for hypercalcemia, renal insufficiency, neurologic or endocrine disease, myocardial involvement, ocular disease, severe lung disease, and rapidly progressive disfiguring skin lesions.778–780 Oral prednisone in a dosage of 1 mg/kg per day is given initially725 and then tapered according to symptoms. The course of treatment is usually 6 months, but this should be modulated by the response and severity of the disease. Most skin lesions heal without scarring. Topical or intralesional corticosteroids are helpful in the treatment of skin lesions and ophthalmologic steroid preparations are effective in symptomatic eye disease.758 Other treatments that may control progression include indomethacin or allopurinol

774. Chesnutt AN. Enigmas in sarcoidosis. West J Med. 1995;162:519–526. 775. Muller-Quernheim J, Zissel G, Schopf R, et al. Differential diagnosis of berylliosis/sarcoidosis in a dental technician. Dtsch Med Wochenschr. 1996;121:1462–1466. 776. du Bois RM. Corticosteroids in sarcoidosis: friend or foe? Eur Respir J. 1994;7:1203–1209. 777. Gibson GJ, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax. 1996;51:238–247. 778. Sharma OP. Pulmonary sarcoidosis and corticosteroids. Am Rev Respir Dis. 1993;147:1598–1600. 779. Sclroos O. Treatment of sarcoidosis. Sarcoidosis. 1994;11:80–83. 780. Bagwell C, Rosen T. Cutaneous sarcoidosis therapy updated. J Am Acad Dermatol. 2007;56:69–83.

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for erythema nodosum, cutaneous lesions781,782 and arthritis; antimalarials for extensive skin lesions,783 and azathioprine, methotrexate, or chlorambucil784 as steroid-sparing agents. Thalidomide has been successful in several case reports.785–788 Isotretinoin may alleviate skin lesions, but does not alter lung disease effectively, and may worsen symptoms of Sjögren syndrome associated with sarcoidosis.787 Tetracyclines have shown mixed results.780 Cyclosporin has met with some success in skin and eye lesions but is disappointing in pulmonary disease.716 Infliximab has been shown to be useful in several studies of cutaneous sarcoidosis780 but a randomized trial showed only modest improvements in lung disease.716 Lung, heart and liver transplants have been performed in patients with sarcoidosis with survival rates similar to that for patients with other disorders. The natural history of sarcoidosis is highly variable in children and adults. The course and prognosis often correlate with the mode of onset.722,725 Acute forms tend to resolve spontaneously and have a good prognosis.777 Chronic, progressive sarcoidosis rarely involutes and tends to be more common in older patients with insidious onset. A poorer prognosis is associated with any of the following: black race, chronic cutaneous plaques, lupus pernio, symptoms that last for longer than 6 months, involve-

ment of more than three organ system, and later stage pulmonary disease.753 The disease is chronic and progressive in 10–20% of patients. The mortality rate is reported to be about 1–5%.733 The degree of organ involvement affects the amount of physical activity the patient is able to perform. If significant lung involvement is encountered, sports activities may have to be curtailed. If cutaneous lesions are persistent, psychosocial considerations should be addressed. Juvenile papular sarcoidosis is seen exclusively in the pediatric age group and has unique features. Corticosteroid usage in childhood can affect growth and should be managed carefully. Severe eye involvement may lead to partial or total blindness and must be followed closely. Because this is a potentially life-threatening disease and because of both its chronicity and variability, care should be orchestrated by a variety of informed specialists including pulmonologists, immunologists, rheumatologists, ophthalmologists, and dermatologists.

781. Brechtel B, Hass N, Henz BM, et al. Allopurinol: a therapeutic alternative for disseminated cutaneous sarcoidosis. Br J Dermatol. 1996;135:307–309. 782. Voelter-Mahlknecht S, Benex A, Metzger S, et al. Treatment of subcutaneous sarcoidosis with allopurinol. Arch Dermatol. 1999;135:1560–1561. 783. Zic JA, Horowitz DH, Arzubiaga C, et al. Treatment of cutaneous sarcoidosis with chloroquine. Review of the literature. Arch Dermatol. 1991;127:1034. 784. Baughman RP, Lower EE. Steroid-sparing alternative treatments for sarcoidosis. Clin Chest Med. 1997;18:853–864.

785. Rousseau L, Beylot-Barry M, Doutre MS, et al. Cutaneous sarcoidosis successfully treated with low doses of thalidomide. Arch Dermatol. 1998;134:1045–1046. 786. Grasland A, Pouchot J, Chaumaiziere D, et al. Effectiveness of thalidomide treatment during cutaneous sarcoidosis. Rev Med Intern. 1998;19:208–209. 787. Waldinger TP, Ellis CN, Quint K, et al. Treatment of cutaneous sarcoidosis with isotretinoin. Arch Dermatol. 1983;119:1003. 788. Lee JB, Koblenzer PS. Disfiguring cutaneous manifestation of sarcoidosis treated with thalidomide: a case report. J Am Acad Dermatol. 1998;39:835–838.

ACKNOWLEDGMENTS The editors gratefully acknowledge contributions by Dr William Weston, and Dr Susan Mallory that were retained from the first three editions of Pediatric Dermatology.

Mary K. Spraker, Leslie P. Lawley and Elizabeth Alvarez Connelly

This chapter covers a variety of conditions that are characterized by sclerosis and atrophy. The term sclerosis means induration or hardening and is taken from the Greek word for hardness, sclerosis. Either the subcutaneous tissues and/or the dermis is indurated or sclerotic. Sclerosis is readily detected by palpation. The skin feels taut, unyielding, and thickened. The term atrophy is derived from the Greek and means ‘wasting away’ or ‘diminution in size.’ Atrophy refers to changes in the epidermis, the dermis, and subcutaneous fat. In contrast to sclerosis, atrophy is diagnosed with the eye rather than by palpation. The classic morphologic finding of epidermal atrophy is loss of the normal skin markings, which are replaced by fine ‘cigarette paper wrinkling,’ best seen when the skin is gently squeezed. The skin may also have a translucent appearance with visible prominence of the underlying vasculature. When the dermis or subcutaneous tissues are atrophic, the skin contour is depressed.

18



from the Mayo Clinic was used by an international consensus group in their retrospective study of 750 children with localized scleroderma.4,5 This latter classification is shown in Box 18.2. When morphea lesions are small and numerous, they are called guttate and the lesions are white. When large plaques are located in different anatomic locations and numerous lesions are present, the patient is said to have the generalized form of morphea. If dermal atrophy occurs without sclerosis, the patients may have atrophoderma of Pasini and Pierini.

Epidemiology

Morphea is a connective tissue disorder of unknown etiology, characterized by sclerosis of the skin and subcutaneous tissues. Because morphea and scleroderma share the same histology, morphea was previously classified as a subset of scleroderma localized to the skin, and called ‘localized cutaneous scleroderma.’ Since systemic involvement rarely occurs in morphea, many clinicians prefer to avoid the term scleroderma completely and instead call the condition ‘morphea.’ There are a number of reviews on the subject.1–3 Progressive systemic sclerosis is discussed in Chapter 23. There are many clinical variants of morphea which are classified according to the distribution and pattern of the disease (Box 18.1). Another classification scheme devised by authors

Morphea is an uncommon disease. Schachner et al.’s analysis of referrals to a pediatric dermatology clinic estimates that only three of 1578 patients (0.19%) seen over a 2-year period had morphea.7 The author states that morphea has become much more frequent in his practice, and now represents over 1% of all office visits (Schachner, pers comm, 2009). In a report from Mexico City (Lourdes Tamayo, Department of Dermatology, National Institute of Pediatrics, Mexico City, pers comm, 2000), 68 children were diagnosed with morphea over a 30-year period (1971–2000). This represents 0.18% of dermatologic patients seen, which is similar to Schachner’s original estimate. Of the 68 cases, 26 were linear (38.2%); 15 were en coup de sabre (22.1%); 14 cases were plaque type (20.6%); nine had generalized morphea (13.2%); and four had the pansclerotic form (5.9%). Girls were more likely to be affected than boys by a ratio of 3 : 1. A retrospective study from France of 70 children showed similar findings.8 In a study conducted on 30 patients at the Hospital for Sick Children in Toronto, 18 were female and 12 were male (ratio 1.5 : 1).1 Linear morphea affected 87% (including en coup de sabre), plaque morphea occurred in 10%, and generalized morphea in one patient (3%). A recent retrospective chart review of 136 children with morphea from one center over 17 years

1.

5.

MORPHEA INTRODUCTION

2. 3. 4.

Uziel Y, Krafchik BR, Silverman ED, et al. Localized scleroderma in childhood: a report of 30 cases. Semin Arthritis Rheum. 1994;23: 328–340. Krafchik BR. Localized cutaneous scleroderma. Semin Dermatol. 1992;11:65–72. Nelson AM. Localized scleroderma including morphea, linear scleroderma, and eosinophilic fasciitis. Curr Probl Pediatr. 1996;26:318–324. Christen-Zaech S, Hakim MD, Afsar FS, et al. Pediatric morphea (localized scleroderma): review of 136 patients. J Am Acad Dermatol. 2008;59:385–396.

MORPHEA

Sclerosing and atrophying conditions

6. 7. 8.

Zulian F, Athreya BH, Laxer R, et al. Juvenile Scleroderma Working Group of the Pediatric Rheumatology European Society (PRES). Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An International Study. Rheumatology (Oxford). 2006;45:614–620. Petersen LS, Nelson AM, Su WPD. Classification of morphea (localized scleroderma). Mayo Clin Proc. 1995;70:1068–1076. Schachner L, Ling NS, Press S. A statistical analysis of a pediatric dermatology clinic. Pediatr Dermatol. 1983;1:157. Bodemer C, Belon M, Hamel-Teilac D, et al. Scleroderma in children: a retrospective study of 70 cases. Ann Dermatol Venereol. 1999;126:691–694.

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BOX 18.1 A TRADITIONAL CLASSIFICATION OF MORPHEA 1. Morphea en plaque

– – – –

Guttate Plaque Bullous Keloidal

2. Linear morphea

– – –

Linear En coup de sabre Parry–Romberg disease (progressive facial hemiatrophy)

3. Generalized MORPHEA

4. Pansclerotic 5. Eosinophilic fasciitis 6. Atrophoderma of Pasini and Pierini 7. Lipoatrophy

BOX 18.2 MAYO CLASSIFICATION OF MORPHEA6 1. Plaque 2. Generalized 3. Bullous 4. Linear – Linear

– –

En coup de sabre Progressive hemifacial atrophy (Parry–Romberg)

5. Deep – Subcutaneous

– – –

Morphea profunda Disabling pansclerotic morphea Eosinophilic fasciitis

revealed that 51.4% had linear morphea (of which 54% affected the trunk and/or limbs and 23% affected the face and head); 37% had plaque type morphea; 9% were diagnosed with generalized morphea and 4% with morphea profunda. Female to male ratio was 2.42 : 1.4 Another multinational multicenter study reported 750 children with morphea. Linear morphea was the most frequent subtype affecting 65% of the study population, followed by plaque morphea occurring in 26%, while generalized and deep morphea affected 7% and 2%, respectively. The female to male ratio was 2.4 : 1.5

History Children with morphea report the insidious onset of a gradually enlarging plaque(s). There are usually no symptoms of skin pain 9.

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Kakimoto CV, Victor Ross E, Uebelhoer NS. En coup de sabre presenting as a port-wine stain previously treated with pulsed dye laser. Dermatol Surg. 2009;35:165–167.

Figure 18.1  Plaque-like, indurated, shiny lesion of morphea. (Courtesy of Dr A. Torrelo.)

or significant pruritus, but the skin may feel tight or ‘bound down,’ especially if the morphea occurs over a joint. In linear morphea, some patients complain of intermittent cramping of the affected limb and in some instances, the child or parent may note joint contractures with decreased range of motion. Parents may first notice the lesions after a traumatic event. In two large case series, possible triggers were described in 13% of patients, mechanical insults being the most commonly reported (67%), followed by infection (25%), drugs (5%) and psychological stress (3%).4,5 Additionally, there have been cases reported of morphea arising in a previously diagnosed vascular lesion such as a port-wine stain or salmon patch.9–11

Physical examination In plaque morphea, there are erythematous, violaceous, indurated plaques, several centimeters in diameter (Fig. 18.1). These lesions are found most commonly on the trunk but may be seen on the extremities, head, and neck. Over time, the central erythema fades, leaving a violaceous border with a white center and in weeks to months, the center may become shiny, firm, waxy, and white to yellow-white. Plaques of morphea are devoid of hair and sweating is absent. Not infrequently, there is associated subcutaneous sclerosis, or at a later stage, atrophy, as abnormal collagen fibers replace the subcutaneous fat. When activity ceases, the red violaceous border fades and a tan hyperpigmentation develops which may represent post-inflammatory changes. Linear morphea (LM) usually affects an extremity, most commonly a leg followed by an arm (Fig. 18.2), but lesions may also affect the thorax, abdomen, or buttocks. Occasionally, linear and plaque forms are both present in the same patient. Linear lesions are usually unilateral, but occasionally bilateral lesions occur. The condition may involve underlying muscle and occasionally bone. Lesions are initially erythematous or violaceous and can 10. Nijhawan R, Bard S, Blyumin M, et al. Early localized morphea mimicking an acquired port-wine stain. J Am Acad Dermatol. 2010;in press. 11. Zulian F, Vallongo C, de Oliveira SK, et al. Congenital localized scleroderma. J Pediatr. 2006;149:248–251.

Sclerosing and atrophying conditions

18

Figure 18.2  (A) In this child with linear morphea,

MORPHEA

white sclerotic bands extend along the length of the arm. (B) Similar changes, with dark sclerotic bands on the lower limb. (B, courtesy of Dr A. Torrelo.)

B

A

be mistaken for cellulitis. They gradually lose their pink color centrally, causing the plaques to have a white shiny center with a violaceous edge. The white centers are often atrophic, or thickened, yellow-white and sclerotic. Linear lesions typically extend along the length of an extremity, possibly following the lines of Blaschko (Fig. 18.3). Severe tightening of the skin over a joint may lead to flexion contractures. If the affected leg becomes shortened, compensatory scoliosis occurs. When LM involves the frontoparietal area, the eponym en coup de sabre is given as the deformity resembles the scar from a saber cut (Fig. 18.4). An ivory sclerotic plaque with peripheral hyperpigmentation appears on the forehead and may extend into the scalp where it causes a linear area of alopecia. En coup de sabre also has a Blaschko line distribution. Sometimes the forehead area alone is involved, but the lesion may extend forward to the nose, cheek, chin, and neck. There are several reports of bilateral en coup de sabre morphea.12 One case report13 described unilateral eyelid erythema and edema preceding the development of en coup de sabre by 8 months. En coup de sabre can occasionally be associated with central nervous system symptoms and signs including headaches, seizures, hemiparesis,14 and eye changes.15,16 Some authors consider progressive 12. Rai R, Handa S, Gupta S, et al. Bilateral en coup de sabre – a rare entity. Pediatr Dermatol. 2000;17:222–224. 13. Long PR, Miller OF. Linear scleroderma: report of a case presenting as persistent unilateral eyelid edema. J Am Acad Dermatol. 1982; 7:541.

Figure 18.3  Subcutaneous atrophy may accompany linear morphea. (Courtesy of Dr A. Torrelo.)

facial hemiatrophy (Parry–Romberg syndrome) to be a variant of en coup de sabre; in this condition atrophy is a more prominent feature than sclerosis and the disease process occurs on the lower rather than on the upper face. (Parry–Romberg syndrome is discussed below.) 14. Higashi Y, Kanekura T, Fukumaru K, et al. Scleroderma en coup de sabre with central nervous system involvement. J Dermatol. 2000;27:486–488. 15. Muchnick RS, Aston SJ, Rees TD. Ocular manifestations and treatment of hemifacial atrophy. Am J Opththalmol. 1979;88:889–897. 16. Holland KE, Steffes B, Nocton JJ, et al. Pediatrics. 2006;117:e132–e136.

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MORPHEA

A

Figure 18.4  The ivory sclerotic band of en coup de sabre morphea results in a vertical depressed linear band on the forehead.

There is a rare severe form of morphea called disabling pansclerotic morphea of children (DMPC)17 (Fig. 18.5). In contrast with the other types that are self-limited, this disease has a relentless course. It usually begins with symmetrical bilateral morphea lesions on the distal extremities that gradually extend longitudinally and circumferentially. Over time, the trunk and neck may also become affected. The disorder differs from other forms of morphea in that in addition to sclerosis of the skin and subcutaneous tissues, the deeper structures including the tendons, fascia, and muscles are involved, producing marked contraction and secondary joint deformity and fixation. Associated hypo­ gammaglobulinemia, lung fibrosis, and esophageal dysmotility have been reported.17 A progressive cardiomyopathy was described in a child who had large ulcerations within the sclerotic plaques on the legs.18 Loss of limb function and amputation are sequelae in severe forms. In disabling pansclerotic morphea, Raynaud’s phenomenon and other physical signs of systemic sclerosis are absent.

B

Associated findings In one series of 68 patients with localized forms of morphea, 32 (47%) had demonstrable anomalies of the vertebral column.19 Most of these changes occurred in the patients with LM. The most common abnormality was spina bifida occulta. There is one report of elastosis perforans serpiginosa occurring within a plaque of morphea located in the antecubital area of a teenager.20 In a recent series4 of 136 children with morphea, three patients (2.2%) had scoliosis or thorax asymmetry and 27 patients (19.9%) reported arthralgias and/or myalgias; 10.2%

17. Diaz-Perez JL, Connolly SM, Winkelmann RK. Disabling pansclerotic morphea of children. Arch Dermatol. 1980;116:169. 18. Wollina U, Looks A, Uhlemann C, et al. Pansclerotic morphea of childhood – follow-up over 6 years. Pediatr Dermatol. 1999;16:245–247.

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Figure 18.5  (A) Chronic sclerotic plaques of the trunk found in disabling pansclerotic morphea of children. (B) Clawing and ulceration of the hand in disabling pansclerotic morphea of children. (C) Late lesions, a chronic ulcerated sclerotic plaque on the leg. All from: Wollina U, Buslau M, et al. Disabling pansclerotic morphea of childhood. Exp Rev Dermatol 2007;2:775–784.   © 2007 Expert Reviews Ltd.

19. Christianson HB, Dorsey CS, O’Leary PA, et al. Localized scleroderma: a clinical study of 235 cases. Arch Dermatol. 1956;74:629. 20. Barr RJ, Seigel JM, Graham JH. Elastosis perforans serpiginosa associated with morphea. J Am Acad Dermatol. 1980;3:19.

Sclerosing and atrophying conditions

Laboratory findings There are no specific laboratory tests that confirm the clinical diagnosis of morphea, but elevations in serum antinuclear antibodies (ANA) and rheumatoid factor (RF) are often present. Elevated RF is detected in approximately 16% of patients (Schachner, pers comm, 2009). The frequency of abnormal ANAs varies in studies from 25% to 59%, being higher in LM.4,5,21 Patterns of ANA vary, the majority being speckled or homogeneous, but nucleolar patterns may also occur.22,23 High titers to single-stranded DNA may be seen, especially in patients with more extensive cutaneous lesions and prolonged disease duration.22 Anti-histone antibodies (against histone H1 and H3) have been correlated with the presence of anti-single-strandedDNA antibodies and both levels are associated with increased disease severity.24–26 Anti-topoisomerase I antibodies, a marker for systemic scleroderma, are not detected and if present indicate progressive systemic sclerosis.3 Anti-Ku antibody (novel DNAbinding protein) was found in one patient with localized morphea who subsequently developed systemic sclerosis and probably had progressive systemic sclerosis at the outset.27 Autoantibodies to fibrillin I have been found in patients with localized plaque morphea and LM.28 The serum concentration of procollagen type I carboxyterminal propeptide (P1cp) correlates with the number of sclerotic lesions in morphea, as does the anti-single-stranded DNA and anti-histone antibodies.29 There is no evidence that any of these laboratory markers plays a role in the pathogenesis or prognosis of the disease. Eosinophilia may be present in localized morphea, occurring in 7–18% of patients, more commonly in those with generalized morphea.4,5,23,30 Acute phase reactants, such as WBC, ESR and

21. Falanga V. Fibrosing conditions in childhood. Adv Dermatol. 1991; 6:145. 22. Falanga V, Medsger TA Jr, Reichlin M, et al. Linear scleroderma. Clinical spectrum, prognosis, and laboratory abnormalities. Ann Intern Med. 1986;104:849. 23. Rosenberg AM, Uziel Y, Krafchik BR, et al. Antinuclear antibodies in children with localized scleroderma. Rheumatol. 1995;22:2337–2343. 24. Sato S, Ihn H, Soma Y, et al. Antihistone antibodies in patients with localized scleroderma. Arthritis Rheum. 1993;36:1137–1141. 25. Ruffatti A, Peserico A, Rondinone R, et al. Prevalence and characteristic of anti-single-stranded DNA antibodies in localized scleroderma. Arch Dermatol. 1991;127:1180–1183. 26. Arkachaisri T, Fertig N, Pino S, et al. Serum autoantibodies and their clinical associations in patients with childhood- and adult-onset linear scleroderma. A single-center study. J Rheumatol. 2008;35:2439–2444. 27. Birdi N, Laxer RM, Thorner P, et al. Localized scleroderma progressing to systemic disease. Arthritis Rheum. 1993;36:410. 28. Arnett FC, Tan FK, Uziel Y, et al. Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin 1, in patients with localized scleroderma. Arthritis Rheum. 1999;42:2656–2659.

CRP, are elevated mainly in deep morphea, especially eosinophilic fasciitis. (Deep morphea is defined by the Pediatric Rheumatology European Society working group on juvenile scleroderma as subcutaneous morphea, morphea profunda, dis­ abling pansclerotic morphea, and eosinophilic fasciitis).5 An increased ESR was seen in 22% of patients with LS and in less than 10% of patients with other types of morphea.5 Similarly, ANAs were present in 47% of patients with LM, 43% with deep morphea and 31–34% of patients with generalized or plaque type.5 Serum IgG was found to be increased in LM and deep morphea (21% and 56% of patients, respectively), IgA was elevated in deep morphea (19%) and IgM was elevated in LM (16%).5 In disabling pansclerotic morphea, laboratory abnormalities are frequently present. Eosinophilia and an increased IgG are seen in most pansclerotic patients and some patients have an elevated erythrocyte sedimentation rate and a positive ANA titer.17 Magnetic resonance imaging (MRI) and/or computed tomography (CT) imaging abnormalities have been reported to be useful in en coup de sabre morphea and Parry–Romberg disease.31 Changes seen include the clinically apparent atrophy of soft tissue and bone, but intracranial calcification and white matter abnormalities in the ipsilateral frontal and parietal lobes have also been reported.31 High resolution ultrasound may be an alternative mode of investigation.

MORPHEA

had central nervous system involvement with headaches being the most common feature, predominantly in en coup de sabre. Four patients had seizures, one patient suffered a stroke and one developed a peripheral neuropathy. Seven patients experienced dysphagia and abdominal pain, and reflux was seen on barium swallow in three of those patients. Six patients experienced dyspnea, two of whom developed evidence of restrictive pulmonary disease. A second autoimmune disease was noted in 13 patients (9.6%). In another series of 750 pediatric patients, 91 (12.1%) reported a family history of autoimmune disease in a first or second degree relative.5

18

Pathophysiology The cause of morphea is unknown. It has been postulated that the underlying process involves abnormalities in the metabolism and turnover of collagen, as evidenced by increases in collagen III production.32 The resemblance and overlap with other collagen vascular diseases suggest an autoimmune cause. Factors such as trauma and infection have been suggested as trigger factors in LM.33 Some authors consider morphea to be the result of an infection with a Borrelia organism because in some cases, antibodies to this organism have been found, particularly in European patients.34 Organisms that are identical or very similar to those seen in Lyme disease have been seen in some skin biopsy samples,35 and some patients improve with antibiotic therapy.35 Skin biopsies from patients with morphea in western Turkey tested positive with polymerase chain reaction (PCR) for Borrelia

29. Vuorio T, Kahari VM, Black C, et al. Expression of osteonectin, decorin and transforming growth factor-beta 1 genes in fibroblasts cultured from patients with systemic sclerosis and morphea. J Rheumatol. 1991;18:247–251. 30. Giardano M, Ara M, Valentini G, et al. Presence of eosinophilia in progressive systemic sclerosis and localized scleroderma. Arch Dermatol Res. 1981;271:411–417. 31. Liu P, Uziel Y, Chuang S, et al. Localized scleroderma: imaging features. Pediatr Radiol. 1994;24:207–209. 32. Rahbari H. Histochemical differentiation of localized morphea, scleroderma and lichen sclerosus et atrophicus. J Cutan Pathol. 1989;16:342. 33. Yamanaka CT, Gibbs NF. Trauma-induced linear scleroderma. Cutis. 1999;63:29–32. 34. Buechner SA, Winkelmann RK, Lautenschlager S, et al. Localized scleroderma associated with Borrelia burgdorferi infection: clinical, histologic, and immunohistochemical observations. J Am Acad Dermatol. 1993;29:190. 35. Abele DC, Anders KH. The many faces and phases of borreliosis II. J Am Acad Dermatol. 1990;23(3 Pt 1):401–410.

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burgdorferi.36 Skin biopsies from patients with morphea and lichen sclerosus in the USA, Japan, and Germany were tested for Borrelia species with PCR assays; some of the German and Japanese but none of the American samples were positive.37 Other authors have also found a lack of evidence for Borrelia in the USA.38,39 Interpretation of the positive PCR testing results is controversial.

Histogenesis

MORPHEA

Jablonska has described the characteristic histologic features in the different variants of morphea (see later). In the early inflammatory stage, there is dermal edema with swelling and degeneration of collagen fibrils and lymphocytic infiltrates around dermal vessels and appendages. This is followed by a progressive increase in dermal thickness with condensation of collagen, loss of appendages, and fragmentation of elastic fibers. There is homo­ genization of collagen bundles parallel to the skin and hyalinized connective tissue may replace subcutaneous fat. Calcification, myositis, myofibrosis, and IgM and C3 perivascular deposits may be found in LM.40 In a small series of pediatric patients with morphea, increased telangiectatic vessels without edema or inflammation early in the disease course were found. These changes may represent the earliest stage of morphea, preceding the characteristic inflammatory and sclerotic phases.10

Differential diagnosis The clinical diagnosis is usually not difficult. The indurated lesions of morphea must be distinguished from eosinophilic fasciitis and scleredema of Buschke. In eosinophilic fasciitis, a linear area of erythema, swelling, pain, and induration develops on an extremity, or occasionally on the trunk. There is blood eosinophilia of 30–70%.41 A deep skin biopsy that includes fascia shows dermal sclerosis and thickening of the deep fascia from inflammation with plasma cells, histiocytes, and eosinophils. Later, there is fibrosis of the fat and fascia. The condition improves with systemic corticosteroids. Eosinophilic fasciitis may be a morphea variant that differs from classic morphea by the acute onset of erythema and pain, the fascial involvement, and the response to corticosteroids. Eosinophilic fasciitis as well as morphea can be mistakenly diagnosed as acute cellulitis. Scleredema of Buschke differs from morphea by its location on the back of the neck or face and the presence on biopsy of acid mucopolysaccharides in the dermis rather than sclerosis. Morphea may be morphologically indistinguishable from the lesions of lichen sclerosus, and both diseases may co-exist in the same patient. This occurs frequently enough that some believe

36. Ozkan S, Atabey N, Fetil E, et al. Evidence for Borrelia burgdorferi in morphea and lichen sclerosus. Int J Dermatol. 2000;39:278–283. 37. Fujiwara H, Fujiwara K, Hashimoto K, et al. Detection of Borrelia burgdorferi DNA (B garinii or B afzelii) in morphea and lichen sclerosus et atrophicus tissues of German and Japanese but not of US patients. Arch Dermatol. 1997;133:41–44. 38. Raguin G, Boisnic S, Souteyrand P, et al. No evidence for spirochaetal origin of localized scleroderma. Br J Dermatol. 1982;127:218. 39. De Vito J, Merogi A, Vo T, et al. Role of Borrelia burgdorferi in the pathogenesis of morphea/scleroderma and lichen sclerosus et atrophicus: a PCR study of thirty-five cases. J Cutaneous Pathology. 1996;23:350–358. 40. Vincent F, Prokopetz R, Miller RAW. Plasma cell panniculitis: a unique clinical and pathologic presentation of linear scleroderma. J Am Acad Dermatol. 1989;21:357–360.

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that they are variants of the same disease. The appearance of lichen sclerosus results from atrophy of the epidermis. Depigmented white areas are seen in vitiligo and indeterminate leprosy, but in these diseases, the skin is not indurated. Early plaques of morphea may resemble the violaceous erythema seen in cutaneous polyarteritis nodosa and in fixed and gyrate erythemas. Lesions may be identical to the depressed, slightly hyperpigmented lesions of atrophoderma of Pasini and Pierini (see Fig. 18.9); some authors consider the latter to be a form of morphea.42 The residual hyperpigmentation seen in resolving morphea lesions may be difficult to diagnose from other causes of postinflammatory hyperpigmentation without the history of previous induration. Other causes of subcutaneous atrophy, such as corticosteroid or vitamin K injection,43 panniculitis, and lipoatrophy may be confused with morphea. A morphea-like reaction has been reported in patients treated with D-penicillamine.44 Cutaneous morphea-like lesions in untreated phenylketonuria have been reported.45 In the report, a 10-month-old female infant developed progressive sclerodermatous changes of the legs and upper trunk, with accompanying flexion contractures.45 Progressive facial hemiatrophy (PFH) (Parry–Romberg syndrome) is considered to be another form of morphea (see below). Whereas en coup de sabre affects the upper face, PFH affects the cheek and mandible area. In PFH, the subcutaneous tissues, muscle, and bone are initially affected, while the overlying skin may be normal and without pigmentary changes. Many cases begin with a flat erythema resembling a port-wine stain that is followed later by the hemiatrophy. Cases of skin involvement overlying PFH may occur and lesions of typical morphea may be seen in other areas. The diagnosis of early progressive systemic sclerosis, mixed connective tissue disease, or an overlap syndrome must always be considered in patients with morphea. These systemic conditions are rare in children with cutaneous morphea. Progressive systemic sclerosis is associated with Raynaud’s phenomenon, nailfold telangiectasias, sclerosis of the face and extremities and there is usually evidence of internal organ involvement.

Prognosis The prognosis depends upon the type of morphea. Most forms of the disease resolve spontaneously, often leaving residual hyperpigmentation. Plaque or generalized forms of morphea resolve with atrophy, linear lesions persisted longer than plaque lesions, but resolved spontaneously over 3–5 years. In a series by Torok and Ablonczy, of the 88 children followed for 10 years, 63 healed with minimal cosmetic alteration; one case progressed to progressive systemic sclerosis.46 None of the 82 patients iden-

41. Falanga V, Medsger TA. Frequency levels and significance of blood eosinophilia in systemic sclerosis, localized scleroderma and eosinophilic fasciitis. J Am Acad Dermatol. 1987;17:648–656. 42. Murphy PK, Hymes SR, Fenske NA. Concomitant unilateral idiopathic atrophoderma of Pasini and Pierini (IAPP) and morphea. Observations supporting IAPP as a variant of morphea. Int J Dermatol. 1990;29:281. 43. Janin-Mercier A, Mosser C, Souteyrand P, et al. Subcutaneous sclerosis with fasciitis and eosinophilia after phytonadione injections. Arch Dermatol. 1985;121:1421. 44. Bernstein RM, Hall MA, Gostelow BE. Morphea-like reaction to D-penicillamine therapy. Ann Rheum Dis. 1981;40:42. 45. Kornreich HK, Shaw KN, Koch R, et al. Phenylketonuria and scleroderma. J Pediatr. 1968;73:571. 46. Torok E, Ablonczy E. Morphea in children. Clin Exp Dermatol. 1986;2:607.

Sclerosing and atrophying conditions

Therapy Specific treatments for localized morphea and its variants have not usually been tested in a controlled fashion. Aggressive treatments are not usually recommended in children with mild disease (other than emollients to diminish the dryness) because the disease regresses spontaneously. Treatment is directed at suppressing the inflammatory and collagen alterations. Local therapy with topical steroids and calcitriol has been used with results that are difficult to evaluate, given the nature of the disease. A potent topical corticosteroid in an ointment vehicle, or injection with intralesional corticosteroid steroids, may be

47. Peterson LS, Nelson AM, Su WP, et al. The epidemiology of morphea (localized scleroderma) in Olmsted County 1960–1993. J Rheumatol. 1997;24:73–80. 48. Uziel Y, Laxer RM, Krafchik BR, et al. Children with morphea have normal self-perception. J Pediatrics. 2000;137:727–730. 49. Parodi PC, Riberti C, Draganic Stinco D, et al. Squamous cell carcinoma arising in a patient with long-standing pansclerotic morphea. Br J Dermatol. 2001;144:417–419. 50. Wollina U, Buslau M, Heinig B, et al. Disabling pansclerotic morphea of childhood poses a high risk of chronic ulceration of the skin and squamous cell carcinoma. Int J Low Ext Wounds. 2007;6:291–298. 51. Petrov I, Gantcheva M, Miteva L, et al. Lower lip squamous cell carcinoma in disabling pansclerotic morphea of childhood. Pediatr Dermatol. 2009;26:59–61. 52. Cunningham BB, Landells ID, Langman C, et al. Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol. 1998;39: 211–215. 53. Bottomley WW, Jutley J, Wood EJ, et al. The effect of calcipotriol on lesional fibroblasts from patients with active morphea. Acta Derm Venereal. 1995;75:364–366. 54. Dytoc MT, Kossintseva I, Ting PT. First case series on the use of calcipotriol-betamethasone dipropionate for morphea. Br J Dermatol. 2007;157:615–618. 55. Hulshof MM, Bouwes BJN, Bergman W, et al. Double-blind, placebocontrolled study of oral calcitriol for the treatment of localized and systemic scleroderma. J Am Acad Dermatol. 2000;43:1017–1023.

helpful. Treatment is continued until the active inflammatory lilac ring has disappeared. A number of reports have discussed the efficacy of topical calcipotriene, as well as a topical calcipotriene-betamethasone combination preparation.52–54 A small study of pediatric patients treated for 3 months with topical calcipotriene showed some improvement in lesions52 although a double-blind study of adults with morphea treated with oral calcitriol showed no more effect than placebo.55 Other topical therapies such as 5% imiquimod cream and 0.1% tacrolimus ointment have also been shown to be effective in the treatment of localized morphea in adults.56–59 A randomized double blinded emollient controlled pilot study in which 10 patients with plaque morphea applied 0.1% tacrolimus twice daily for 12 weeks revealed significant improvement in the areas treated.60 For LM, physical therapy is extremely helpful. An active exercise program with deep massage and splinting improves and possibly prevents contractures. In the last decade, effective treatment for most children with severe morphea and LM has been achieved using low-dose methotrexate and corticosteroids.61–64 Methotrexate used alone at a dose of 15 mg per week in nine adults with widespread morphea yielded a beneficial effect.61 The first reported protocol for children with severe morphea and/or LM involved the use of monthly pulsed steroid in the dose of 30 mg/kg per day for 3 days for 3 months and weekly 0.5–1 mg/kg per week methotrexate.62 Another reported protocol included two courses of high dose intravenous methylprednisolone (IVMP) at a dose of 30 mg/kg per day, each containing three pulses, given on two consecutive weeks. Oral prednisolone was prescribed on the days between the two courses of IVMP, stopped before the second course and then continued on a tapering regimen following the second course of IVMP. Maintenance treatment with weekly methotrexate (initial dose 10 mg/m2) was then initiated 1 week following the second course of IVMP.65 This protocol reportedly halted disease progression in 94% of the 34 patients studied. Other reports of the combined use of methotrexate and systemic corticosteroid therapy showed similar promising results with long periods of remission and relatively low toxicity.63,64

MORPHEA

tified in a population study in Olmsted county, Minnesota, diagnosed over a period of 33 years, developed systemic sclerosis.47 However, some of the patients with LM in this series had severe cosmetic, orthopedic, and psychological sequelae.47 Fifty percent of patients overall had softening of the skin lesions by 3.8 years in the Olmsted county series.47 Plaque morphea resolved faster (50% by 2.7 years), compared with deep lesions (50% resolution in 5 years).47 Linear lesions persist longer than plaque lesions, but resolve spontaneously over time. There may be residual flexion contractures, limb atrophy and occasional calcinosis requiring surgical removal. Children with localized morphea have a normal life expectancy.2,47 A quality of life survey and self-esteem profile for children with various forms of morphea showed normal self-worth and high quality of life; patients with facial lesions were no more likely to have abnormal scores.48 The prognosis is not as good in disabling pansclerotic morphea of childhood. Of the 14 children reported by Diaz-Perez et al., two died, one of unknown cause and another from bronchopneumonia.17 The other patients had progression of their disease with loss of function and amputation: two patients improved.17 There have been three reported cases of squamous cell carcinoma arising in chronic ulcerations resulting from DMPC.49–51 All three patients died within 1 year of diagnosis from metastatic disease, gangrene or sepsis, respectively.

18

56. Campione E, Paternò EJ, Diluvio L, et al. Localized morphea treated with imiquimod 5% and dermoscopic assessment of effectiveness. J Dermatol Treat. 2009;20:10–13. 57. Man J, Dytoc MT. Use of imiquimod cream 5% in the treatment of localized morphea. J Cutan Med Surg. 2004;8:166–169. 58. Dytoc M, Ting PT, Man J, et al. First case series on the use of imiquimod for morphea. Br J Dermatol. 2005;153:815–820. 59. Stefanaki C, Stefanaki K, Kontochristopoulos G, et al. Topical tacrolimus 0.1% ointment in the treatment of localized scleroderma. An open label clinical and histological study. J Dermatol. 2008;35:712–718. 60. Kroft EB, Groeneveld TJ, Seyger MM, et al. Efficacy of topical tacrolimus 0.1% in active plaque morphea: randomized, double-blind, emollientcontrolled pilot study. Am J Clin Dermatol. 2009;10:181–187. 61. Seyger MM, van den Hoogen FH, de Boo T, et al. Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol. 1998;39:220–225. 62. Uziel Y, Feldman BM, Krafchik BR, et al. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;136:91–95. 63. Kroft EB, Creemers MC, van den Hoogen FH, et al. Effectiveness, side-effects and period of remission after treatment with methotrexate in localized scleroderma and related sclerotic skin diseases: an inception cohort study. Br J Dermatol. 2009;160:1075–1082. 64. Fitch PG, Rettig P, Burnham JM, et al. Treatment of pediatric localized scleroderma with methotrexate. J Rheumatol. 2006;33:609–614. 65. Weibel L, Sampaio MC, Visentin MT, et al. Evaluation of methotrexate and corticosteroids for the treatment of localized scleroderma (morphea) in children. Br J Dermatol. 2006;155:1013–1020.

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Phototherapy is a treatment option. Nineteen children treated with a combination of topical calcipotriol ointment and lowdose UVA1 phototherapy had softening and repigmentation.66 Several studies suggest improvement after UVA1 phototherapy.67,68 PUVA may be effective.69 Extracorporeal photochemotherapy was effective in an adult patient with generalized deep morphea.70 There have also been two randomized blinded controlled trials demonstrating the efficacy of extracorporeal photochemotherapy in adults with systemic sclerosis and severe morphea.71,72 Systemic therapy with other medications has yielded conflicting results. In some cases of morphea in Europe there may be an association with borreliosis, and improvement with systemic antibiotics has been reported.35 A child from Germany with LM and negative serology for Borrelia was treated with intravenous penicillin G for 10 days and showed diminished dermal thickness measured by ultrasound.73 The role of antibiotic therapy remains controversial as Borrelia-like organisms have not usually been seen in biopsies obtained in the USA.38,39 Penicillamine, a penicillin breakdown product that decreases collagen synthesis by inhibiting the cross-linking of collagen fibers, has been used in the past to treat morphea.74,75 Significant toxicity with renal disease was seen in half the patients, necessitating the discontinuation of treatment in one-third. The major side-effect of penicillamine is proteinuria, but others include bone marrow suppression, allergic reactions, and autoimmune disorders. There have been no controlled trials on the use of penicillamine in morphea, and the two deaths in Falanga’s series make its use questionable.74 Therapy with antimalarials, phenytoin,76 azathioprine, cyclosporine, colchicine,77 disodium edetate,78 and mycophenolate mofetil79 has also been reported. In patients with disabling pansclerotic morphea, there is no known satisfactory treatment. There was no response to penicillamine, antimalarial agents, or systemic steroids in the series

by Diaz-Perez et al.17 and no response to cytotoxic agents, although two patients in the above series did not develop new lesions while receiving cyclophosphamide (Cytoxan). Large ulcerations within the sclerotic plaques on the legs of a patient with pansclerotic morphea improved with intravenous gammaglobulin, and later with PUVA bath treatments.18 There is one report of a child treated with a dual endothelin receptor antagonist, bosentan, with improvement noted in limb ulcers, sclerotic skin lesions and joint mobility.80 The depressed plaques of en coup de sabre and linear facial morphea have been successfully corrected by autologous dermal fat implants.81,82 One young adult with cosmetically unacceptable morphea involving the left zygomatic area was treated with local injections of collagen with good cosmetic correction.83 Bone defects in en coup de sabre have been corrected with a hydroxyapatite cement.84 Surgical excision of localized morphea lesions during the active inflammatory phase of the disease is not recommended because recurrence can result around the scar.85

66. Kreuter A, Gambichler T, Avermaete A, et al. Combined treatment with calcipotriol ointment and low dose ultraviolet A1 phototherapy in childhood morphea. Pediatric Dermatology. 2001;18:241–245. 67. Gruss CJ, von Kobyletzki G, Behrens-Williams SC, et al. Effects of low dose ultraviolet A-1 phototherapy on morphea. Photodermatol, Photoimmunol Photomed. 2001;17:149–155. 68. Camacho NR, Sanchez JE, Martin RF, et al. Medium-dose UVA1 phototherapy in localized scleroderma and its effect in CD34-positive dendritic cells. J Am Acad Dermatol. 2001;45:697–699. 69. Usmani N, Murphy A, Veale D, et al. Photochemotherapy for localized morphoea: effect on clinical and molecular markers. Clin Exp Dermatol. 2008;33:698–704. 70. Neustadter JH, Samarin F, Carlson KR, et al. Extracorporeal photochemotherapy for generalized deep morphea. Arch Dermatol. 2009;145:127–130. 71. Cribier B, Faradji T, Le Coz C, et al. Extracorporeal photochemotherapy in systemic sclerosis and severe morphea. Dermatology. 1995;191:25–31. 72. Knobler RM, French LE, Kim Y, et al. Systemic Sclerosis Study Group. A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis. J Am Acad Dermatol. 2006;54:793–799. 73. Mohrenschlager M, Jung C, Ring J, et al. Effect of penicillin G on corium thickness in linear morphea of childhood: an analysis using ultrasound technique. Pediatric Dermatology. 1999;16:314–316. 74. Falanga V, Medsger TA Jr. D-penicillamine in the treatment of localized scleroderma. Arch Dermatol. 1990;126:609. 75. Moynahan EJ. Morphoea (localized cutaneous scleroderma) treated with low-dosage penicillamine (4 cases, including en coup de sabre). Proc R Soc Med. 1973;66:1083. 76. Neldner KH. Treatment of localized linear scleroderma with phenytoin. Cutis. 1978;22:569–572. 77. Alarcon-Segovia D, Ramos-Niembor F, Ibanez de Kasep G, et al. Long-term evaluation of colchicine in the treatment of scleroderma. J Rheumatol. 1979;6:705–712.

78. Neldner KH, Winkelmann RK, Perry HO. Scleroderma: An evaluation of treatment with disodium edetate. Arch Dermatol. 1962;86:305–309. 79. Martini G, et al. New therapeutic methods in morphea. Rheumatology. 2009;48:1410–1413. 80. Roldan R, Morote G, Castro Mdel C, et al. Efficacy of bosentan in treatment of unresponsive cutaneous ulceration in disabling pansclerotic morphea in children. J Rheumatol. 2006;33:2538–2540. 81. Lapiere JC, Aasi S, Cook B, et al. Successful correction of depressed scars of the forehead secondary to trauma and morphea en coup de sabre by en bloc autologous dermal fat graft. Dermatol Surg. 2000;26:793–797. 82. Roh MR, Jung JY, Chung KY. Autologous fat transplantation for depressed linear scleroderma-induced facial atrophic scars. Dermatol Surg. 2008;34:1659–1665. 83. Stoner JG, Swanson NA, Siegle RJ. Treatment of localized morphea with Zyderm collagen implant. J Dermatol Surg Oncol. 1984;8:626. 84. Hwang DY, Paik HW, Byeon JH. Correction of facial linear scleroderma ‘coup de sabre’ with BoneSource. Plast Reconstr Aesthet Surg. 2009;62:e25–e28. 85. Kamath NV, Usmani A, Pellegrini A. When is surgical treatment not appropriate for morphea? Ann Plast Surg. 2000;45:199–201. 86. Gorlin RJ, Pindorb JJ, Cohen MM. Syndromes of the head and neck. New York: McGraw-Hill; 1976. 87. von Romberg MH. Trophoneurosen. In: Romberg Klinische Ergebnisse. Berlin: Forstner; 1846:75–81. 88. Parry CH. Facial hemiatrophy. Collections from the unpublished medical writings of the late Caleb Hillier Parry. Vol I. London: Underwood; 1825:478–480. 89. Blaszcyk M, Jablonska S. Linear scleroderma en coup de sabre. Relationship with progressive facial hemiatrophy. Adv Exp Med Biol. 1999;455:101–104. 90. Lehman TJ. The Parry–Romberg syndrome of progressive facial hemiatrophy and linear scleroderma en coup de sabre. Mistaken diagnosis or overlapping conditions? (Editorial). J Rheumatol. 1992;19:844.

PROGRESSIVE FACIAL HEMIATROPHY Progressive facial hemiatrophy (PFH) (Parry–Romberg syndrome) is a rare neurocutaneous disorder that presents with severe atrophy of the soft tissues of half of the face. It may be accompanied by contralateral Jacksonian seizures, trigeminal neuralgia, migraine headaches, eye symptoms and signs, hair abnormalities, and malalignment of the jaw, causing dental problems.86 The disorder was reported by Romberg in 1846,87 but had been mentioned as early as 1825 by Parry.88 There is a long-standing controversy about its relationship to en coup de sabre morphea. Most authors think these disorders are variants of the same disease process, although in PFH the atrophy is deeper than that seen in linear morphea.89,90

Sclerosing and atrophying conditions

Epidemiology

18

Oral 91

PFH typically develops in the first or second decade of life, but it can begin at any age.92 Nearly all cases of PFH are sporadic, but there have been a few cases in families.93,94 Females are affected more often than males with female to male ratios ranging from 2–4 : 1.91,95

The tongue and upper lip on the involved side of the face are usually markedly atrophic. The maxilla and mandible do not fully develop, resulting in malocclusion. The teeth may have atrophic roots or be slow to erupt.86

Laboratory findings Cutaneous Subcutaneous atrophy characteristically develops over the maxillary region and may extend to the chin and forehead. The overlying skin often becomes hyperpigmented. The process may extend to the brow, angle of the mouth, and neck and occasionally involves the ipsilateral half of the body, although both ipsilateral and contralateral limb involvement have been reported.96 Lesions often extend beyond the hairline causing circumscribed alopecia on the temporoparietal scalp, eyebrow, and eyelashes.86 Atrophy or growth arrest of the underlying bone and cartilage occurs, probably at the same time as the other changes. The muscles may also be involved but function is maintained. The disease progresses slowly for approximately 3 years and then stabilizes over 3–5 years, often leaving a severe cosmetic defect with progressive disfigurement as the unaffected side grows normally.97

There are no known laboratory abnormalities, but there may be many radiological abnormalities. High-resolution ultrasound and magnetic resonance imaging can be used to document dermal and subcutaneous changes.100

Pathophysiology and histogenesis The cause of this disease is not understood. In several patients, a history of trauma was elucidated, especially following tooth injury or extraction,97 but the role of injury is controversial. Three reported cases suggest a role for Borrelia infection.101–103 In another report, PFH was associated with an intracranial vascular malformation; the authors propose that PFH may be the result of an arrested angiogenic process affecting the central nervous system during growth and development.104

Differential diagnosis

The eye is often involved in PFH. Loss of periorbital fat results in enophthalmos, and loss of underlying bone may displace the outer canthus downward. Ocular muscle paralysis, ptosis, Horner syndrome, heterochromia iridis, and dilated fixed pupils have been reported.99 In addition, keratitis, iritis, choroiditis, cataracts, and papillary edema may occur.99

En coup de sabre and Parry–Romberg disease are difficult to distinguish from one another; there are many who argue that the two conditions are variants of the same disease rather than two distinct entities.37 En coup de sabre resolves with atrophy of the skin, subcutaneous tissue, and bone that is morphologically identical to hemiatrophy. En coup de sabre typically affects the forehead area. During the acute phase of en coup de sabre, the skin and deeper tissues are indurated, whereas in hemiatrophy, they are not. In PFH, it is the deeper tissues rather than the skin that are atrophic. In addition, facial morphea tends to progress over a longer period than the average 3 years in PFH. Congenital facial hypoplasia is present at birth and includes diminution in the size of the teeth on the involved side, which may also occur with PFH. Other forms of lipoatrophy are usually not localized to the face. Neuromuscular paralysis following polio can result in secondary atrophy of the face. In the oculoauricular vertebral syndrome, the facial bones are not fully developed and the mandibular ramus is absent. In contrast to

91. Stone J. Parry–Romberg syndrome: a global survey of 205 patients using the internet. Neurology. 2003;61:674–676. 92. Chang S-E, Huh J, Choi J-H, et al. Parry–Romberg syndrome with ipsilateral cerebral atrophy of neonatal onset. Pediatr Dermatol. 1999;16:487–488. 93. Lewkonia RM, Lowry RB. Progressive hemifacial atrophy (Parry–Romberg syndrome). Report with review of genetics and nosology. Am J Med Genet. 1983;14:385. 94. Anderson PJ, Molony D, Haan E, et al. Familial Parry–Romberg disease. Int J Pediatr Otorhinolaryngol. 2005;69:705–708. 95. Tollefson MM, Witman PM. En coup de sabre morphea and Parry– Romberg syndrome: a retrospective review of 54 patients. J Am Acad Dermatol. 2007;56:257–263. 96. Slimani S, Hounas F, Ladjouze-Rezig A. Multiple linear sclerodermas with a diffuse Parry–Romberg syndrome. Joint Bone Spine. 2009;76:114–116. 97. Crikelear GF, Moss ML, Khuri A. Facial hemiatrophy. Plast Reconstr Surg. 1962;29:5. 98. Miao J, Liu R, Lin H, et al. Severe bilateral pyramidal tract involvement in a patient with Parry-Romberg syndrome. Am J Med Sci. 2009;337:212–214.

99. Hoang-Xuan T, Foster CS, Jakobiec FA, et al. Romberg’s progressive hemifacial atrophy: an association with scleral melting. Cornea. 1991;10:361. 100. Mauer J, Knollmann FD, Schlecht I, et al. High-resolution magnetic resonance imaging in patients with facial hemiatrophy. Acta DermatoVenereologica. 1999;70:373–375. 101. Abele DC, Dedingfield RB, Chandler FW, et al. Progressive facial hemiatrophy (Parry–Romberg syndrome) and borreliosis. J Am Acad Dermatol. 1990;22:531. 102. Sahin MT, Bariş S, Karaman A. Parry–Romberg syndrome: a possible association with borreliosis. J Eur Acad Dermatol Venereol. 2004;18:204–207. 103. Baskan EB, Kaçar SD, Turan A, et al. Parry-Romberg syndrome associated with borreliosis: could photochemotherapy halt the progression of the disease? Photodermatol Photoimmunol Photomed. 2006;22:259–261. 104. Miedziak AI, Stefanyszyn M, Flanagan J, et al. Parry–Romberg syndrome associated with intracranial vascular malformations. Arch Ophthalmol. 1998;116:1235–1237.

Central nervous system Trigeminal neuralgia or facial paresthesias occurs in some patients and may precede the other changes.32 Contralateral seizures may occur and are usually Jacksonian in type. Migraine headaches are common. Developmental delay with ipsilateral atrophy of the right hemisphere was documented in one neonate with PFH.92 Severe bilateral pyramidal tract involvement has also been reported.98

Ocular

PROGRESSIVE FACIAL HEMIATROPHY

Clinical manifestations

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hemiatrophy, the ears are not fully formed and epibulbar dermoids are common.

Therapy and prognosis The disease tends to progress for 3 years on average and then becomes stationary. Antibiotic therapy for possible borreliosis may be attempted. Treatment, as in the more severe forms of morphea, is advocated by some (see Morphea, above). Serial MRIs may be useful to follow the effect of prednisone and metho­ trexate therapy.105 When the disease is no longer progressive, plastic surgical correction can be considered.106–108

SCLEREDEMA SCLEREDEMA

Scleredema affects localized areas of the face and back of the neck. These areas become indurated and tight. It was first recognized as a distinct entity by Buschke in 1900, and has also been called ‘scleredema adultorum,’ even though the disease may occur in children.109–114 Scleredema is rare, with 223 cases having been reported since 1965.111 Females are more frequently affected than males. There are occasional reports of familial involvement.111 In one series, 29% of cases started before the age of 10 years, 22% between the ages of 10 and 20, and the remainder in adulthood.110 There is one report of neonatal scleredema.112

Presenting history There may be a prodrome of slight fever, malaise, muscle and joint pain which is followed by induration, usually on the back and sides of the neck or on the face. Pustules may appear on the skin before the onset of the scleredema.109 The patient may complain of difficulty in smiling, in wrinkling the forehead, or in opening the mouth. If the tongue and pharynx are involved, there may be difficulty in swallowing. A history of paresthesias and joint stiffness may occur. Later, the shoulders, arms, hands, and upper trunk may become affected. Occasionally, the abdomen is involved. A history of diabetes or precipitation by an infection has been recorded (see Pathogenesis, below).

Laboratory findings The streptozyme titer may be raised, especially in children, and the erythrocyte sedimentation rate elevated. Elevation of serum proteins and increased levels of paraproteins have been reported.117,118 Electrocardiographic abnormalities have been reported and are probably associated with complications of diabetes.109

Pathophysiology and histogenesis

The skin is markedly thickened, non-pitted and hard, and usually skin colored. The thickening causes marked limitation in neck

The cause of scleredema is unknown. It was originally thought that most patients had a history of an antecedent infection within a few days to 6 weeks before the onset of the disease. In a 1984 review from the Mayo Clinic, only eight of 33 patients with scleredema without diabetes had a history of antecedent infection.109 Although streptococcal infections are the most common precursors, other infections reported include influenza, pharyngitis, measles, mumps, pertussis, impetigo, and cellulitis. A 3-month-old infant reported by Heilbron and Saxe112 had a preceding cytomegalovirus pneumonia. A large number of adult cases have been found in association with long-standing diabetes mellitus and obesity.119 The diabetes is of late onset and difficult to control. Monoclonal gammopathy has been described in association with scleredema.118,120

105. Goldberg-Stern H, deGrauw T, Passo M, et al. Parry–Romberg syndrome: follow-up imaging during suppressive therapy. Neuroradiology. 1997;39:873–876. 106. Inigo F, Rojo P, Ysunza A. Aesthetic treatment of Romberg’s disease: experience with 35 cases. Br J Plast Surg. 1993;46:194. 107. Mordick TG, Larossa D, Whitaker L. Soft-tissue reconstruction of the face: a comparison of dermal-fat grafting and vascularized tissue transfer. Ann Plast Surg. 1992;29:390. 108. Inigo F, Jimenez-Murat Y, Arroyo O, et al. Restoration of facial contour in Romberg’s disease and hemifacial microsomia: experience with 118 cases. Microsurgery. 2000;20:167–172. 109. Venencie PY, Powell FC, Su WP, et al. Scleredema: a review of thirty-three cases. J Am Acad Dermatol. 1984;11:128. 110. Greenberg LM, Geppert C, Worthen HG, et al. Scleredema ‘adultorum’ in children: report of 3 cases with histochemical study and review of world literature. Pediatrics. 1963;32:1044. 111. Curtis AC, Shulak BM. Scleredema adultorum. Not always a benign self-limited disease. Arch Dermatol. 1965;92:526.

112. Heilbron B, Saxe N. Scleredema in an infant. Arch Dermatol. 1986;122:1417. 113. Burke MJ, Seguin J, Bove KE. Scleredema: an unusual presentation with edema limited to scalp, upper face, and orbits. J Pediatr. 1982;101:960. 114. Wright RA, Bernie H. Scleredema adultorum of Buschke with upper esophageal involvement. Am J Gastroenterol. 1982;77:9. 115. Wu EB, Fuller LC, Hughes RA, et al. Images in cardiovascular medicine: rare cause of cardiomyopathy. Circulation. 2001;103:2867. 116. Engin B, Mat MC, Demirkesen C, et al. Scleredema adultorum associated with hyperkeratosis. Pediatr Dermatol. 2005;22:36–39. 117. Kovary PM, Vakilzadeh F, Macher E, et al. Monoclonal gammopathy in scleredema. Observations in three cases. Arch Dermatol. 1981;117:536. 118. Ohta A, Uitto J, Oikarinen AI, et al. Paraproteinemia in patients with scleredema. J Am Acad Dermatol. 1987;16:96. 119. Fleischmajer R, Faludi G, Krol S. Scleredema and diabetes mellitus. Arch Dermatol. 1970;101:21. 120. Stables GI, Taylor PC, Highet AS. Scleredema associated with paraproteinaemia treated by extracorporeal photopheresis. Br J Dermatology. 2000;142:781–783.

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movement. The involved skin is not well demarcated from uninvolved skin, as the indurated area gradually fades into normal skin, in contrast to the well-circumscribed lesions of morphea. The skin feels bound down to the underlying structures. In patients with diabetes, the skin may be erythematous.109 In one pediatric patient, the scleredema was limited to the upper face and scalp and was initially diagnosed as edema and temporal tarsorrhaphies were required to prevent exposure keratitis.113 The tongue and pharynx are frequently involved, resulting in dysarthria and dysphagia. There is one report of an adult with pharyngeal involvement who developed infiltration of the upper esophagus, with progressive dysphagia, chronic aspiration, pneumonia, and ultimate death from acute aspiration.114 Pleural and pericardial effusions may occasionally occur, and skeletal and cardiac muscles may be affected.115 Occasionally, the eyelids and conjunctiva become indurated. The parotid gland may also be affected. In one pediatric case, there was an associated linear skin thickening along the upper extremities and focally over metacarpal joints.116

Sclerosing and atrophying conditions

Differential diagnosis The rapid onset makes this condition distinctive. The indurated lesions of morphea are more gradual in onset, ivory-colored, and well circumscribed. Patients with progressive systemic sclerosis usually have Raynaud’s phenomenon and other systemic findings. Swelling of the skin can be seen in dermatomyositis, but heliotrope changes and Gottron’s papules are helpful differentiating features. Trichinosis can also cause facial edema. Mucinosis, myxedema, scleromyxedema, and mucopolysaccharidosis all cause cutaneous induration but may be distinguished by skin biopsy. Sclerema neonatorum and subcutaneous fat necrosis are diseases of the newborn and differ histologically.

Therapy and prognosis Twenty-five percent of cases clear in 2 years, some in months111 but others occasionally persist for many years. It has been suggested that scleredema associated with an acute respiratory tract infection may resolve more rapidly;109 however, this was true in only three of Venencie et al.’s cases.109 No effective therapy is known. Therapy with topical and systemic corticosteroids, methotrexate, penicillamine, thyroid hormones, hyaluronidase, estradiol, fibrolysin, pilocarpine, thorium X, and physical therapy have all met with inconsistent results. Scleredema associated with paraproteinemia has been treated successfully with extracorporal photophoresis.120

SCLEREMA NEONATORUM (SN) In this disease, diffuse hardening of the subcutaneous tissues occurs in debilitated pre-term to term newborns.122 The skin becomes smooth, cold, and stony hard and appears to be bound down to underlying structures. The face looks mask-like, and the joints are immobile. This induration can resolve within 2 weeks, but most patients do not survive for that length of time.

121. Christy WC, Buckingham RB, Barnes EL, et al. Scleredema adultorum of Buschke: a clinical, pathologic, and cell culture study of 2 patients. J Rheumatol. 1983;10:595. 122. Fretzin DF, Arias AM. Sclerema neonatorum and subcutaneous fat necrosis of the newborn. Pediatr Dermatol. 1987;4:112. 123. Zeb A, Rosenberg RE, Ahmed NU, et al. Risk factors for sclerema neonatorum in preterm neonates in Bangladesh. Pedatr Infect Dis J. 2009;28:435–438. 124. Chisti MJ, Saha S, Roy CN, et al. Predictors of mortality in infants with sclerema presenting to the Centre for Diarrhoeal Disease, Dhaka. Ann Trop Paediatr. 2009;29:45–50. 125. Navarini-Meury S, Schneider J, Buhrer C. Sclerema neonatorum after therapeutic whole-body hypothermia. Arch Dis Child Fetal, Neonatal Ed. 2007;92:F307.

SN is a non-specific sign of severe underlying disease. Several factors herald the development of the condition including poor feeding, severe malnutrition, elevated serum ammonia and CRP, jaundice, bacteremia and septic shock.123,124 In one study, the risk of death in infants with SN was 46.5-fold higher than for patients with those diseases but without SN.123 Induced hypothermia was associated with the development of SN in one infant but the lesions resolved spontaneously and the infant did well.125 The histologic changes on skin biopsy are minimal. There is some thickening of the fibrous trabeculae in the subcutaneous fat and minimal inflammatory change. Adipocytes contain needle-shaped clefts that are oriented radially.126 The disease must be distinguished from subcutaneous fat necrosis of the newborn (to which it is related), generalized edema, Milroy’s disease, and Turner syndrome. (See Ch. 6 for further details.) Treatment depends solely on treating the underlying causative disorder.

STIFF SKIN SYNDROME

Skin biopsy shows a marked increase in dermal thickness.119 The epidermis is normal. In the dermis, there are thick, swollen collagen bundles separated by large interfibrous spaces. These fenestrations contain increased levels of acid mucopolysaccharide, probably as a result of an accumulation of hyaluronic acid. The collagen replaces large areas of the subcutaneous tissue. Unlike scleroderma and morphea, the appendageal structures are unchanged. Fibroblast cultures from the involved skin of two patients yielded increased amounts of glycosaminoglycans, especially hyaluronic acid, but only slightly more collagen.121

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STIFF SKIN SYNDROME Esterly and McKusick127 reported four patients with localized areas of stony-hard skin associated with limited joint mobility and mild hirsutism. The skin was normal in appearance but hard, immovable, and firmly bound to the underlying tissues; these changes were most severe over the buttocks, thighs, legs and joints. Skin changes begin in the neonatal period. Joint stiffness occurs in early childhood with mild limitation of movement. A lordotic stance is present in all patients, preventing full spinal flexion. In Esterly’s series, the two most severely affected patients were unable to extend the hips and knees completely. Biopsies of affected skin show abnormal amounts of acid mucopolysaccharide in the dermis, but mucopolysacchariduria is not present. The occurrence in a mother and two children suggested an autosomal-dominant inheritance.127 After Esterly’s initial description, other cases were reported from Japan128 and Poland.129 Skin biopsy shows thickening and homogenization of the connective tissue stroma, with proliferation of connective tissue and an increased number of fibroblasts in the subcutis.129 Colloidal iron-reactive material is present in the dermis and subcutis and is digestible by hyaluronidase. There are increased numbers of fibroblasts. Jablonska et al.130 found that the fascia was considerably thickened in their cases, and suggested that their patients had a variant of stiff skin syndrome. They proposed the name congenital fascial dystrophy and considered the disorder to be a human counterpart of the tight-skin mouse, a dominant mutant mouse strain characterized by thickened skin firmly

126. Prieto VG, Ivan D. Panniculitis: a diagnostic algorithm. Diagn Histopathol. 2009;15:195–202. 127. Esterly NB, McKusick VA. Stiff skin syndrome. Pediatrics. 1971;47: 360. 128. Kikuchi I, Inoue S, Hamada K, et al. Stiff skin syndrome. Pediatr Dermatol. 1985;3:48. 129. Jablonska S, Schubert H, Kikuchi I. Congenital fascial dystrophy: stiff skin syndrome – a human counterpart of the tight-skin mouse. J Am Acad Dermatol. 1989;21:943. 130. Jablonska S, Groniowski J, Krieg T, et al. Congenital fascial dystrophy—a noninflammatory disease of fascia: the stiff skin syndrome. Pediatr Dermatol. 1984;2:87.

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bound to the underlying tissues, and excessive collagen accumulation in the dermis and subcutaneous tissue. Jablonska and Blaszczyk reported four patients with stone-hard indurations of skin and subcutaneous tissue primarily on the buttocks and thighs; the fascia was markedly enlarged.131 Collagen fibrils were seen in affected fascia on electron microscopy. The authors called this a localized or ‘abortive’ form of congenital fascial dystrophy because it was localized to the buttocks and thighs, not progressive, and involved the fascia only. Affected patients have a nonprogressive and localized disease, aside from joint contractures and an occasional modest decrease in pulmonary function if the chest wall is involved.130 Liu et al. reviewed a series of pediatric patients with stiff skin syndrome with disease onset ranging from infancy to 6 years of age.132 In their series, 50% of cases were associated with hypertrichosis and extracutaneous manifestations consisted of joint restriction and postural and thoracic wall irregularities. There is no known cause and no known treatment. Although there is constriction of movement, children survive into adulthood.

RESTRICTIVE DERMOPATHY Restrictive dermopathy (RD) or tight skin contracture syndrome is a rare lethal genodermatosis, which is inherited in an autosomal-recessive or dominant manner and caused by mutations in the LMNA gene or in the ZMPSTE24 gene.133–136 Clinically, the skin is abnormal at birth. It is tight, shiny, and taut and may tear or fissure when extended. Erosions can be extensive and mistakenly diagnosed as aplasia cutis congenita. The skin becomes increasingly rigid over time. The facies are distinctive: a small pinched nose with a fixed round open mouth, micrognathia, hypertelorism, and large fontanelles with widened sutures. The extremities have marked flexion contractures. Some patients have natal teeth, skeletal abnormalities, and pulmonary hypoplasia with respiratory insufficiency. Histologic examination of the skin shows acanthosis, a thin dermis, absent or small elastic fibers, and collagen bundles abnormally oriented in parallel fashion to the epidermis, as seen in a scar or tendon. Keratin filaments and collagen fibrils are abnormal on electron microscopy. RD is a primary or secondary laminopathy, caused by de novo LMNA mutations or recessive null ZMPSTE24 mutations. Lamin A is an intermediate filament protein that provides stability and strength to the nuclear envelope. Prelamin A is processed within the cell before becoming part of the nuclear lamina. The accumulation of truncated or normal length prelamin A gene is a shared feature in recessive and dominant RD.136 ZMPSTE24 is

131. Jablonska S, Blaszczyk M. Scleroderma-like indurations involving fascias: an abortive form of congenital fascial dystrophy (stiff skin syndrome). Pediatr Dermatol. 2000;17:105–110. 132. Liu T, McCalmont TH, Frieden IH, et al. The stiff skin syndrome: case series, differential diagnosis of the stiff skin phenotype and review of the literature. Arch Dermatol. 2008;144:1351–1359. 133. Welsh KM, Smoller BR, Holbrook KA, et al. Restrictive dermopathy. Report of two affected siblings and a review of the literature. Arch Dermatol. 1992;128:228. 134. Graham J, Esterly NB. What syndrome is this? Pediatr Dermatol. 1999;16:151–153. 135. Nijsten TEC, DeMoor A, Colpaert CG, et al. Restrictive dermopathy: a case report and a critical review of all hypotheses of its origin. Pediatr Dermatol. 2002;19:67–72.

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a metalloproteinase specifically involved in the post-translational processing of lamin A precursors. All patients carrying a ZMPSTE24 mutation show a loss of expression of lamin A, as well as abnormal nuclear patterning and abnormal localization of lamin-associated proteins.136 RD can be readily differentiated from sclerema neonatorum and subcutaneous fat necrosis both clinically by a history of intrauterine growth retardation, presence at birth, typical facies, and presence of erosions, and histologically by no abnormalities in fat cells. Stiff skin syndrome and congenital fascial dystrophy are not present at birth, are more localized and usually have a more benign course.135 Most affected infants die shortly after birth, but with ventilation and nutritional support, some have survived for several weeks to months. There is one report of decreased fetal movement visualized via ultrasonography in an affected fetus at the end of the second trimester.137

KELOIDS AND HYPERTROPHIC SCARS When skin is wounded, an inflammatory response is triggered and healing follows. If the wound is deep and extends into the dermis, the resultant wound heals with a scar. In some individuals and on some locations of the body, this scar is proliferative, resulting in a thick band of fibrous tissue that is elevated above the surface of the skin. The raised scar is called hypertrophic if it remains confined to the site of the injury and resolves in a year; it is called a keloid if it extends and invades the surrounding uninjured skin. Keloids are common. References to their existence have been found in papyrus writings from the Pyramid Age, 3000– 2500BC.138 Oral and sculptural art forms dating from the 10th century AD show that the ancient Yoruba people of western Nigeria practiced ritual facial markings which commonly resulted in keloid formation. They appreciated a familial predisposition to keloids and a time interval between trauma to the skin and keloid formation.138 Keloids were described in the modern literature by Alibert in 1806.139,140 He initially called them ‘les cancroids’ because of their cancer-like extensions and later introduced the term ‘les cancroides ou keloids’, taken from the Greek chele, meaning crab’s claw, and referring to the tendency of the lesions to extend laterally into normal tissue. For the next 100 years, there was interest in the rare entity known as ‘true keloids,’ keloids that arise spontaneously, and how to differentiate them from ‘false or cicatricial’ keloids, which arise at sites of trauma. This distinction is no longer emphasized.138

136. Navarro CL, De Sandre-Giovannoli A, Bernard R, et al. Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identity restrictive dermopathy as a lethal neonatal laminopathy. Hum Mol Genet. 2004;13:2493–2503. 137. Mulder EJ, Beemer FA, Stoutenbeek P. Restrictive dermopathy and fetal behaviour. Prenatal Diagn. 2001;21:581–585. 138. Murray JC, Pollack SV, Pinnell SR. Keloids: a review. J Am Acad Dermatol. 1981;4:461. 139. Schneider LF, Warren SM. The relationship between keloid growth pattern and stretching tension – visual analysis using the finite element method: A brief history of keloids [Invited discussion]. Ann of Plast Surg. 2008;60:452–454. 140. Alibert JLM. Description des maladies de la peau observées à l’hôpital Saint-Louis et exposition des meillieures méthodes suives pour leur traitement. Barrois l’aine et fils. 1806;113.

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Keloids occur equally in males and females. They can occur at any age, but most cases have been reported in patients between the ages of 10 and 30. Prepubescent children and older adults are less commonly affected. Keloids are more common in darkly pigmented individuals.138 The incidence in random samplings of African populations is approximately 6%. Polynesians are even more susceptible than Africans.141 Keloids do not develop in albinos.142 There is a familial predilection for keloids, but no known genetic predisposition to the development of hypertrophic scars. A pedigree study examining 14 pedigrees with familial keloids found that the pattern of inheritance was autosomal dominant with incomplete clinical penetrance and variable expression.143 Seven individuals were obligate unaffected carriers, implying environmental factors may also play a role.143

Presenting history Patients note the gradual onset of scar hypertrophy 3–6 weeks after the inciting trauma to the skin. Common examples of skin injury in the pediatric patient include varicella, ear piercings, lacerations, and surgical incisions. At times there may be no recollection of prior injury; such ‘spontaneous keloids’ have been reported in the Rubinstein–Taybi syndrome (broad thumbs and broad toes, mental and motor retardation, characteristic facies, and renal and cardiovascular anomalies).144,145 Infection of a wound and thermal or chemical injury increase the risk of keloid formation.142 After several months, a hypertrophic scar stops growing and becomes less red; a keloid, on the other hand, becomes hypersensitive, and sometimes severely pruritic. Even the pressure of clothing may incite irritability. The patient presents either for cosmetic reasons or because of the discomfort.

Physical examination Hypertrophic scars occur in the area in which trauma occurred, usually at an operation site. After a few months, the erythema abates and the scar flattens. Keloids can occur anywhere on the body, but are most frequently found over the upper trunk and upper arms and on the earlobes. Posterior earlobe keloids are usually larger than anterior earlobe keloids.142 The scar is raised and thickened, forming a well-defined, firm, red or pink plaque, sometimes with telangiectatic blood vessels coursing through it. After 2–3 months, the scar becomes smooth and round and extends beyond the original wound (Fig. 18.6). Over time, the diagnosis of a keloid becomes obvious; it continues to grow, sometimes for years, with the formation of large, irregular, often linear, lesions with crablike projections. The epidermis is thin but does not ulcerate. Lesions may vary in size from 2 to 5 mm

141. Nemeth AJ. Keloids and hypertrophic scars. J Dermatol Surg Oncol. 1993;19:738. 142. Kelly AP. Update on the management of keloids. Sem Cutan Med Surg. 2009;28:71–76. 143. Marneros AG, Norris JE, Olsen BR, et al. Clinical genetics of familial keloids. Arch Dermatol. 2001;137:1429–1434. 144. Rubinstein JH. Broad thumb-hallux (Rubinstein–Taybi) syndrome 1957–1988. Am J Med Genet. 1990;6:3.

papules, to large pedunculated tumors. In most patients there are one to two lesions, but there may be more.

Laboratory findings There are no known laboratory abnormalities in patients with hypertrophic scars or keloids.

Histology In the early stages, normal wounds, hypertrophic scars, and keloids share similar histologic findings and it is difficult to differentiate amongst them;138 they show inflammation and early fibroplasia. There are mast cells, plasma cells, and lymphocytes in the inflammatory infiltrate. In a keloid, fibroplasia progresses past the third week of wound healing. Nodular vascular proliferations, heavily cuffed by fibroblasts, enlarge and transform into thickened masses of hyalinized collagen bundles with proteoglycan. In a hypertrophic scar, the number of fibroblasts in capillaries slowly decreases by the fifth week as the collagen bundles organize in a parallel fashion. Scanning electron microscopy shows that, in normal skin wounds, collagen bundles lie in discrete groups oriented parallel to the skin surface. In keloids, discrete bundles are absent, and collagen fibers are loosely connected and oriented randomly. Electron microscopy of a keloid shows that the lesion is composed entirely of myofibroblasts.146

KELOIDS AND HYPERTROPHIC SCARS

Epidemiology

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Pathogenesis The pathogenesis of keloids remains unknown. In 1889, Buck observed that keloids have a predilection for areas of the body under high tension.139 In a recent paper, the authors used a computerized program based on a mathematical model called finite element modeling, an applied mathematical tool used, for example, to estimate airplane wing and fuselage flexibility, to analyze keloids. They concluded that high tension was observed at the edges of keloids and not in the center and that expansion of a keloid occurred in the direction to which it was pulled.147 The bulk of a keloid is composed of extracellular material, proteoglycan, especially chondroitin-4-sulfate, and water.138 Keloids and hypertrophic scars are more cellular than normal skin wounds, but fibroblasts isolated from keloids appear to have normal growth characteristics.138 The fibroblasts synthesize increased amounts of collagen, especially types I and III. Keloidal collagen differs from normal dermal collagen by being more soluble and having cross-linking similar to that of young skin. There is increased expression of transforming growth factor (TGF-β) in keloid fibroblasts; and TGF-β ligands and receptors in keloids may increase collagen production. It is possible that fibrous tissue accumulates in the keloid because collagen is not degraded, but collagenase levels are increased rather than

145. Selmanowitz VJ, Stiller MJ. Rubinstein–Taybi syndrome: cutaneous manifestations and colossal keloids. Arch Dermatol. 1981;117:504. 146. James WD, Besanceney CD, Odom RB. The ultrastructure of a keloid. J Am Acad Dermatol. 1980;3:50. 147. Akaishi S, Akimoto M, Ogawa R, et al. The relationship between keloid growth pattern and stretching tension: visual analysis using the finite element method. Ann Plast Surg. 2008;60:445–451.

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Figure 18.6  (A) Keloid on upper arm. (B) Keloid on neck. (C) Keloid on ear.

A KELOIDS AND HYPERTROPHIC SCARS B

C

decreased.138,141 Another theory proposes a balance abnormality between proliferation and apoptotic cell death in keloidal fibroblasts. Keloid fibroblasts may be resistant to apoptosis because they overexpress the insulin-like growth factor receptor I, thereby allowing persistent proliferation and production of excess extracellular matrix. Expression of Gli-1 protein was shown to be strongly elevated in keloids compared with normal scars. Mast cells are prominent in both keloids and hypertrophic scars, and it has been proposed that histamine causes the pruritus.138 A higher than normal concentration of neuropeptides has been shown in hypertrophic scars, which may cause the itching and also stimulate growth.148

Differential diagnosis The clinical morphology of a keloid is so distinctive that it is usually easy to diagnose. It should be differentiated from a 148. Crowe R, Parkhouse N, McGrouther DA, et al. Neuropeptide containing nerves in painful hypertrophic scar tissue. Br J Dermatol. 1994;130:444–452.

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hypertrophic scar. The keloid’s characteristic of extending beyond the original wound is helpful in differentiating between the two. Keloids are often hypersensitive or pruritic; hypertrophic scars may or may not be pruritic. Although helpful at times, these distinctions may be blurred enough to be of limited usefulness clinically. Dermatofibrosarcoma protuberans is a slowly growing, firm, dermal, fibrous mass that at times can look similar to a keloid. These lesions are usually solitary, there is no preceding history of skin trauma, and they can be readily differentiated histologically. Exuberant keloid formation is a feature of Rubinstein–Taybi syndrome144,145 and should be considered in patients with spontaneous keloids and dysmorphic features.

Therapy and prognosis Many treatment modalities have been proposed for the treatment of keloids, most with limited success. Currently, the most utilized treatment, either alone or combined with surgery, is

repeated intralesional injections of triamcinolone.142 Steroids increase the rate of collagen degradation. Murray et al.138 recommend utilizing test doses of triamcinolone acetonide in concentrations varying from 10 to 40 mg/mL injected into various keloid sites to establish a minimum effective dose for each patient; there is considerable variation in patient response. A topical anesthetic under occlusion can be applied prior to injection. Keloidal tissue is extremely dense and difficult to inject. A Luer-Lok syringe can be helpful. Cryotherapy with liquid nitrogen has been recommended before injection because the freeze causes the keloid to become edematous and therefore less dense. Injections are repeated on a monthly basis.138 Care must be taken to infuse the injection into the bulk of the keloid, rather than into the contiguous dermis or epidermis, to minimize steroidinduced perilesional atrophy and to prevent extension of the keloid from the injection. Other injectables reported to have effect include bleomycin, 5 fluorouracil, and interferon.142 If unresponsive to intralesional steroids, surgical excision is an option, frequently in combination with intra-lesional steroids. The wound edges are injected at the time of keloidectomy and at 2–4 week intervals postoperatively, usually with triamcinolone acetonide 10 mg/mL. Adverse effects of corticosteroid use include localized atrophy, telangiectasia, depigmentation, necrosis, and ulceration. If systemic absorption is significant, the patient can become Cushingoid. Most of these effects are reversible. If the patient is exquisitely sensitive, the injection itself may incite further keloid formation. Keloids usually recur after simple excision; .therefore excision is usually combined with other modalities such as intralesional and oral corticosteroid or pressure therapy. To reduce the probability of recurrence, it is recommended that a minimum amount of suture be used, that hematoma and wound dead space be avoided, and wound tension minimized.138 To achieve the latter, flaps or Z-plasties are frequently performed. The presence of residual keloid tissue remaining after excision does not enhance recurrence, and it is reported that only the central area of the keloid needs excising.149 Pressure applied to the area after surgical excision may prevent recurrence, but constant pressure must be maintained for 4–6 months postoperatively, which is difficult to achieve. Application to the earlobe with a spring-clip clothespin-like device150 and to other areas with various types of elastic wraps may be helpful. Carbon dioxide laser removal of keloids compared with surgical excision does not reduce recurrence. However, when used in

combination with intralesional corticosteroids and secondary intention wound healing, results have been good in some patients.141 Some authors believe that the 585-nm flashlamppumped pulsed dye laser improves the erythema, height, and pliability of some keloids and hypertrophic scars.151 A therapeutic option that is effective in some patients is the topical application of a sheet of silastic gel. Initially thought to exert an effect through pressure, new findings suggest the mechanism of action is by hydration and occlusion,152 or that the surface electrical charge of the skin is altered. Silicone gel and non-silicone gel dressings may be equally effective.153 X-ray treatment in the immediate postoperative period is thought to be an effective measure for preventing recurrence: X-ray treatment of benign lesions in children is controversial because of the potential long-term hazards of radiation. Protocols that combine surgical excision with radiation, including low-megavoltage single-dose electron beam and roentgen irradiation have been used in adults.141,154 The response to imiquimod has been good in some instances and not in others.155–158 Methotrexate,159 other cytotoxic agents,97,159 and topical retinoic acid solution 0.05% have been recommended.159 When the latter was applied to 28 patients with keloids and hypertrophic scars, 77% had decreased pruritus and bulk.159 Some reports advocate the use of cryotherapy in keloids that are less than 2 years’ duration.160,161 The cryogen was delivered intralesionally in one study.162

149. Lee Y, Minn KW, Baik RM, et al. A new surgical treatment of keloid: keloid core excision. Ann Plast Surg. 2001;46:135–140. 150. Russell R, Horlock N, Gault D. Zimmer splintage: a simple effective treatment for keloids following ear-piercing. Br J Plast Surg. 2001;54:509–510. 151. Manuskiatti W, Fitzpatrick RE, Goldman MP. Energy density and numbers of treatment affect response of keloidal and hypertrophic sternotomy scars to the 585-nm flashlamp-pumped pulsed-dye laser. J Am Acad Dermatol. 2001;45:557–565. 152. Sawada Y, Sone K. Hydration and occlusion treatment for hypertrophic scars and keloids. Br J Plast Surg. 1992;8:599. 153. de Oliveira GV, Nunes TA, Magna LA, et al. Silicone versus nonsilicone gel dressings: a controlled trial. Dermatol Surg. 2001;27:721–726. 154. Ragoowansi R, Cornes PG, Glees JP, et al. Ear-lobe keloids: treatment by a protocol of surgical excision and immediate postoperative adjuvant radiotherapy. Br J Plast Surg. 2001;54:504–508. 155. Berman B, Harrison-Balestra C, Perez OA, et al. Treatment of keloid scars post-shave excision with imiquimod 5% cream: A prospective, doubleblind, placebo-controlled pilot study. J Drugs Dermatol. 2009;8(5):455–458.

156. Stashower ME. Successful treatment of earlobe keloids with imiquimod after tangential shave excision. Dermatol Surg. 2006;32(3):380–386. 157. Cacao FM, Tanaka V, Messina MC. Failure of imiquimod 5% cream to prevent recurrence of surgically excised trunk keloids. Dermatol Surg. 2009;35(4):629–633. 158. de Mesquita CJ, Leite JA, Fechine FV, et al. Effect of imiquimod on partial-thickness burns. Burns. 2009;36(1):97–108. 159. De Limpens J. The local treatment of hypertrophic scars and keloids with topical retinoic acid. Br J Dermatol. 1980;103:319. 160. Rusciani L, Rossi G, Bono R. Use of cryotherapy in the treatment of keloids. J Dermatol Surg Oncol. 1993;19:529. 161. Zouboulis CC, Blume U, Buttner P, et al. Outcomes of cryosurgery in keloids and hypertrophic scars. Arch Dermatol. 1993;129:1146. 162. Gupta S, Kumar B. Intralesional cryosurgery using lumbar puncture and/or hypodermic needles for large, bulky, recalcitrant keloids. Int J Dermatol. 2001;40:349–353. 163. Dinehart SM, Herzberg AJ, Kerns BJ, et al. Acne keloidalis: a review. J Dermatol Surg Oncol. 1989;15:642.

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ACNE KELOIDALIS NUCHAE

Sclerosing and atrophying conditions

Prognosis In general, keloids continue to enlarge slowly for some years, then remain dormant, and eventually flatten over many years (Krafchik, pers. comm., 2002). Hypertrophic scars flatten spontaneously after 1–3 years.

ACNE KELOIDALIS NUCHAE Acne keloidalis nuchae (folliculitis nuchae, folliculitis keloidalis, sycosis nuchae, or dermatitis papillaris capillitii) is a chronic inflammatory and scarring folliculitis and perifolliculitis that occurs on the nape of the neck and on the occipital scalp, usually in black males. It was first called dermatitis papillaris capillitii by Kaposi in 1869.163 Basin introduced the term acne keloidalis to describe the later stages of the process.163 Hebra added the

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term sycosis frambesiformis, referring to the raspberry-like appearance of the clustered papules.163

Epidemiology The disease can occur occasionally in whites and women, but it is primarily a disease of young black males.163 It does not occur in young children. In a study of 453 high school, college, and professional football players, acne keloidalis was associated with a family history of similar lesions or a positive personal or family history of keloid formation.164

Presenting history ACNE KELOIDALIS NUCHAE

The patient complains of papules in the occipital area that may slowly increase in size and number; they may be pruritic and are often associated with hair loss. Many patients report a short haircut or shaving of the nape of the neck before the onset of the problem.

Physical examination Firm, dull-pink, 1–3 mm rounded, hard, follicular papules develop along the posterior hairline of the scalp (Fig. 18.7). Early papules may show a hair protruding from the center of the lesion, which has been described by Cosmon and Wolff165 as ‘trees being engulfed by a moving sand dune.’ The hair is not embedded or ingrown. Pustules are occasionally present. As the disease progresses, the papules enlarge, coalesce and may form tumors or a thick sclerotic pseudokeloidal band across the occipital area of the scalp; the area is eventually devoid of hair. Draining purulent sinus tracts occasionally develop. There is usually no evidence of acne vulgaris, folliculitis, or keloid formation in other areas.

Laboratory findings Staphylococcus aureus is present in intact pustules or from surface cultures in 75% of cases.163 There are no other known abnormalities.

Pathophysiology and histogenesis Initially, there is a lymphocytic and neutrophilic folliculitis of the upper third of the hair follicle. This is followed by a perifolliculitis. Later, excessive fibroplasia becomes the dominant feature. Hair follicles disappear or are engulfed by deep collagenous bands that are separated by sheets of plasma cells. The exact mechanism of scar production is unclear. The lesions are not ingrown hairs, as in pseudofolliculitis barbae. They are also not true keloids, as evidenced by the histologic differences and the absence of keloid formation elsewhere. Almost all patients have used hair pomades, and in many there is a history of trauma from a close haircut or friction from a stiff collar. S. aureus is frequently present, but its role in the pathophysiology is probably secondary. There are a few reports of an association with the use of cyclosporin, possibly because cyclosporin can stimulate granulation tissue.166

Differential diagnosis Perifolliculitis capitis abscendens et suffodiens (dissecting cellulitis) is also a chronic disease of the scalp that occurs primarily in blacks and causes alopecia. The primary lesions in this disease are nodules containing purulent material that coalesce to form interlacing sinus tracts, in contrast to the fleshy papules and scars of acne keloidalis; often, there is an associated severe acne or hidradenitis suppurativa. In folliculitis decalvans, a pustular dermatitis results in scarring alopecia; there are no raised papules. With a true keloid, there is usually a history of preceding trauma.

Therapy and prognosis

Figure 18.7  Acne keloidalis in a teenage patient with Down syndrome.

164. Knable AL Jr, Hanke CW, Gonin R. Prevalence of acne keloidalis nuchae in football players. J Am Acad Dermatol. 1997;37:570–574. 165. Cosmon B, Wolff M. Acne keloidalis. Plast Reconstr Surg. 1972;50:25. 166. Carnero L, Silvestre JF, Guijarro J, et al. Nuchal acne keloidalis associated with cyclosporine. Br J Dermatol. 2001;144:429–430.

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The disease is difficult to treat. A recent roundtable discussion summarizes approaches to therapy.167 Antiseptics and topical and systemic antibiotics are often used empirically. Some success occurs with the frequent administration of intralesional cortico­ steroids in combination with systemic or topical antibiotics and/or cryotherapy or carbon dioxide laser therapy. Localized excision with healing by secondary intention is advocated for patients with severe disease. Local excision with primary closure is an alternative.168 For patients with severe disease, Glenn et al. advocate an elliptical excision down to the level of the fascia or deep subcutaneous tissues of the posterior aspect of the scalp including the posterior hairline followed by secondary intention healing.168 Local excision with primary closure, in one or multiple stages, is an alternative.169

167. Acne keloidalis nuchae. Dermatol Ther. 2007;20:128–132. 168. Glenn MJ, Bennett RG, Kelly AP. Acne keloidalis nuchae: treatment with excision and second intention healing. J Am Acad Dermatol. 1995;33(2 Pt 1):243–246. 169. Gloster JM Jr. The surgical management of extensive cases of acne keloidalis nuchae. Arch Dermatol. 2001;136(11):1376–1379.

Sclerosing and atrophying conditions

Ainhum is a condition characterized by the development of constricting bands around a digit that may ultimately lead to spontaneous amputation. The term is derived from an African word meaning ‘to saw.’ True ainhum, compared with pseudoainhum, is a disease seen mostly in middle-aged men of African descent. Constricting bands can also be found in other situations, and then the term pseudo-ainhum is used. There are several categories of pseudo-ainhum: congenital constricting bands, acquired ainhum-like bands associated with other diseases, and constriction due to artifacts.170

Epidemiology True ainhum (dactylolysis spontanea) is primarily a disease seen in tropical Africa in black males who are usually barefoot. In a series by Cole,171 of patients admitted for any reason to a university hospital in Nigeria, ainhum was present in 2%. It has also been reported in all races and in many parts of the world. At least 125 cases have been reported in the USA, most occurring in the South.172 Truae ainhum usually occurs in adults, but may occasionally occur in children.170 The epidemiology of pseudo-ainhum is more complex, since it is not a single entity. Congenital constricting bands are usually not inherited, although there have been several familial cases reported.170 Pseudo-ainhum due to tourniquets from a hair or thread constricting a digit is seen in infants and children and occasionally in the mentally retarded.

Presenting history In true ainhum, the patient or parent notes the gradual development and widening of a groove at the base of the toe. Edema may develop distally and the underlying bone resorbs. The patient is usually asymptomatic, although there may be intermittent pain. The process slowly progresses over the ensuing 3–10 years, leaving a digit dangling by a piece of soft tissue. Finally, this necrotizes, and autoamputation is complete. In pseudo-ainhum, the patient presents with a band-like constriction; it is acute if due to external forces such as tourniqueting by a hair or thread.

Physical examination

encircle the toe finally.173 The usual site of involvement is the fifth toe; this is usually bilateral but may be unilateral. Edema develops distally, and the underlying bone resorbs.

Congenital pseudo-ainhum due to amniotic bands In congenital pseudo-ainhum, fibrous bands are found encircling one or more parts of the body, usually the distal portion of an extremity.170 Any part of the body may be involved, including the trunk. In extreme cases, spontaneous in utero amputation may result. Bands vary from shallow depressions to deep constrictions that may extend to and involve bone. They can be single or multiple. More than 50% of affected patients have other associated congenital anomalies, most commonly syndactyly or club foot. Occasionally, cleft palate and lip, aplasia cutis, or microdactyly is present.174 Amniotic bands can occasionally be associated with large body-wall defects causing visceral extravasation of thoracic and/or abdominal organs.175

AINHUM AND PSEUDO-AINHUM

AINHUM AND PSEUDO-AINHUM

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Pseudo-ainhum due to acquired ainhum-like bands associated with other diseases Pseudo-ainhum which is not present at birth can be associated with a variety of diseases.170 These include conditions that diminish the vascular supply, such as Raynaud’s disease, diabetes, and scleroderma, and conditions that diminish sensation, such as leprosy, tertiary lues, syringomyelia, and peripheral neuritis. Constricting bands and digit loss may occur in the verrucous hyperkeratotic plantar lesions of yaws. Vohwinkel syndrome is a hereditary condition in which palmar and plantar hyperkeratoses and starfish-shaped and linear keratoses are found on the extremities; constricting bands may develop at puberty.176,177 Other palmar/plantar keratodermas and the keratoderma associated with pityriasis rubra pilaris, pachyonychia congenita, lamellar ichthyosis178 and Papillon–Lefèvre syndrome179 can be associated with pseudo-ainhum. A patient was reported with palmar psoriasis who developed pseudo-ainhum of a digit as a result of a thick epidermal cast.180 In this patient, the condition resolved when the cast was removed. Traumatic scarring from burns and frostbite may also cause constricting scars, as can epidermolysis bullosa.181 Psuedo-ainhum developed in a patient with linear scleroderma.182

Ainhum

Pseudo-ainhum due to constriction from artifacts (tourniquet syndrome)

A sulcus or groove occurs at the base of the toe on the plantar surface and gradually deepens and widens circumferentially to

Threads, hair, or other strands may encircle a body part, such as a digit, nipple, clitoris or the penis (Fig. 18.8).183 This results in

170. Raque CJ, Stein KM, Lane JM, et al. Pseudoainhum constricting bands of the extremities. Arch Dermatol. 1972;105:434. 171. Cole GJ. Ainhum: an account of 54 patients with special reference to etiology and treatment. Br J Bone Joint Surg. 1965;47:43. 172. Rossiter JW, Anderson PC. Ainhum: treatment with intralesional steroids. Int J Dermatol. 1976;15:379. 173. Browne SG. Ainhum. Int J Dermatol. 1976;15:348. 174. Izumi AK, Arnold HL. Congenital annular bands (pseudoainhum): association with other congenital abnormalities. JAMA. 1974;229:1208. 175. Martinez-Frias ML, Bermejo E, Rodriquez-Pinilla E. Body stalk defects, body wall defects, amniotic bands with and without body wall defects, and gastroschisis: comparative epidemiology. Am J Med Genet. 2000;92:13–18. 176. Camisa C, Rossana C. Variant of keratoderma hereditaria mutilans (Vohwinkel’s syndrome): treatment with orally administered isotretinoin. Arch Dermatol. 1984;120:1323.

177. Peris K, Salvati EF, Torlone G, et al. Keratoderma hereditarium mutilans (Vohwinkel’s syndrome) associated with congenital deaf-mutism. Br J Dermatol. 1995;132:617–620. 178. Al Aboud K, Al Hawsawi K, Ramesh V. Bilateral pseudoainhum in lamellar ichthyosis. Pediatr Dermatol 2004:21(2):181. 179. Mashhood AA, Humayun A, Saleem M, et al. Papillon–Lefevre syndrome associated with pseudoainhum. J Am Acad Dermatol. 2004;51:S134–S136. 180. McLaurin CI. Psoriasis presenting with pseudoainhum. J Am Acad Dermatol. 1982;7:130. 181. Kim YS, Hong HJ, Roh TS. Surgical correction of pseudoainhum in chronic epidermolysis bullosa: a case report. J Plast Reconstr Aesthet Surg. 2009;62:e191–e193. 182. Park BS, Hyun Cho K, Youn JI, et al. Pseudoainhum associated with linear scleroderma. Arch Dermatol. 1996;132:1520–1521. 183. Alpert JJ, Filler R, Glaser H. Strangulation of an appendage by hair wrapping. N Engl J Med. 1965;273:866.

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AINHUM AND PSEUDO-AINHUM

Figure 18.8  Pseudo-ainhum: constriction of toe from a hair. (Courtesy of Dr Peter Lynch.)

acute soft tissue swelling that causes the ligating band to be invisible, making the diagnosis difficult. The problem is usually seen in infants and children, but can occur in adults. Five affected infants were analyzed by Quinn,184 who reported fine threads from clothing embedded in the skin of two affected children; the remaining three cases were due to tourniqueting by human hair. Although usually accidental, this problem may be self-induced or may be a manifestation of child abuse.184

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the subcutaneous fat. Coarse elastic fibers extended into the connective tissue strands. Sweat glands were present and normal in appearance. The cause of congenital bands is unknown. It is assumed to be a developmental abnormality. It has been suggested that the amniotic membrane may adhere to the fetus and in some way trigger the formation of a constricting band, or that the amniotic membrane itself may encircle the affected part.186 If this is so, it is difficult to understand why the constrictions seen are always circular instead of spiral.186 A theory that the umbilical cord encircles the part to cause the constriction is doubtful because the cord is thicker than the digits of the fetus.186 It has been assumed that cases of congenital amputation are an extreme form of pseudo-ainhum in which the annular constricting bands are deep enough to constrict the limb during embryonic growth, causing in utero amputation. There have been several reports of infants born with the absence of a limb in whom the amputated part is recovered at delivery.170 Embryologists have thought that limb amputation may be due to a focal degenerative process in the limb itself and not due to extrinsic factors.170 Moessinger187 reported cases of congenital constricting bands in which there was a history of amniocentesis. There are rare cases of hereditary congenital pseudo-ainhum, and congenital constricting bands have been associated with Ehlers–Danlos syndrome.188

Differential diagnosis The diagnosis is obvious from the appearance of the affected part. The type of ainhum or pseudo-ainhum is diagnosed according to the presence of the lesion at birth or later, its location, the presence of associated conditions and the finding of constricting material.

Pathophysiology and histogenesis

Treatment and prognosis

The exact cause of true ainhum is not known, but is probably related to fissuring and infection of the plantar sulcus from walking barefoot. The fissure heals temporarily but breaks down when the toe is extended while walking.173 This chronic trauma results in the disease process. Four cases reported from India were associated with Trichosporon cutaneum infection,185 but in the series of 83 cases from Nigeria,173 no cases of dermatophyte infection were identified. The only constant feature in these patients was chronic fissuring at the site of constriction, often in patients with hyperkeratotic skin. Other theories suggest that ainhum might be due to an abnormal blood supply to the foot, either as a partial blockade of the posterior tibial artery, or to the absence of the plantar arch artery and its branches.173 Congenital amniotic bands are not due to the formation of scar tissue. A skin biopsy obtained after partial surgical excision of a band from an infant’s ankle showed deep invagination of the skin in the central portion of the specimen, with thinning of the underlying dermis.170 Beneath the thin dermis were fingerlike strands of connective tissue that projected down deep into

The acute onset of constriction with erythema and edema of the distal portion of the body part should prompt consideration of the tourniquet syndrome. Treatment of the tourniquet syndrome requires ligation of the offending fiber. Because the area is often edematous, this is not an easy procedure and when the problem has been present for some time, the offending fiber may be buried in scar tissue. If the end of a thread is visible, it can be explored with fine-tipped forceps, but this may result in incomplete removal. If these measures are not feasible, a deep longitudinal incision across the constriction is effective. Constrictions caused by congenital bands do not usually require intervention, other than for cosmetic reasons, or rarely if gangrenous changes develop soon after birth.170 These bands do persist, however, and can still be seen in the adult.174 The pseudo-ainhum of several patients with severe keratodermas have temporarily improved on treatment with a systemic retinoid.176,177 Patients with pseudo-ainhum from severe keratodermas have been successfully treated surgically by excision of the constriction band and closure with Z-plasties,171,189,181

184. Quinn NJ. Toe tourniquet syndrome. Pediatrics. 1971;48:145. 185. Kamalam A, Thambiah AS. Ainhum, trichosporosis, and Z-plasty. Dermatologica. 1981;162:372. 186. Neumann A. Pseudoainhum: report of congenital case involving several fingers and left wrist. Arch Dermatol Syphilol. 1953;68:421.

187. Moessinger AC. Amniotic band syndrome associated with amniocentesis. Am J Obstet Gynecol. 1981;141:588. 188. Young ID, Lindenbaum RH, Thompson EM, et al. Amniotic bands in connective tissue disorders. Arch Dis Child. 1985;60:1061. 189. Luk KDK, Orth MC, Wu PC, et al. Keratoma hereditaria mutilans: report of a case with successful surgical treatment. Am J Hand Surg. 1986;11A:269.

Sclerosing and atrophying conditions

STRIAE Mature striae are linear, white, atrophic bands, commonly called ‘stretch marks; ‘ other medical synonyms include striae distensae and striae atrophicae.

ate or tear.193 Striae of pregnancy occur most commonly on the abdomen and on the breasts. The striae of Cushing syndrome are typically wider and more broadly distributed. Striae induced by topical corticosteroid use are often found in the inguinal folds192 but may occur in almost any areas on which a topical corticosteroid is used, particularly on thin skinned areas or under occlusion, and when the product used is potent.

Laboratory findings There are no known laboratory abnormalities unless the patient has Cushing syndrome, in which case serum and urinary glucocorticoid levels are increased.

Pathophysiology and histogenesis

Striae are linear lesions, commonly several centimeters long and 1–10 mm wide. Their long axis is oriented perpendicular to the direction of skin tension lines. Commonly affected sites include the thighs, buttocks, and breasts in girls and the outer thighs and lumbosacral area in boys. The earliest lesion is usually raised and pink, but soon becomes flat and vivid blue-red in color with a fine wrinkled surface. Over time, the lesion becomes white and less conspicuous. Very rarely, severe, extensive striae may ulcer-

Striae result from breaks in the connective tissue. Some individuals are more susceptible to the development of striae than others.194 There is a familial predisposition.195 It has been hypothesized that striae are caused by stretching of the dermal skin and that physical stress ruptures connective tissue. However, striae almost never develop after the use of tissue expanders,196 although there are rare exceptions,197–199 implying there are factors other than mechanical stresses alone. Striae are associated with weight gain, especially if the weight gain is rapid.200 If skin distension is slow and progressive, striae are less likely to develop. Striae cannot be produced experimentally and there is no animal model. In pregnancy, females with greater weight gain, primigravidas, and younger pregnant women are more likely to develop striae.201 Striae are less common in older primigravidas. A history of breast or thigh striae during adolescence is predictive of striae developing during pregnancy.202 Striae gravidarum do not occur in pregnant females with Marfan syndrome.200 Obesity is associated with the presence of striae only at puberty191 or with associated corticosteroid use. Striae are absent in obese pre-adolescents. When striae occur after systemic corticosteroid use, they do not usually develop until adolescence, implying some priming by hormonal factors. Striae have been noted in cachectic states, such as tuberculosis, typhoid fever, and after intense slimming diets. The striae associated with endogenous or topical corticosteroids are thought to be caused by the epidermal and dermal atrophy that corticosteroids can induce.203 Atrophy occurs because of epidermal thinning and a reduction in dermal collagen. Histologic evidence of epidermal atrophy in human skin

190. Ahn SJ, Oh SH, Chang SE, et al. A case of infantile psoriasis with pseudoainhum successfully treated with topical pimecrolimus and low-dose narrowband UVB phototherapy. J Eur Acad Dermatol Venereol. 2006;20:1332–1334. 191. Sisson WR. Colored striae in adolescent children. J Pediatr. 1954; 45:520. 192. Barkey WF. Striae and persistent tinea corporis related to prolonged use of betamethasone dipropionate 0.05% cream/clotrimazole 1% cream (Lotrisone cream) (letter). J Am Acad Dermatol. 1987;17:518. 193. Stroud JD, Van Dersarl JV. Striae. Arch Dermatol. 1971;103:103. 194. Pottkotter L, Pyeritz RE, Glesby MJ. Striae and systemic abnormalities of connective tissue. JAMA. 1989;262:3132. 195. DiLernia V, Bonci A, Cattania M, et al. Striae distensae (rubrae) in monozygotic twins. Pediatr Dermatol. 2001;18:261–262. 196. Marcus J, Horan DB, Robinson JK. Tissue expansion: past, present and future. J Am Acad Dermatol. 1990;23:813–825.

197. Ergun SS, Ozcan RH, Kural YB. Striae distensae: A rare complication resulting from overinflation of the tissue expander. Aesth Plast Surg. 2007;606–607. 198. Chan WY, Akhtar S, Phipps AR. Striae distensae in tissue-expanded skin in the upper arm. Ann of Plast Surg. 2006;57:240–241. 199. Huang GJ, York CE, Mills DC. Striae distensae as a complication of augmentation mammaplasty. Plast Reconstr Surg. 2008;122;90e–93e. 200. Elsaie ML, Baumann LS, Elsaaiee LT. Striae distensae (stretch marks) and different modalities of therapy: an update. Dermatol Surg. 2009;35:563–573. 201. Osman H, Rubeiz N, Tamim H, et al. Risk factors for the development of striae gravidarum. Am J Obstet Gynecol. 2007;196:62.e1–e5. 202. Chang Al, Agredano YZ, Kimball AB. Risk factors associated with striae gravidarum. J Am Acad Dermatol. 2004;51:881–885. 203. Epstein NN, Epstein WL, Epstein JH. Atrophic striae in patients with inguinal intertrigo. Arch Dermatol. 1963;87:450.

Epidemiology Striae occur most frequently during puberty as a physiological change or in women during pregnancy. They are common at puberty and are found in more than 25% of girls and about 10% of boys aged 9–16.191 They do not develop in the elderly. Striae may be found in endocrine disease, especially in Cushing syndrome, and may occur as a side-effect of systemic corticosteroids, and in some patients after prolonged use of high-potency topical corticosteroids, especially if used under occlusion in pubertal children.192 Their presence is one of the minor diagnostic criteria for Marfan syndrome.

Presenting history The patient notes the appearance of asymptomatic linear lesions that may initially be raised and red but over a period of months to years become white and flat.

Physical examination

STRIAE

A child with pseudo-ainhum and psoriasis improved after treatment with topical pimecrolimus and narrowband UVB phototherapy.190 True ainhum is a progressive problem that ultimately results in spontaneous amputation. Cole171 reported reversal of the problem by excision of the groove, followed by single or multiple Z-plasties. Others reported reversal of the process in a patient treated early in the course of the disease with monthly injections of intralesional triamcinolone acetonide, 5 mg/mL, for 10 months.172

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after 1 week of daily occlusion with fluocinolone acetonide has been reported.204 The histologic findings are similar to that of a scar.200 The epidermis overlying striae is flattened and thin. As in scars, appendageal structures are lost. Biopsy specimens of striae rubrae show a perivascular inflammatory infiltrate with lymphocytes, monocytes, occasional neutrophils, an increased number of mast cells, and fibroblasts.200 Sheu et al.205 describe mast cell degranulation and elastolysis in the early stage of striae distensae. In mature striae, there has been controversy whether the problem is with the elastic fibers or with the collagen fibers. Zheng et al.206 concluded that the elastic fibers in mature striae are normal. They are dense and well developed on scanning electron microscopy, and may have been previously underestimated with routine staining because immature fibers contain an insufficient protein matrix and do not stain well. The same authors showed that the collagen fibers are packed horizontally in bundles and are thin and straight, in contrast to the wavy, thick, randomly arranged collagen fibers seen in normal skin. This horizontal stacking of collagen is identical to the connective tissue arrangement seen in scars. They concluded that striae are scars. This conclusion is strengthened by the fact that, because of the great tensile strength of collagen fibers, it is not possible in an in vivo situation for mechanical stretching to cause parallel alignment of collagen fibers. They further hypothesized that in the early stage of striae formation (striae rubrae), there is an inflammatory reaction that destroys collagen and elastin. Healing would then occur, with regeneration of new elastin and collagen and orientation of the collagen fibers in the direction of stress imposed by mechanical forces.206 It has been demonstrated that striae are associated with a loss of fibrillin, which could explain a beneficial effect from retinoic acid therapy.

LICHEN SCLEROSUS Lichen sclerosus (LS) is an uncommon disease of unknown cause in which white, atrophic plaques develop on the body and/or vulva, penis, and perianal areas. The disease is seen most commonly in prepubertal girls and boys and in adults over 50 years.207 Previously called lichen sclerosus et atrophicus, the designation is now LS. In the past, pruritic white lichenified plaques on the vulva were called kraurosis vulvae (kraurosis means ‘shriveling’) (McKay, pers comm, 2002). It was not appreciated at the time that many but not all patients with kraurosis vulvae actually had LS by histologic examination.208 When the disease involves the genital area of males, it is known as balanitis xerotica obliterans. Some believe LS to be a variant of morphea and the two conditions can co-exist in the same patient.

Epidemiology

The patient can be reassured that, over time, the lesions will become less noticeable. If the striae are due to systemic or topical

LS may occur at any age and in either sex. Of affected individuals, 10–15% have the onset before the age of 13, and 70% of childhood cases begin before 7 years.209,210 The youngest reported case was several weeks of age.209 The disease has no recognized inherit­ance pattern, although familial cases have been reported, and up to 17% of children with LS have a family history of the disease.211–213 There may also be a family history of autoimmune diseases including vitiligo, morphea, and thyroid disease.214 Initially thought to be a disease mostly affecting females, studies show equal prevalence of LS in females and males. In a cross-sectional study of 50 237 outpatient dermatologic visits, 0.22% were for LS.207 Of 130 prepubertal girls reporting to a pediatric dermatology clinic with a vulvar complaint, 18% had LS.215 Genital LS in males occurs at any age, more commonly in young men, with the highest incidence between the ages of 9–11 years.207,216 LS is the most common indication for circumcision for phimosis in males.217 In a prospective study of 1178 boys with phimosis, 40% had LS.216,218

204. Arndt KA, Clark RA. Principles of topical therapy. In: Fitzpatrick FB, Eisen AZ, Wolff K, et al, eds. Dermatology in general medicine, New York: McGraw-Hill; 1979:1753. 205. Sheu HM, Yu HS, Chang CH. Mast cell degranulation and elastolysis in the early states of striae distensae. J Cutan Pathol. 1991;18:41. 206. Zheng P, Lavker RM, Kligma AM. Anatomy of striae. Br J Dermatol. 1985;112:185. 207. Kyriakis KP, Emmanuelides S, Terzoudi S, et al. Gender and age prevalence distributions of morphea en plaque and anogenital lichen sclerosus. JEADV. 2007;21:825–826. 208. Ridley CM. Lichen sclerosus. Dermatol Clin. 1992;10:309–323. 209. Chernosky ME, Derbes VJ, Burks JW. Lichen sclerosus et atrophicus in children. Arch Dermatol. 1957;75:647. 210. Clark JA, Mulb SA. Lichen sclerosus et atrophicus in children. A report of 24 cases. Arch Dermatol. 1967;95:476. 211. Murphy FR, Lipa M, Haberman HF. Familial vulvar dystrophy of lichen sclerosus type. Arch Dermatol. 1982;117:329.

212. Sahn EE, Bluestein EL, Oliva S. Familial lichen sclerosus et atrophicus in childhood. Pediatr Dermatol. 1994;11:160–163. 213. Powell J, Wojnarowska F. Childhood vulvar lichen sclerosus: an increasingly common problem. J Am Acad Dermatol. 2001;44:803–806. 214. Powell J, Wojnarowska F, Winsey S, et al. Lichen sclerosus premenarche: autoimmunity and immunogenetics. Br J Dermatol. 2000;142:481–484. 215. Fischer G, Rogers M. Vulvar disease in children: a clinical audit of 130 cases. Pediatr Dermatol. 2000;17:1–6. 216. Kiss A, Kiraly L, Kutasy B, et al. High incidence of balanitis xerotica obliterans in boys with phimosis: prospective 10-year study. Pediatr Dermatol. 2005;22:305–308. 217. Chalmers RJ, Burton PA, Bennett RF, et al. Lichen sclerosus et atrophicus. A common and distinctive cause of phimosis in boys. Arch Dermatol. 1984;120:1025–1027. 218. Meuli M, Briner J, Hanimann B, et al. Lichen sclerosus et atrophicus causing phimosis in boys: a prospective study with 5-year followup after complete circumcision. J Urol. 1994;152:987–989.

Differential diagnosis The diagnosis is usually obvious because of the distribution and linearity of the lesions, and the lack of preceding trauma, as in a scar. The fish-mouthed scars of Ehlers–Danlos syndrome may resemble striae, but occur after mild trauma and are usually located over the knees and elbows. Endocrine evaluation to exclude the diagnosis of Cushing syndrome is recommended if there is no other obvious cause and the lesions are severe.

Therapy and prognosis

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corticosteroids, the medication should be reduced or stopped if possible. Many advocate the topical application of tretinoin, especially for striae rubrae. No single modality has been consistently more effective than others.200 Therapies include hydrating creams, oil massage, glycolic, alphahydroxy and trichloroacetic acid peels, microdermabrasion, fractional photothermolysis, radiofrequency devices, and various lasers, including the pulsed-dye, excimer and ND:YAG.200

B

A

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LICHEN SCLEROSUS

Sclerosing and atrophying conditions

C

Figure 18.9  (A) Lichen sclerosus on the leg of a 14-year-old girl. (B) Lichen sclerosus with purpura on labia. (C) Classic hourglass appearance of lichen sclerosus.

Presenting history

The characteristic primary lesion of extragenital LS is a shiny, ivory-white angular macule or papule several millimeters in diameter. Papules may coalesce into plaques of various sizes that, over time, become atrophic and show fine wrinkling of the epidermis (Fig. 18.9A). Within the plaques, the follicular open-

ings are characteristically dilated and hyperkeratotic (called follicular delling) and appear prominent and plugged. The plaques may occur anywhere, but are often distributed over the clavicles, on the chest and back, around the umbilicus, and on the flexor surfaces of the extremities, neck, and axillae. Occasionally, extensive bullae, telangiectasias, and purpura are found. On resolution, the bullae may heal with milia. The Koebner phenomenon has been documented in this disorder, and lesions may occur in surgical scars, vaccination sites, and other areas of trauma or irritation. Lesions of biopsy-proven LS may occur in association with biopsy-proven morphea. The shiny white changes seen in both disorders are the result of epidermal thinning. Occasionally, blue and white plaques may occur inside the mouth, on the tongue, or on mucosal surfaces. Some patients have associated vitiligo. Genital LS in females presents with white, atrophic plaques on vulval and perianal areas in an hourglass or figure-of-eight configuration (Fig. 18.9B,C). Bullae with hemorrhage may occur and small telangiectasias and purpuric areas are common. Because of friction and moisture in the area, the affected skin may break down resulting in a raw, red, macerated surface. There

219. Loening-Baucke V. Lichen sclerosus et atrophicus in children. Am J Dis Child. 1991;145:1058. 220. Labandeira J, Pereiro M, Roson E, et al. Rectorrhagia and lichen sclerosus in childhood. Pediatr Dermatol. 2001;18:543–545.

221. Attaran M, Rome E, Gidwani GP. Unusual presentation of lichen sclerosus in an adolescent. J Pediatr Adolesc Gynecol. 2000;13:99. 222. Maronn ML, Esterly NB. Constipation as a feature of anogenital lichen sclerosus in children. Pediatrics. 2005;115:e230–e232.

Most patients present with pruritus and discomfort in the vulvar area. Another presentation is with constipation and painful defecation due to perianal LS.219 Bleeding is a rare presentation.220 There is one case report of urinary incontinence from partial obstruction of the urethra due to LS involving the vulva and clitoral head.221 A vaginal discharge may precede the disease. In a retrospective review of 18 girls with LS, 78% experienced itching, 67% severe constipation, and 89% at least one gastrointestinal symptom.222 Extragenital LS may be pruritic or asymptomatic; patients may present because their parents noticed the skin lesions.

Physical examination

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LICHEN SCLEROSUS

are several case reports of infantile pyramidal protrusion as a manifestation of LS.223 Infantile pyramidal protrusion is a pyramid-shaped red soft tissue swelling that can occur on the perineal median raphe of girls: it is often misdiagnosed as a ‘skin tag,’ skin biopsy shows epidermal acanthosis, marked edema of the upper dermis, and mild dermal inflammation.224 Of the four girls in this report, three had subtle classic LS and the other patient developed LS months later. All four pyramidal papules showed LS histologically. There is a relationship between vulvar LS, leukoplakia, and malignancy. The histological changes of LS are frequently found in association with vulvar squamous cell carcinoma, seemingly related to the role chronic inflammation can play in oncogenesis. Vulvar intraepithelial neoplasia was found in 9% of adult women with symptomatic LS in one series, and 21% had invasive squamous cell carcinoma.225 These dysplastic changes have not been found in children. However, there is one report of a woman with a known history of childhood LS resolving in puberty who succumbed to vulvar carcinoma at age 32.226 Information on the incidence of vulvar carcinoma in LS is sparse. A study from a tertiary referral center for vulvar disease revealed that of 1309 vulval biopsies, 191 had signs of LS and 53 of the latter showed vulvar squamous cell carcinoma: a rate of 27.7%.227 This number is much higher than previous estimates which may indicate selection bias. In affected males, the prepuce becomes sclerotic and cannot be retracted, and the glans is blue-white and shiny. Telangiec­ tasias or hemorrhagic bullae may occur, especially when the skin is irritated during intercourse. The bullae may cause blood-stained urine if located near the urethral meatus. When the perimeatal mucosa is involved, there may be difficulty in micturition because of phimosis,218 and back-pressure may affect the urinary tract. Occasionally the penile shaft is involved, but the scrotum and perianal area are almost always normal. Secondary leukoplakia and carcinoma may occur in males.228 In a retrospective review of the literature, the risk for malignant transformation in adults with penile LS was estimated to be 4–8%.229

The cause of the disease is unknown. The predominance of the condition in women, frequent onset at menopause, and spontaneous improvement in many patients at puberty all suggest a hormonal influence. Women with LS have low androgen levels,231 androgen receptors are diminished in lesional skin232 and there is local production of 5-alpha reductase.231 Skin biopsies from affected adult females revealed oxidative damage to lipids, DNA, and proteins in the affected skin.233 In 2000, a higher incidence of HLA-DQ7 in both children and adults with LS was reported.214 Further studies have found specific haplotypes with increased susceptibility to developing LS, while others may be protective.234 The common history of preceding vaginitis or balanitis suggests that infection may play a role. There is a clinical overlap between LS and localized scleroderma (morphea). B. burgdorferi infection has been implicated in some patients with morphea and in two patients with both morphea and extragenital LS in Europe but not in North America.34 The histology is distinctive. A skin biopsy shows thinning of the epidermis, vacuolar changes at the dermal–epidermal junction, marked edema of the papillary dermis, and a lymphohistiocytic infiltrate that is band-like and beneath the edematous zone. Vulvar LS may have histologic variants; the minimal histologic criterion for LS is vacuolar interface changes in conjunction with dermal sclerosis.235 The distribution of collagen I and III and of elastin and fibrillin is altered, which may contribute to the fragility, scarring, and atrophy seen clinically.236

Differential diagnosis

Autoantibodies against thyroid cytoplasm, gastric parietal cells,230 and against single-stranded DNA may be present.

The diagnosis is not difficult when typical lesions with follicular plugging are seen or when white plaques involve the anogenital area in an hourglass configuration. Other causes of white patches and plaques should be considered, including morphea, vitiligo, atrophic lichen planus, and annular discoid lupus erythematosus. Lesions in the vulva should be distinguished from candidiasis, bacterial vulvovaginitis, lichen simplex chronicus, pinworm infestations, and psoriasis. The disease may be mistaken for sexual abuse, but the diagnosis of LS should not exclude this possibility because there have been several reported cases of well-documented LS in sexually abused children.237

223. Cruces MJ, De La Torre C, Losada A, et al. Infantile pyramidal protrusion as a manifestation of lichen sclerosus et atrophicus. Arch Dermatol. 1998;134:1118–1120. 224. Kayashima K, Kitoh M, Ono T. Infantile perianal pyramidal protrusion. Arch Dermatol. 1996;132:1481–1484. 225. Carlson JA, Ambros R, Malfetano J, et al. Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia. Human Pathol. 1998;29:932–948. 226. Powell J, Wojnarowska F. Childhood vulvar lichen sclerosus. The course after puberty. J Repro Med. 2002;47:706–709. 227. Eva LJ, Ganesan R, Chan KK, et al. Differentiated-type vulval intraepithelial neoplasia has a high risk assocation with vulval squamous cell carcinoma. Int J Gynecol Cancer. 2009;19:741–744. 228. Weber P, Rabinovitz H, Garland L. Verrucous carcinoma in penile lichen sclerosus et atrophicus. J Dermatol Surg Oncol. 1987;13:529. 229. Ranjan N, Singh SK. Malignant transformation of penile LS: How common is it? Int J Dermatol. 2008;47:1308–1309. 230. Goolamali SK, Barnes EW, Irvine WJ, et al. Organ-specific antibodies in patients with lichen sclerosus. BMJ. 1974;4:78.

231. Friedrich EG Jr, Kalra PS. Serum levels of sex hormones in vulvar lichen sclerosus and the effects of topical testosterone. N Engl J Med. 1984;310:488. 232. Clifton MM, Garner IB, Kohler S, et al. Immunohistochemical evaluation of androgen receptors in genital and extragenital lichen sclerosus: evidence for loss of androgen receptors in lesional epidermis. J Am Acad Dermatol. 1999;41:43–46. 233. Sander CS, Ali I, Dean D, et al. Oxidative stress is implicated in the pathogenesis of lichen sclerosus. Br J Dermatol. 2004;151:627–635. 234. Gao XO, Barnardo MC, Winsey S, et al. The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated DRB10301/04/DQB10201/02/03 haplotype protects from vulval lichen sclerosus. J Invest Dermatol. 2005;125:895–899. 235. Carlson JA, Lamb P, Malfetano J, et al. Clinicopathologic comparison of vulvar and extragenital lichen sclerosus: histologic variants, evolving lesion, and etiology of 141 cases. Mod Pathol. 1998;11:844–854. 236. Farrell AM, Dean D, Millard PR, et al. Alterations in fibrillin as well as collagens I and III and elastin occur in vulval lichen sclerosus. J Eur Acad Dermatol Venereol. 2001;15:212–217. 237. Harrington CL. Lichen sclerosus (letter). Arch Dis Childh. 1990;65:335.

Laboratory findings

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Sclerosing and atrophying conditions

There is no known cure for this disease. Therapy is aimed at alleviating symptoms. Because non-genital lesions are usually asymptomatic, therapy is usually not needed but is usually requested if the lesions are widespread. Genital lesions are often symptomatic and require treatment. A low-potency topical steroid such as 1% hydrocortisone in an ointment base may be effective in alleviating most symptoms in children. LoeningBaucke219 in a 1991 report noted improvement in all children with hydrocortisone 1% ointment bid. However, with the introduction of ultra-potent topical corticosteroids in the mid 1990s, initial therapy with an ultra-potent topical corticosteroid is often recommended twice daily, The response to the corticosteroid is usually dramatic, and treatment can be changed to once daily and once every other day and then discontinued completely or maintained with a low-potency product.238,239 Flares of disease activity can be retreated with a short course of an ultra-potent steroid. One study of 15 girls with symptomatic LS revealed a 90% response rate to high potency topical corticosteroid; however 63% reported intermittent flares following taper of the ointment.240 Treatment is well tolerated with rare minor complications that are easily treated. Topical calcineurin inhibitors have been reported to provide relief of symptoms of LS in girls and boys.241–243 Some authors have questioned whether these products should be used in conditions with malignant potential.244 In patients who complain of tenderness or maceration, a thick coating of zinc oxide paste helps protect the area and give symptomatic relief, particularly before urinating or defecating. If secondary infection is present, a topical antifungal or antibacterial agent can be added. Topical anesthetics are sometimes useful. Because of the possibility of vulvar or extragenital carcinoma, all cases that persist beyond puberty or occur in adults should be observed every year.245 Areas of leukoplakia, nodules, and persistent erosions should be biopsied. While the treatment of LS with high potency topical corticosteroids provides resolution of symptoms in a large number of patients, the clinical signs of LS show total resolution in only 22% of girls. It is not clear if continued clinical LS increases the risk of malignant transformation later in life.246 The prognosis of LS with onset in childhood is better than in the adult-onset form of the disease, which tends to be chronic and usually permanent. Fifty percent of childhood cases clear within a period of 1–10 years (average 5 years). Approximately two-thirds of cases improve or undergo involution before or at the time of puberty, leaving no residual atrophy.209,210 In Helm

238. Dalziel KL, Millard PR, Wojnarowska F. The treatment of vulval lichen sclerosus with a very potent topical steroid (clobetasol propionate 0.05%) cream. Br J Dermatol. 1991;124:461–464. 239. Garzon MC, Paller AS. Ultrapotent topical corticosteroid treatment of childhood genital lichen sclerosus. Arch Dermatol. 1999;135:525–528. 240. Smith YR, Quint EH. Clobetasol propionate in the treatment of premenarchal vulval lichen sclerosus. Obstet Gynecol. 2001;98:588–591. 241. Hengge UR, Krause W, Hofmann H, et al. Multicentre, phase II trial on the safety and efficacy of topical tacrolimus ointment for the treatment of lichen sclerosus. Br J Dermatol. 2006;155:1021–1028. 242. Boms S, Gambichler T, Freitag M, et al. Pimecrolumus 1% cream for anogenital lichen sclerosus in childhood. BMC Dermatol. 2004;4:14. 243. Ebert AK, Rosch WH, Vogt T. Safety and tolerability of adjuvant topical tacrolimus treatment in boys with lichen sclerosus: a prospective phase 2 study. Eur Urol. 2008;54:932–937. 244. Lewis FM, Neill SM. Safety of calcineurin inhibitors in the management of lichen sclerosus. Br J Dermatol. 2007;156:1389–1390.

et al.’s247 series of 52 children and young adults, the average age at resolution was 15, which was slightly after menarche. Some children may continue to have the disease beyond menarche. In children in whom the disease does not involute, atrophy of the clitoris and labia minora may occur, sometimes with fusion of the latter and stricture of the introitus.210 Two patients reported by Loening-Baucke219 had anal stenosis, and over time atrophy may cause shrinkage of the vulva, particularly of the labia minora and clitoris. A dilating procedure is sometimes indicated. The disease may be reactivated years later in patients who have improved, especially during pregnancy or after the use of oral contraceptives.248 Males with LS of the glans may require urethral dilation, meatomy, and circumcision.249

ATROPHODERMAS

ATROPHODERMAS

Treatment, prognosis, and complications

18

ATROPHODERMA OF PASINI AND PIERINI This distinctive form of dermal atrophy resembles the resolved stage of morphea and some authors believe it to be a morphea variant.250 Atrophic plaques occur primarily on the trunk of young women and, less frequently, young men in their teens and 20s (Fig. 18.10). The plaques are well circumscribed and soft, and have a depressed center with a ‘cliff-drop’ border. They lack the induration and preceding inflammatory phase typical of morphea.251 The color ranges from normal to blue-brown,

Figure 18.10  Atrophoderma on back.

245. Sergeant A, Vernall N, Mackintosh LJ, et al. Squamous cell carcinoma arising in extragenital lichen sclerosus. Clin Exp Dermatol. 2009;34:e278–e279. 246. Cooper SM, Gao XH, Powell JJ, et al. Does treatment of vulval lichen sclerosus influence its prognosis? Arch Dermatol. 2004;140:702–706. 247. Helm KF, Gibson LE, Muller SA. Lichen sclerosus et atrophicus in children and young adults. Pediatr Dermatol. 1991;8:97. 248. Rook A, Wilkinson DS, Ebling FJ, eds. Textbook of dermatology. London: Blackwell Scientific; 1979. 249. Barbagli G, Lazzeri M, Palminteri E, et al. Lichen sclerosus of male genitalia involving anterior urethra. Lancet. 1999;354:429. 250. Murphy PK, Hymes SR, Fenske NA. Concomitant unilateral idiopathic atrophoderma of Pasini and Pierini (IAPP) and morphea. Observations supporting IAPP as a variant of morphea. Int J Dermatol. 1990;29:281. 251. Canizares O, Sachs P, Jaimovich L, et al. Idiopathic atrophoderma of Pasini and Pierini. Arch Dermatol. 1958;77:42.

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violaceous or hypopigmented.252 Lesions vary in size from a few centimeters to 20 or more. They are seen most commonly on the back and extremities; the hands, feet, and face tend to be spared but there are rare reports of facial involvement.252 The disease may remain active for 10–20 years. Morphea-like changes may occur within a lesion or develop elsewhere. In a study by Jablonska, 139 patients with atrophoderma of Pasini and Pierini (APP) were followed long-term. Induration resembling morphea appeared within the plaques of atrophoderma in 17% of patients, and in 22%, morphea plaques coexisted outside the atrophic areas; nevertheless, no case evolved into full-blown morphea. Histologically, APP preserves appendageal structures but elastic fibers may be decreased or clumped. A review of 16 patients revealed 35% with moderate to severe decrease of elastic fibers with fragmentation. These authors proposed a histopathologic continuum of elastic fibers in APP from normal to absent which must be distinguished from anetoderma clinically.253 Advanced lesions of atrophoderma are indistinguishable from morphea histologically. In 1992, Moulin reported five patients, reviewed by Wollenberg et al., with a new variant of atrophoderma.254 The patients had multiple unilateral acquired hyperpigmented depressed linear plaques following Blaschko’s lines. The lesions began during the first or second decades and rapidly evolved. They were asymptomatic, with no inflammatory or sclerotic phase. Skin biopsies only showed epidermal hyperpigmentation. A 16-yearold had preceding inflammation.255 The cause of APP is unknown. As in morphea and lichen sclerosus, there have been reports of Borrelia organisms in some patients.256 Lasser et al.257 described two siblings with phenylketonuria, one with APP and the other with severe segmental morphea. DeBracco et al.258 reported a family with hereditary C2 deficiency in which one sibling had APP and the other had discoid lupus erythematosus. Two patients have been reported with coexisting APP and juvenile idiopathic arthritis.259,260 There is no universally recognized form of treatment. There is one report of lightening of the hyperpigmentation following

252. Selah A, Abbas O, Dahdah M, et al. Atrophoderma of Pasini and Pierini: A clinical and histopathological study. J Cutan Pathol. 2008;35:1108–1114. 253. Kencka, D, Blaszcyk M, Jablonska S. Atrophoderma Pasini–Pierini is a primary atrophic abortive morphea. Dermatology. 1995;190:203–206. 254. Wollenberg A, Baumann L, Plewig G. Linear atrophoderma of Moulin: a disease which follows Blaschko’s lines. Br J Dermatol. 1996;135:277–279. 255. Browne C, Fisher BK. Atrophoderma of Moulin with preceding inflammation. Int J Dermatol. 2000;39:850–852. 256. Buechner SA, Rufli T. Atrophoderma of Pasini and Pierini. Clinical and histopathologic findings and antibodies to Borrelia burgdorferi in 34 patients. J Am Acad Dermatol. 1994;30:441–446. 257. Lasser AE, Schultz BC, Beaff D, et al. Phenylketonuria and scleroderma. Arch Dermatol. 1978;114:1215. 258. DeBracco M, Bianchi C, Bianchi O, et al. Hereditary complement (C2) deficiency with discoid lupus erythematosus and idiopathic atrophoderma. Int J Dermatol. 1979;18:713. 259. Ramanan AV, Baildam E, Judge MR. Atrophoderma and juvenile idiopathic arthritis. Ann Rheum Dis. 2001;60:900–901. 260. Kim YS, Lee CW. Overlap between atrophoderma of Pasini and Pierini and juvenile idiopathic arthritis. Clin Exp Dermatol. 2009;34:82–83. 261. Arpey CJ, Patel DS, Stone MS, et al. Treatment of atrophoderma of Pasini and Pierini-associated hyperpigmentation with the Q-switched alexandrite laser: a clinical, histologic, and ultrastructural appraisal. Lasers Surg Med. 2000;27:206–212. 262. Artola Igarza JL, Sanchez Conejo-Mir J, Corbi Llopis MR, et al. Linear atrophoderma of Moulin: treatment with Potaba. Dermatology. 1996;193:345–347.

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treatment with the Q-switched alexandrite laser.261 Potaba was helpful in one case;262 and intravenous penicillin had no effect in another case.263 Another patient with a long history of APP and positive anti-nuclear antibodies resolved after one year of hydroxychloroquine.264

FOCAL FACIAL DERMAL DYSPLASIAS In this group of disorders, congenital atrophic lesions are present on both temples.265 In some reported families, the inheritance has been autosomal dominant and in others it is recessive. There may be additional facial features, such as facial clefts and absent or double rows of eyelashes (Seitlis syndrome). One reported family had upward-slanting and laterally displaced eyebrows, midline grooves below the lower lip, nystagmus, and dysplastic ears in addition to bitemporal atrophic plaques.266 Kowalski and Fenske proposed a classification based on clinical features and mode of inheritance.267

FOLLICULAR ATROPHODERMAS The follicular atrophodermas are a rare group of inflammatory conditions, most of which develop in childhood. They are characterized by the presence of follicular plugging, followed by atrophy, and vary in their distribution and degree of preceding inflammation. Intermediate forms occur. In addition to the conditions described below, follicular atrophoderma can be seen in Conradi–Hunermann syndrome and in keratosis palmaris et plantaris. There is one case report associated with congenital pseudoarthrosis of the tibia.268 Two families with follicular atrophoderma and diffuse congenital ichthyosis with hypohidrosis and hypotrichosis have been reported,269,270 and a mutation in ST14 which encodes matriptase, a type II transmembrane serine protease inhibitor involved in profilaggrin processing, has been found.271 A family with a perioral and pigmented follicular atrophoderma with numerous milia and epidermoid cysts has been reported.272

263. Rompel R, Mischke AL, Langner C, et al. Linear atrophoderma of Moulin. Eur J Dermatol. 2000;10:611–613. 264. Carter J, Valeriano J, Vasey F. Hydroxychloroquine as a treatment for atrophoderma of Pasini and Pierini. Int J Dermatol. 2006;45:1245–1246. 265. Magid M, Prendiville J, Esterly N. Focal facial dermal dysplasia: bitemporal lesions resembling aplasia cutis congenita. J Am Acad Dermatol. 1988;18:1203–1207. 266. Graul-Neumann LM, Stieler KM, Blume-Peytavi U, et al. Autosomal dominant inheritance in a large family with focal facial dermal dysplasia (Brauer–Setleis syndrome). Am J Med Genet Part A. 2009;149A:746–750. 267. Kowalski D, Fenske N. The focal facial dermal dysplasias: report of a kindred and a proposed new classification. J Am Acad Dermatol. 1992;27:575–582. 268. Perkins W, Webb DW, White JE. Follicular atrophoderma in association with congenital pseudarthrosis of the tibia. J Roy Soc Med. 1995;88:291P–292P. 269. Lestringant GG, Kuster W, Frossard PM, et al. Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis: a new genodermatosis? Am J Med Genet. 1998;75:186–189. 270. Tursen U, Kaya TI, Ikizoglu G, et al. Genetic syndrome with ichthyosis: congenital ichthyosis, follicular atrophoderma, hypotrichosis, and wooly hair; 2nd report. Br J Dermatol. 2002;147:604–606. 271. Alef T, Torres S, Hausser I, et al. Ichthyosis, follicular atrophoderma and hypotrichosis caused by mutation in ST14 is associated with impaired profilaggrin processing. J Invest Dermatol. 2009;129:862–869. 272. Inoue Y, Ono T, Kayashima K, et al. Hereditary perioral pigmented follicular atrophoderma associated with milia and epidermoid crusts. Br J Dermatol. 1998;139:713–718.

Sclerosing and atrophying conditions

18

Atrophoderma vermiculatum has been reported in the Rombo syndrome (milia, hypotrichosis, basal cell carcinoma, and peripheral vasodilation with cyanosis).278,281 Chloracne resulting in atrophoderma vermiculatum was observed in Italian children exposed to dioxin in the Seveso chemical accident.282

KERATOSIS PILARIS ATROPHICANS

large pits are seen under the cheek. From Handrick C, Alster TS. Laser treatment of atrophoderma vermiculata. J Am Acad Dermatol 2001;44:693–695, with permission of Elsevier.

ATROPHODERMA VERMICULATUM In classic atrophoderma vermiculatum (folliculitis ulerythematosa reticulata, honeycomb atrophy), there are reticulated atrophic pits on the cheeks bilaterally (Fig. 18.11).273,274 The condition is occasionally inherited as an autosomal dominant disorder. The disease begins in childhood between the ages of 5 and 12. Erythema and pinhead follicular plugs are usually the first signs. The plugs are then shed, resulting in reticulate atrophy from widely dilated follicles. Well demarcated atrophic pits 1–2 mm across and 1 mm deep are separated from each other by narrow ridges of normal skin, giving the skin a honeycomb or worm-eaten (‘vermiculata’) appearance. The cheeks and preauricular areas are most commonly involved, although the process can extend to the forehead, chin, and ears. A child with a unilateral form of the disorder has been reported;275 the lesions followed Blaschko’s lines.276 Another report of unilateral involvement had associated cataracts and seizures.277 Lesions improve over time, with spontaneous regression in most cases.278 Derm­ abrasion and laser therapy279 have both been utilized. Progression of the disease was halted in one patient after a prolonged course of isotretinoin.280

273. Rozyn KT, Mehregan AH, Johnson SA. Folliculitis ulerythematosa reticulata: a case with a unilateral lesion. Arch Dermatol. 1972;106:388. 274. Odom RB, James WD, Berger TG, eds. Andrews’ diseases of the skin – clinical dermatology. Philadelphia: WB Saunders; 2000:711–713. 275. Nico MM, Valente NY, Sotto MN. Folliculitis ulerythematosa reticulata (atrophoderma vermiculata): early detection of a case with unilateral lesions. Pediatr Dermatol. 1998;15:285–286. 276. Cambiaghi S, Restano L, Tadini G. Atrophoderma vermiculata along Blaschko lines (letter). Pediatr Dermatol. 1999;16:165. 277. Hsu S, Nikko A. Unilateral atrophic skin lesion with features of atrophoderma vermiculatum: a variant of the epidermal nevus syndrome? J Am Acad Dermatol. 2000;43:310–312. 278. Frosch PJ, Brumage MR, Schuster-Pavlovic C, et al. Atrophoderma vermiculatum: case reports and review. J Am Acad Dermatol. 1988; 18:538. 279. Handrick C, Alster TS. Laser treatment of atrophoderma vermiculata. J Am Acad Dermatol. 2001;44:693–695. 280. Weightman W. A case of atrophoderma vermiculatum responding to isotretinoin. Clin Exp Dermatol. 1998;23:89–91. 281. van Steensel MA, Jaspers NG, Steijlen PM. A case of Rombo syndrome. Br J Dermatol. 2001;114:1215–1218.

ATROPHODERMAS

Figure 18.11  In atrophoderma vermiculatum, reticulated atrophic small and

Keratosis pilaris atrophicans (ulerythema ophryogenes) is characterized by persistent erythema and small horny follicular papules that classically involve the lateral third of the eyebrows.274 The process begins in early childhood. The eyebrow follicles are eventually destroyed, resulting in alopecia on the lateral margins of the eyebrows. When the disorder is confined to the lateral eyebrows, it is known as ulerythema ophryogenes. The same follicular process may begin on the cheeks or temples instead of the eyebrows, or extend there from the eyebrows, or involve all of these areas. The disorder is then called keratosis pilaris atrophicans faciei (KPAF) which can be inherited in an autosomal-dominant fashion with incomplete penetrance.283 KPAF has been reported in association with Noonan syndrome and cardio-facio-cutaneous (CFC) syndrome, both linked to mutations in the RAS-ERK pathway.284,285 Nystrom et al. suggests these syndromes are allelic, but Neri et al. disagree and implicate gene mutations in PTPN11, SOS1, and RAF1 as the cause for Noonan and BRAF, MEK1 and MEK2 for CFC syndrome.286 According to Neri et al.,287 cases with cutaneous features such as KPAF would fall into the spectrum of CFC syndrome. KPAF has also been described in association with Cornelia de Lange, Rubenstein Taybi and monosomy 18p.288 Pulsed dye laser has been successfully utilized to treat the erythema.289

KERATOSIS PILARIS DECALVANS Keratosis pilaris decalvans (keratosis follicularis spinulosa decalvans (KFSD), follicular ichthyosis, or Siemen syndrome) begins in early infancy with facial keratosis pilaris.274,290 This may be associated with numerous milia in early infancy. Later, follicular plugs develop on the neck and limbs. Shedding of the follicular plugs results in atrophic lesions on the cheeks. A cicatricial alopecia of the scalp and eyebrows develops during early adoles-

282. Pocchiare F, Silano V, Zampieri A, et al. Human health effects from accidental release of TCDD (tetra choloro dibenzo-p-dioxin) at Seveso, Italy. Proc NY Acad Sci. 1979;320:300. 283. Callaway SR, Lescher JL. Keratosis pilaris atrophicans: case series and review. Pediatr Dermatol. 2004;21:14–17. 284. Snell JA, Mallory SB. Ulerythema ophryogenes in Noonan syndrome. Pediatr Dermatol. 1990;7:77–78. 285. Borradori L, Blanchet-Bardon C. Skin manifestations of cardio-faciocutaneous syndrome. J Am Acad Dermatol. 1993;28:815–819. 286. Nystrom AM, Ekvall S, Berglund E, et al. Noonan and cardio-faciocutaneous syndromes: two clinically and genetically overlapping disorders. J Med Genet. 2008;45:500–506. 287. Neri G, Allanson J, Kavamura MI. No reason yet to change diagnostic criteria for Noonan, Costello, and cardio-facio-cutaneous syndromes. J Med Genet. 2008;45:832. 288. Florez A, Fernandez-Redondo V, Toribio J. Ulerythema ophryogenes in Cornelia de Lange syndrome. Pedriatr Dermatol. 2002;19:42–45. 289. Clark SM, Mills, CM, et al. Treatment of keratosis pilaris atrophicans with the pulsed tunable dye laser. J Cutan Laser Ther. 2000;2:151–156. 290. Maroon M, Tyler WB, Marks VJ. Keratosis pilaris and scarring alopecia. Keratosis follicularis spinulosa decalvans. Arch Dermatol. 1992;128:397.

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cence. The condition is inherited in some patients in an X-linked recessive fashion and in others it is autosomal dominant.291 In some patients, KFSD tends to be mildly inflammatory and regress at puberty. A subset of patients develop pustular eruptions of the scalp that begin at puberty and may persist. Oranje et al. suggested that this process be referred to as folliculitis spinulosa decalvans (FSD).292 While treatments typically give unsatisfactory results, there have been single case reports of temporary improvement on isotretinoin and dapsone Laser hair removal has been reported to be helpful for KFSD.293–295 In some cases, corneal opacities, vascularization, and photophobia have been reported, as well as ichthyosis vulgaris.296 A mild palmoplantar keratoderma occurs in some pedigrees.297 Alopecia, generalized follicular keratosis, and reduced sweating were reported in one patient.298 Bazex syndrome is a follicular atrophoderma that occurs on the backs of the hands and feet in infancy.299 Multiple basal cell carcinomas occur on the face from adolescence onward presenting as lightly pigmented papules. There may be associated hypo­ trichosis and hypohidrosis. The condition is inherited in an autosomal-dominant fashion and. the gene mapped to chromosome Xq.300 There is a report of an adult woman with papulocystic lesions of the face and upper trunk since childhood who subsequently developed vermiculate atrophoderma, entropion with loss of eyelashes, and at the age of 30 developed numerous basal cell carcinomas on the face.301

Clinical manifestations Primary anetoderma (idiopathic anetoderma of Schweninger and Buzzi, and anetoderma of Jadassohn and Pellizzari)

Anetoderma is a localized depression or outpouching of the skin caused by laxity and weakening of the dermal connective tissue as a result of focal loss of elastic fibers. The term is derived from the Greek word anetos meaning ‘relaxed.’ The loss of normal skin elasticity causes the dermis and subcutis to be either slightly depressed or to protrude, with outpouching of the overlying epidermis. With palpation, this herniation can be readily pushed back into the subcutis. The overlying epidermis is often thinned. The anetodermas are sometimes called macular atrophy, a term no longer widely used because true atrophy is not an essential

In the past, primary anetoderma was divided into two distinct categories; however this division is no longer routinely used because the two forms may co-exist and the clinical features and prognosis are indistinguishable. Large numbers of 5–20 mm oval or round blue-white macules, some of which are slightly protuberant, appear in crops over most of the body, favoring the trunk. Lesions may coalesce to form larger lesions. In idiopathic anetoderma of Schweninger and Buzzi there is no preceding inflammation. In the Jadassohn and Pellizzari variant of anetoderma, inflammatory lesions precede the development of an anetoderma but they are both identical in their end stage. The preceding inflammatory lesions are discrete, small, erythematous macules or urticarial lesions. Middle-aged women are affected most commonly in both forms of primary anetoderma, but the disease can occur in childhood.302–304 They rarely resolve, and new lesions continue to appear for many years. Congenital anetoderma has been reported in twins and premature infants and is thought to be related to very low birthweight.305,306 Seven families with familial anetoderma have been recognized;307 the onset of the disease tends to occur at younger ages and spontaneously. Both autosomal recessive and autosomal dominant transmission were reported.306,308 A report of two siblings who developed an anetoderma shortly after hepatitis B immunization suggests an immunologic or infectious pathogenesis.304 When localized to the face, primary non-inflammatory anetoderma has been called atrophia maculosa varioliformis cutis; one case has been reported in a 5-year-old child.309 There have been occasional reports of autoimmune abnormalities associated with anetoderma, such as the presence of antinuclear antibodies, antiphospholipid antibodies, Sjögren’s and Graves’ disease,306,310 but the etiology is generally unknown.

291. Castori M, Covaciu C, Paradisi M, et al. Clinical and genetic heterogeneity in keratosis follicularis spinulosa decalvans. Eur J Med Genet. 2009;52:53–58. 292. Oranje AP, van Osch LD, Oosterwijk JC. Keratosis pilaris atrophicans: one heterogenous disease or a symptom in different clinical entities. Arch Dermatol. 1994;130:500–502. 293. Di Lernia V, Ricci C. Folliculitis spinulosa decalvans: An uncommon entity within the keratosis pilaris atrophicans spectrum. Pediatr Dermatol. 2006;23:255–258. 294. Kunte C, Loeser C, Wolff H. Folliculitis spinulosa decalvans: successful therapy with dapsone. J Am Acad Dermatol. 1998;39:891–893. 295. Chui CT, Berger TG, Price VH, et al. Recalcitrant scarring follicular disorders treated by laser-assisted hair removal: a preliminary report. Dermatol Surg. 1999;25:34–37. 296. Zeligman I, Fleisher TL. Ichthyosis follicularis. Arch Dermatol. 1959;80:413. 297. Kuokkanen K. Keratosis follicularis spinulosa decalvans in a family from northern Finland. Acta Derm Venereol (Stockh). 1971;51:146. 298. Morris J, Ackerman AB, Koblenzer PF. Generalized spiny hyperkeratosis, universal alopecia, and deafness. Arch Dermatol. 1969;100:692. 299. Viksnins P, Berlin A. Follicular atrophoderma and basal cell carcinomas: the Bazex syndrome. Arch Dermatol. 1977;113:948. 300. Vabres P, Lacombe D, Rabinovitz LG, et al. The gene for Bazex-DuperChristol syndrome maps to chromosome Xq. J Invest Dermatol. 1995;195:87–91.

301. Pujol RM, Nadal C, Matias-Guiu X, et al. Multiple follicular hamartomas with sweat gland and sebaceous differentiation, vermiculate atrophoderma, milia, hypotrichosis, and late development of multiple basal cell carcinomas. J Am Acad Dermatol. 1998;39:853–857. 302. Venencie PY, Winkelmann RK, Moor BA. Anetoderma: Clinical findings, associations, and long term follow-up evaluation. Arch Dermatol. 1984;120:1032. 303. Karrer S, Szeimies RM, Stolz W, et al. Primary anetoderma in children: report of two cases and literature review. Pediatr Dermatol. 1996;13:382–385. 304. Daoud MS, Dicken CH. Anetoderma after hepatitis B immunization in two siblings. J Am Acad Dermatol. 1997;36:779–780. 305. Zellman GL, Levy ML. Congenital anetoderma in twins. J Am Acad Dermatol. 1997;36:483–485. 306. Wain EM, Mellerio JE, Robson A, et al. Congenital anetoderma in a pre-term infant. Pediatr Dermatol. 2008;25:626–629. 307. Peterman A, Scheel M, Sams WM, et al. Hereditary anetoderma. J Am Acad Dermatol. 1996;35:999–1000. 308. Friedman SJ, Venencie PY, Bradley RR, et al. Familial anetoderma. J Am Acad Dermatol. 1987;16:341. 309. Paradisi M, Angelo C, Conti G, et al. Atrophia maculosa varioliformis cutis: a pediatric case. Pediatr Dermatol. 2001;18:478–480. 310. Hodak E, Shamai-Lubovitz O, David M, et al. Primary anetoderma associated with a wide spectrum of autoimmune abnormalities. J Am Acad Dermatol. 1991;25:415.

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component of the process. The various forms of anetoderma may occur alone, or accompany other disorders.

Sclerosing and atrophying conditions

Secondary anetoderma Inflammatory dermatoses may result in an anetoderma; common examples are varicella (Fig. 18.12) and acne but these changes have also been described after secondary syphilis, cutaneous tuberculosis, molluscum contagiosum, Borrelia, leprosy, HIV, pilomatricoma, Schwannoma, lymphocytoma cutis, cutaneous B-cell lymphoma, juvenile xanthogranuloma, hamartomatous congenital melanocytic nevi, xanthoma, systemic lupus erythematosus, lichen planus, sarcoidosis, mastocytosis, Sweet’s syndrome, arthropod bites, generalized granuloma annulare, and penicillamine therapy. Perifollicular anetoderma is a condition in which small atrophic papules are seen on the upper back. When first reported, the authors believed that there had been no preceding folli­ culitis or other inflammation: an elastase-producing strain of Staphylococcus epidermidis was cultured that caused elastolysis of normal skin grown in culture.311 Later, Wilson et al. described a common eruption occurring most frequently in patients with acne, that they interpreted to be postacne scars, which is identical to the changes described in the patients with perifollicular elastolysis.312 Focal depressions or outpouchings of skin from loss of dermal elastic tissue have been reported in premature infants in which the lesions corresponded to the placement of monitoring leads.313,314 This is known as anetoderma of prematurity. Marshall et al.315 reported an unusual ‘anetoderma’ that began in infancy. Erythematous papules enlarged to form large plaques, 2–10 cm in diameter. The face, ears, and neck of these patients were always involved, but other areas of the skin could also be

311. Veroli DP, Soqueton AC. Perifollicular elastolysis. Br J Dermatol. 1970;83:143. 312. Wilson BB, Dent CH, Cooper PH. Papular acne scars: a common finding. Arch Dermatol. 1990;126:797. 313. Prizant TL, Lucky AW, Frieden IJ, et al. Spontaneous atrophic patches in extremely premature infants. Arch Dermatol. 1996;132:671–674. 314. Colditz PB, Dunster KR, Joy GJ, et al. Anetoderma of prematurity in association with electrocardiographic electrodes. J Am Acad Dermatol. 1999;41:479–481. 315. Marshall J, Heyl T, Weber HW. Post-inflammatory elastolysis and cutis laxa. S Afr Med J. 1966;40:1016.

affected, with sparing of the palms and soles. As the lesions subsided, the skin became lax and resembled cutis laxa. A similar infant reported by Muster et al.316 as ‘localized cutis laxa’ developed an anetoderma after the resolution of widespread erythematous plaques diagnosed histologically during the acute phase of Sweet syndrome. This infant subsequently died of cardiac disease due to elastotic changes in the aorta. Lewis et al. reported a case of a child with post-inflammatory elastolysis and subsequent ‘cutis laxa’, which developed 2 months after the initial inflammatory eruption.317 A secondary anetoderma was seen in one child who had had a granulomatous papular cutaneous eruption and Takayasu’s arteritis.318 Acrodermatitis chronica atrophicans (ACA) is a late and chronic manifestation of infection caused by B. burgdorferi. It begins with erythema, edema, and induration of a localized area of the skin, usually in an acral location. Gradually the erythema fades, and the involved areas become hyperpigmented and markedly atrophic. An anetoderma may occur at the borders of the lesions. Skin biopsy shows dermal fibrosis and mild inflammation, with visualization of spirochetes similar to B. burgdorferi. Treatment is with the same antibiotics used to treat Lyme disease. Many patients respond well to therapy. The disease had been seen chiefly in elderly Europeans. A 12-year-old girl’s only manifestation of Lyme disease was small patches of atrophy and hyperpigmentation on both wrists.319

ANETODERMA

Figure 18.12  Anetoderma from chickenpox scars on chest.

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Associated conditions Isolated and perhaps coincidental abnormalities have been reported in patients with anetoderma. These include eye changes (keratoconus, cataracts, corneal opacities, blue sclerae, optic atrophy, and iritis), bony abnormalities (calcifications, kyphoscoliosis, limb shortening, congenital fusion of cervical vertebrae, spina bifida, osteopetrosis, and metaphyseal dysplasia), cardiac disorders (mitral valve prolapse and aortic insufficiency), endocrine disorders (Addison’s disease and hypothyroidism with vitiligo), and systemic and discoid lupus erythematosus.302 There are two described genetic disorders which include anetoderma: metaphyseal dysplasia, anetoderma, and optic atrophy (OMIN 250450) and exostoses with anetoderma and brachydactyly type E (OMIN 133690).

Pathophysiology and histogenesis All forms of anetoderma have a focal loss of normal elastic fibers with persistence of abnormal fine or twisted elastic fibers. A perivascular lymphocytic infiltrate is seen with C3 and IgM at the basement membrane zone; C3 on elastic fibers suggests an immune mechanism. Elastic fiber diameter and volume are decreased in anetoderma, while normal or elevated levels are

316. Muster AJ, Bharati S, Hermann JJ, et al. Fatal cardiovascular disease and cutis laxa following acute febrile neutrophilic dermatosis. J Pediatr. 1983;102:243. 317. Lewis PE, Hood AF, Barnett NK, et al. Postinflammatory elastolysis and cutis laxa. J Am Acad Dermatol. 1990;22:40. 318. Taieb A, Dufillot D, Pellegrin-Carloz, et al. Postgranulomatous anetoderma associated with Takayasu’s arteritis in a child. Arch Dermatol. 1987;123:796. 319. Gillis SE, Stadecker MJ, Steere AC. Spirochetes in atrophic skin lesions accompanied by minimal host response in a child with Lyme disease. J Am Acad Dermatol. 1991;25:395.

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seen in other conditions involving elastic fibers – cutis laxa, pseudoxanthoma elasticum, Buschke–Ollendorff and Williams– Beuren syndromes – and they can be differentiated on the basis of these measurements.320 Cultured skin from anetodermic lesions shows increased production and activation of matrix metalloproteins (MMP) and decreased activity of tissue inhibitor of MMP (TIMP1, TIMP2). This altered balance may cause the degradation of elastic fibers seen in anetoderma.321,322 The amount of preelastic and mature elastic fibers in anetoderma is significantly decreased.

Differential diagnosis

FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME)

An anetoderma must be differentiated from atrophic conditions such as scars (particularly varicella scars), morphea, lichen sclerosus, and atrophoderma. It should be differentiated from other conditions that cause protuberance of the skin such as neuro­ fibromatosis, juvenile elastomas, connective tissue nevi, nevus lipomatosus superficialis, focal dermal hypoplasia (Goltz syndrome), and localized acquired cutis laxa.

Treatment and prognosis New lesions of anetoderma continue to appear for many years. One study154 examined 16 patients retrospectively and found that the disease was still active 15 or more years after its onset in a large percentage of patients. Only prompt treatment of any preceding inflammatory conditions or surgical excision of cosmetically unacceptable lesions has any benefit.

FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME) Focal dermal hypoplasia is a rare inherited syndrome. Its hallmark is thinning of the dermis, which results in depressed linear lesions and red-yellow outpouchings of the skin caused by herniation of subcutaneous fat. There are numerous associated cutaneous and systemic mesoectodermal abnormalities. The syndrome was first identified in 1962 by Goltz et al.323 who reported three affected girls.

320. Ghomrasseni S, Dridi M, Bonnefoix M, et al. Morphometric analysis of elastic skin fibres from patients with: cutis laxa, anetoderma, pseudoxanthoma elasticum, and Buschke-Ollendorff and Williams-Beuren syndromes. J Eur Acad Dermatol Venereol. 2001;15:305–311. 321. Venencie PY, Bonnefoy A, Gogly B, et al. Increased expression of gelatinases A and B by skin explants from patients with anetoderma. Br J Dermatol. 1997;137:517–525. 322. Ghomrasseni S, Dridi M, Gogly B, et al. Anetoderma: an altered balance between metalloproteinases and tissue inhibitors of metalloproteinases. Am J Dermatopathol. 2002;24:118–129. 323. Goltz RW, Peterson WC, Gorlin RJ, et al. Focal dermal hypoplasia. Arch Dermatol. 1962;86:52. 324. Hall EH, Terezhalmy GT. Focal dermal hypoplasia syndrome: case report and literature review. J Am Acad Dermatol. 1983;9:443. 325. Temple IK, MacDowall P, Baraitser M, et al. Focal dermal hypoplasia (Goltz syndrome). J Med Genet. 1990;27:180–187. 326. Giam Y-C, Khoo B-P. What syndrome is this? Focal dermal hypoplasia (Goltz syndrome). Pediatr Dermatol. 1998;15:399–402. 327. Burgdorf WH, Goltz RW. Focal dermal hypoplasia. In: Demis DJ, ed. Clinical dermatology. Vol 1. Philadelphia: Harper & Row; 1985:1.

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Epidemiology A total of 125 cases had been reported by 1980 and another 50 cases by 1990.324,325 Some 90% of reported cases are females.326 The disease is congenital and many pedigrees suggest an X-linked dominant mode of inheritance with male lethality, although an X-linked inheritance pattern does not explain the 10% occurrence in males. The affected males possibly have a less severe mutation and are mosaics carrying the gene on only some of their X chromosomes, or are examples of postzygotic mutations.327,328 The variation in severity among affected females is also explained by mosaicism as a consequence of the Lyon hypothesis. There are at least two reports of the disease in a father and daughter, suggesting an inheritance pattern other than X-linked dominant.329,330 The fathers were mildly involved and had only cutaneous abnormalities; their disease had never been diagnosed until they fathered daughters with severe multisystem disease.329,330 Chromosomal analysis of one case of father-todaughter transmission suggested that the father was a mosaic for a mutant focal dermal hypoplasia allele.331 A more recent report of a mother-to-daughter transmission from an unaffected mother who had also experienced a male stillbirth with significant abnormalities suggests strong skewing of X-inactivation in the mother.332

Presenting history Mothers of affected females often have a history of frequent miscarriages or stillbirths. Typical asymptomatic skin lesions and most systemic abnormalities are present at birth,325 except for the papillomatous lesions, which usually appear during the first few months of life and continue to develop over years. The disorder can be mild and localized, or it can be severe and multisystemic;333 this variability in clinical severity can be seen even within a single family cluster.334

Physical examination Because of the near absence of the dermis, there are circumscribed areas in which the skin is thinned and its surface depressed or pouched out (Fig. 18.13).335 Fat may herniate through the thinned dermis, causing soft erythematous or tan outpouchings from the skin’s surface. Other lesions are

328. Happle R, Daniels O, Koopman RJ. MIDAS syndrome (microphthalmia, dermal aplasia, and sclerocornea): an X-linked phenotype distinct from Goltz syndrome. Am J Genet. 1993;47:710. 329. Burgdorf WH, Dick GF, Soderberg MD, et al. Focal dermal hypoplasia in a father and daughter. J Am Acad Dermatol. 1981;4:273. 330. Mahe A, Couturier J, Mathe C, et al. Minimal focal dermal hypoplasia in a man: a case of a father-to-daughter transmission. J Am Acad Dermatol. 1991;25:879. 331. Gorski JL. Father-to-daughter transmission of focal dermal hypoplasia associated with nonrandom X-inactivation: support for X-linked inheritance and paternal X chromosome mosaicism. Am J Med Genet. 1991;40:332. 332. Mianda SB, Delmaestro D, Bertoli R, et al. Focal dermal hypoplasia with exuberant fat herniations and skeletal deformities. Pediatr Dermatol. 2005;22:420–423. 333. Han XY, Wu SS, Conway DH, et al. Truncus arteriosus and other lethal internal anomalies in Goltz syndrome. Am J Med Genet. 2000;90:45–48. 334. Kilmer SL, Grix AW, Isseroff RR. Focal dermal hypoplasia: four cases with widely varying presentation. J Am Acad Dermatol. 1993;28:839–843. 335. Goltz RW, Henderson RR, Hutch JM, et al. Focal dermal hypoplasia syndrome: a review of the literature and report of two cases. Arch Dermatol. 1970;101:1.

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FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME)

Sclerosing and atrophying conditions

B C

A

Figure 18.13  (A) Infant with cutaneous, mucosal, and skeletal abnormalities of focal dermal hypoplasia. (B) Poikilodermatous grouped linear lesions on the arm of a female adolescent. (C) Linear hypopigmentation on chest wall in a Blaschkoid distribution.

telangiectasias on a hypo- or hyperpigmented background. Because of the atrophy and pigmentary changes, the lesions are frequently described as poikilodermatous. Lesions are grouped in a Blaschko-linear pattern. The focal areas of atrophy make the skin appear reticulated and cribriform. At birth, some areas may be ulcerated, as in aplasia cutis congenita; these defects are usually small and heal spontaneously. Bullae and erythematous or urticarial lesions may also be present at birth; histologic studies of one such patient showed a perivascular lymphocytic infiltrate and marked edema of the papillary dermis.336 There are reports of mild forms of the disease; the patients have linear atrophic telangiectatic scaly macules and patches without fat herniations.330,337 Characteristic of focal dermal hypoplasia is the progressive development of raspberry-like papillomas around the lips, anus, genitalia, on the digits and, occasionally, elsewhere on the skin.338 These are not present at birth but develop within the first few months of life. They can become very large and may ulcerate and bleed.336 Papillomas in the larynx can cause stricture, prompting tracheostomy and resection339 and esophageal papillomas can also result in strictures.340

Other cutaneous changes that have been reported include urticaria, dermographism, hyperkeratosis of the soles, radial folds that emanate from the corners of the mouth, photosensitivity, sweating abnormalities, and dermatoglyphic changes.327 Adnexal tumors such as hidrocystoma, apocrine nevi, and syringocystadenoma papilliferum have been described.341 Although several cases have been reported with abnormalities limited to the skin, most patients have extracutaneous findings.337 The scalp hair may be sparse and brittle, with focal alopecia in areas of severe atrophy or aplasia and the nails may be dystrophic or absent. Numerous dental abnormalities are associated with Goltz syndrome, including absence of the teeth, enamel defects, and small, defectively formed teeth that erupt slowly. Cleft lip and/or palate may occur. Skeletal defects are the second most common extracutaneous abnormalities seen in 60–70% of patients.325 The most common is fusion or absence of the fingers or toes but other bones may also be absent. Vertebral abnormalities are common and include scoliosis, kyphosis, vertebral body fusions, and spina bifida. Many patients have short stature. One side of the face or body may be underdeveloped.342 A wide variety of other changes have

336. Goltz RW. Focal dermal hypoplasia: an update (editorial review). Arch Dermatol. 1992;128:1108. 337. Pujol RM, Casanova JM, Perez M, et al. Focal dermal hypoplasia (Goltz syndrome): report of 2 cases with minor cutaneous and extracutaneous manifestations. Pediatr Dermatol. 1992;9:112. 338. Kore-Eda S, Yoneda K, Ohtani T, et al. Focal dermal hypoplasia (Goltz syndrome) associated with multiple giant papillomas. Br J Dermatol. 1995;133:997–999. 339. Gordjani N, Herdeg S, Ross UH, et al. Focal dermal hypoplasia (Goltz– Gorlin syndrome) associated with obstructive papillomatosis of the larynx and hypopharynx. Eur J Dermatol. 1999;9:618–620.

340. Brinson RR, Schuman BM, Mills LR, et al. Multiple squamous papillomas of the esophagus associated with Goltz syndrome. Am J Gastroenterol. 1987;82:1177–1179. 341. Schaffer JV, Cantatore-Francis JL, Shin HT, et al. Syringocystadenoma papilliferum in a patient with focal dermal hypoplasia due to novel PORCN mutation. Arch Dermatol. 2009;145:218–219. 342. Landa N, Oleaga JM, Raton JA, et al. Focal dermal hypoplasia (Goltz syndrome): an adult case with multisystemic involvement. J Am Acad Dermatol. 1993;28:86–89.

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been reported including mental retardation; diffuse cortical and cerebellar atrophy can be seen with magnetic resonance imaging.343 Eye abnormalities are found in 20% of patients.325 These include but are not limited to colobomas of the iris, retina, and globe; microphthalmia, anophthalmia, tear duct anomalies, and ocular muscle and corneal abnormalities.344 The pinnae may be misshapen and some patients have hearing loss. Cardiac, renal, and genitourinary defects have been described.327,336,345 Multiple central giant-cell-like tumors of the maxilla and mandible have been reported.346

fibroblast recruitment and proliferation, inhibition of adipogenesis, and osteoblast differentiation. Given the distribution of lesions along the lines of Blaschko, focal dermal hypoplasia most likely represents extreme skewing of X-chromosome inactivation in familial cases and post-zygotic mutation in sporadic cases. Paller hypothesized that the pattern indicates that Wnt proteins stimulate epidermal-dermal signals to induce changes in the dermis.352 Reports of additional focal dermal hypoplasia patients with PORCN mutation reveal point mutations in sporadic cases and larger deletions in familial cases.353

Laboratory findings

Differential diagnosis

Radiographic findings

The linear pattern and pigmentary changes are suggestive of incontinentia pigmenti, but can be readily differentiated clinically and histologically. The eosinophilic spongiosis seen in incontinentia pigmenti is not present in focal dermal hypoplasia and herniations of fat are not seen in incontinentia pigmenti. An epidermal nevus can be linear and associated with underlying skeletal anomalies but is hypertrophic rather than atrophic, and is readily distinguished with a biopsy. In CHILD syndrome (congenital ichthyosiform erythroderma with limb defects); there is no dermal hypoplasia and the lesions are unilateral. Areas of epidermal aplasia can be seen in congenital aplasia cutis and in Bart syndrome (local congenital absence of skin associated with epidermolysis bullosa), but these lesions are usually solitary and not associated with the other changes seen in focal dermal hypoplasia. A variant of aplasia cutis, the Adams–Oliver syndrome, has associated limb abnormalities but many of these patients have an associated cutis marmorata. In Rothmund–Thomson syndrome, the poikiloderma is more severe, and there is an associated photosensitivity and dwarfism. Nevus lipomatosis superficialis is similar to focal dermal hypoplasia histologically but clinically is composed of raised papules and plaques. Happle et al.328 reported linear lesions of dermal aplasia in an infant with microphthalmia, sclerocornea and a congenital heart defect who had a gene defect involving Xp 22.3. The skin lesions differed from Goltz syndrome as there was no herniation. They called this condition the MIDAS complex and argued that it is distinct from focal dermal hypoplasia. Harmsen et al. confirmed this distinction in four female patients with microphthalmia who had linear skin defects that did not exhibit the PORCN mutations.354 Focal dermal hypoplasia papillomas can be readily differentiated from condylomata acuminata clinically and by skin biopsy.

FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME)

Most of the radiographic changes correspond to the clinical skeletal anomalies. Typical of focal dermal hypoplasia are radiographs of the long bone that show fine linear striations, called osteopathia striata, at or near the epiphyseal junctions. These occur in many, but not all, patients.336 A characteristic change is widening of the symphysis pubis. The bones usually have decreased density, sometimes with cyst formation.347 Media­stinal dextroposition and intestinal malrotation have been reported.348

Pathophysiology and histogenesis A skin biopsy of an atrophic lesion shows a normal or thinned epidermis overlying a severely hypoplastic dermis, with adipose tissue impinging on the epidermis. A narrow remnant of dermis is usually present along the dermal–epidermal junction and around appendageal structures; in less severely affected areas, there may be remnants of fibrous tissue, especially near the dermal blood vessels. In focal areas where no residual dermis remains, the epidermis cannot survive and ulceration results.327 The papillomas are fibrovascular structures which, on electron microscopy of an atrophic site, show loose collagen bundles, collagen fibers with loss of regular bands, abnormal fibroblasts, and disruption of the basement membrane zone, suggesting abnormal formation of type IV collagen.349 The gene defect in focal dermal hypoplasia was reported simultaneously in 2007 by two separate investigative groups to be in PORCN whose product, an O-acyltransferase, helps regulate targeting and secretion of Wnt proteins.350,351 These proteins have significant roles in embryonic development and homeostatic self-renewal with multiple reported activities such as

343. Gunduz K, Gunalp I, Erden I. Focal dermal hypoplasia (Goltz’s syndrome). Ophthalmic Genet. 1997;18:143–149. 344. Lueder GT, Steiner RD. Corneal abnormalities in a mother and daughter with focal dermal hypoplasia (Goltz-Gorlin syndrome). Am J Ophthalmol. 1995;120:256–258. 345. Reddy J, Laufer MR. Congenital anomalies of the female reproductive tract in a patient with Goltz syndrome. J Pediatr Adolesc. 2009;22:e71–e72. 346. Selzer G, David R, Revach M, et al. Goltz syndrome with multiple giant-cell tumor-like lesions in bones. Ann Intern Med. 1974;80:714. 347. D’Alise MD, Timmons CF, Swift DM. Focal dermal hypoplasia (Goltz syndrome) with vertebral solid aneurysmal bone cyst variant. A case report. Pediatr Neurosurg. 1996;24:151–154. 348. Irvine AD, Stewart FJ, Bingham EA, et al. Focal dermal hypoplasia (Goltz syndrome) associated with intestinal malrotation and mediastinal dextroposition. Am J Med Genet. 1996;62:213–215. 349. Lee IJ, Cha MS, Kim SC, et al. Electronmicroscopic observation of the basement membrane zone in focal dermal hypoplasia. Pediatr Dermatol. 1996;13:5–9.

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350. Grzeschik KH, Bornholdt D, Oeffner F, et al. Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia. Nat Genet. 2007;39:833–835. 351. Wang X, Reid Sutton V, Omar Perzaz-Lianes J, et al. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet. 2007;39:836–838. 352. Paller AS. Wnt signaling of focal dermal hypoplasia. Nat Genet. 2007;39:820–821. 353. Clements SE, Mellerio JE, Holden ST, et al. PORCN gene mutations and the protean nature of focal dermal hypoplasia. Br J Dermatol. 2009;160:1103–1109. 354. Harmsen MB, Azzarello-Burri S, Garcia Gonzalez MM, et al. Goltz-Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap. Eur J Hum Genet. 2009;17(10):1207–1215.

Sclerosing and atrophying conditions

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Therapy and prognosis

A APLASIA CUTIS CONGENITA

There is no known effective treatment for this disease; patients have a normal life span and can lead normal lives. Surgical correction of skeletal defects should be considered. Families should receive genetic counseling. In some patients, the areas of cutaneous involvement may slowly progress over time. There is one report of a patient with focal dermal hypoplasia in whom a vascular pelvic mass occurred; it was successfully treated with embolization.355 Cryotherapy effectively controlled giant papillomas on the trunk and extre­ mities in one patient,338 and pulsed dye laser has been used to treat cutaneous lesions.356 In one patient with exophytic granulation tissue resistant to treatment with topical corticosteroids, cryotherapy, and pulsed dye laser, debulking with curettage followed by photodynamic therapy was effective.357

APLASIA CUTIS CONGENITA Aplasia cutis congenita (ACC) is characterized by the absence of localized or widespread areas of skin at birth. The defect is most common on the scalp. It can be associated with other developmental anomalies. More than 500 cases have been reported since Cordon’s original article in 1767. Frieden358 classifies the disorder into nine categories.

Epidemiology There is no sexual or racial predilection. The incidence of ACC has been reported to be 2.8 cases per 10 000 newborns.359 While most cases are sporadic, there have been familial cases reported in Frieden groups 1, 2, 5, 6, 7, and 9. Transmission has been reported as autosomal dominant, autosomal recessive, and autosomal dominant with germline mosaicism.

Presenting history The clinical findings are present at birth. In some cases, there may be a family history of a similar disorder. The discussion below follows Frieden’s classification.358

Physical examination Group 1: Scalp without multiple anomalies The scalp is the most common site of involvement (Fig. 18.14). Nearly 86% of all solitary lesions occur on the vertex of the scalp near the parietal hair whorl.360,361 Some 70–75% of scalp lesions

355. Lynch RD, Leshner RT, Nicholls PJ, et al. Focal dermal hypoplasia (Goltz’s syndrome) with an expansile iliac lesion. Am J Bone Joint Surg. 1971;63:470. 356. Alster TS, Wilson F. Focal dermal hypoplasia (Goltz’s syndrome). Treatment of cutaneous lesions with the 585-nm flashlamp-pumped pulsed dye laser. Arch Dermatol. 1995;131:143–144. 357. Mallipeddi R, Chaudhry SI, Darley CR, et al. A case of focal dermal hypoplasia (Goltz) syndrome with exophytic granulation tissue treated by curettage and photodynamic therapy. Clin Exp Dermatol. 2006;31:228–231. 358. Frieden IJ. Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol. 1986;14:646. 359. Martinez-Regueira S, Vazquez-Lopez ME, Somoza-Rubio C, et al. Aplasia cutis congenita in a defined population from northwest Spain. Pediatr Dermatol. 2006;23:528–532.

B

Figure 18.14  (A) Scar lesions of aplasia cutis congenita at birth. (B) Ulcerated scalp lesion of aplasia cutis congenita.

are single, 20% have two lesions, and the remainder are multiple. They range in size from 0.5 to 5.0 cm,358 and may be circular, oval, linear, or stellate. Scars present at birth, especially in the midline area of the scalp, when there is no history of preceding trauma, are highly suggestive of ACC. Lesions may be scarred, superficially eroded, or deeply ulcerated, sometimes down to the dura or meninges. There are a few reports of a scalp lesion covered by a membranous epithelium, giving the lesion the appearance of a bulla.362,363 There are reports of scalp ACC without other defects in family members.364 At times, coarse scalp hairs surround the periphery of a scalp ACC defect. This has been called the ‘hair collar sign’ and may indicate an underlying neural tube defect.365

360. Ingalls NW. Congenital defects of the scalp: studies in the pathology of development. Am J Obstet Gynecol. 1933;25:861. 361. Stephan MF, Smith DW, Ponzi JW, et al. Origin of scalp vertex aplasia cutis. J Pediatr. 1982;101:850. 362. Yudkin S. Congenital defect of the scalp: an infant with a bullous lesion at birth. Arch Dis Child. 1948;23:61. 363. Colon-Fontanez F, Friedlander SF, Newbury R, et al. Bullous aplasia cutis congenita. J Am Acad Dermatol. 2003;48:S95–S98. 364. Tan HH, Tay YK. Familial aplasia cutis congenita of the scalp: a case report and review. Ann Acad Med, Singapore. 1997;26:500–502. 365. Drolet B, Prendiville J, Golden J, et al. Membranous aplasia cutis with hair collars. Congenital absence of skin or neuroectodermal defect. Arch Dermatol. 1995;131:1427–1431.

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Figure 18.15  Adams–Oliver with limb shortening. By definition, infants with group 1 ACC do not have multiple anomalies, but patients with isolated anomalies are included in this group. Examples are cleft palate, tracheoesophageal fistula, double cervix and uterus, congenital heart disease, omphalocele, polycystic kidneys, mental retardation, cutis marmorata telangiectatica congenita, and congenital nystagmus with high myopia.358,366

Group 2: Scalp with limb anomalies (Adams–Oliver syndrome) In this distinct subtype, distal limb reduction abnormalities are found in association with solitary midline scalp defects (Fig. 18.15). There have been 15 cases reported, usually with an autosomal dominant inheritance pattern of variable genetic expression.367 Scalp lesions vary in size but tend to be large and associated with dilated scalp veins and underlying skull defects.368 The most common limb malformation is hypoplastic or absent distal phalanges, syndactyly, ectrodactyly, club foot, and distal limb absence. Limb malformations reported can be as minor as hypoplastic nails.369 Other anomalies include persistent cutis marmorata telangiectatica congenita (Fig. 18.16) in up to 20%, hemangiomas, cranial arteriovenous malformation, skin tags, supernumerary nipples, and wooly hair.358 Intracranial calcifications were seen in one infant,368 dysplasia of the cerebral cortex in another,370 and polymicrogyria with psychomotor retardation in two siblings.371 Congenital cardiac malformation occurs in approximately 20% of patients with this subtype. Given the phenotypic variability in family members, Snape et al. suggested major and minor diagnostic criteria for this syndrome.369 366. Gershoni-Baruch R, Leibo R. Aplasia cutis congenita, high myopia, and cone-rod dysfunction in two sibs: a new autosomal recessive disorder. Am J Med Genet. 1996;61:42–42. 367. Wilson WG, Harcus SJ. Variable expressions of a congenital scalp defect/ limb malformations syndrome in 3 generations. Birth Defects. 1982;18:123. 368. Romani J, Puig L, Aznar G, et al. Adams-Oliver syndrome with unusual central nervous system alterations. Pediatr Dermatol. 1998;15:48–50. 369. Snape K MG, Ruddy D, Zenker M, et al. The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects. Am J Med Genet Part A. 2009;149A:1860–1881. 370. Savarirayan R, Thompson EM, Abbott KJ, et al. Cerebral cortical dysplasia and digital constriction rings in Adams–Oliver syndrome. Am J Med Genet. 1999;86:15–19. 371. Amor DJ, Leventer RJ, Hayllar S, et al. Polymicrogyria associated with scalp and limb defects: variant of Adams–Oliver syndrome. Am J Med Genet. 2000;93:328–334.

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Figure 18.16  Adams–Oliver with cutis marmorata telangiectatica congenita.

Group 3: Scalp with epidermal and sebaceous nevi There have been several cases reported of ACC associated with epidermal or sebaceous nevi involving the scalp, usually adjacent to the ACC.358 Some patients have also had ophthalmic and neurologic findings similar to those found in the epidermal nevus syndrome, including seizures, mental retardation, corneal opacities, and eyelid colobomas. There have been no familial cases reported. An extremely rare association has been observed in three patients with sebaceous nevus syndrome, central nervous system malformations, aplasia cutis congenita, limbal dermoids, and giant congenital melanocytic nevus, coined SCALP syndrome by Lam et al.372 A distinct organoid nevus, nevus psiloliparus, has been described in close proximity to ACC in two infants, explained by the theoretical occurrence of twin spotting or didymosis.373

Group 4: Overlying embryologic malformations In various types of major malformations, there may be a congenital absence of skin overlying the deeper defect. Examples include meningomyelocele, gastroschisis, omphalocele, ilial atresia,374 bilial mid-gut atresia,375 spinal dysraphism, porencephaly, leptomeningeal angiomatosis, and cranial stenosis. The inheritance 372. Lam J, Dohil MA, Eichenfield LF, et al. SCALP syndrome: sebaceous nevus syndrome, CNS malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus (giant congenital melanocytic nevus) with neurocutaneous melanosis: a distinct syndromic entity. J Am Acad Dermatol. 2008;58:884–888. 373. Torrelo A, Boente Mdel C, Nieto O, et al. Nevus psiloliparus and aplasia cutis: a further possible example of didymosis. Pediatr Dermatol. 2005;22:206–209. 374. Al-Sawan RMZ, Soni AL, Al-Kobrosly AM, et al. Truncal aplasia cutis congenita associated with ileal atresia and mesenteric defect. Pediatr Dermatol. 1999;16:498–509. 375. Lane W, Zanol K. Duodenal atresia, biliary atresia, and intestinal infarct in truncal aplasia cutis congenita. Pediatr Dermatol. 2000;17:290–292.

Sclerosing and atrophying conditions

18

membranes can be performed to look for the presence of the fetus papyraceus.380

Group 6: Associated with epidermolysis bullosa

APLASIA CUTIS CONGENITA

Figure 18.17  Bilateral aplasia cutis from fetus papyraceous.

There have been many reports of ACC, usually occurring on the lower extremities, in cases of epidermolysis bullosa (EB). This was initially thought to represent a distinct entity known as Bart syndrome, but it has been shown to represent a specific presentation of EB. Multiple types of EB have been reported with ACC: recessive dystrophic EB, dominant dystrophic EB, localized and generalized EB simplex, and junctional EB including JEB with pyloric atresia. Frieden358 proposed that the lesions develop on the lower extremities because of mechanical trauma in utero due to fetal kicking, which leads to in utero blistering and subsequent erosions.

Group 7: Extremities without epidermolysis bullosa pattern in this group depends on the associated underlying condition. It was suggested by Herron et al. that the combination of a vascular stain and the hair collar sign should heighten concern for underlying dysraphism and prompt imaging with MRI.376

Group 5: Associated with fetus papyraceus or placental infarct Mannino et al.377 reviewed 17 cases of extensive truncal and limb ACC (Fig. 18.17). This is associated with the presence of a fetus papyraceus, which is found at delivery in the placenta and is caused by the death of a twin fetus during the second trimester. In a large proportion of twin pregnancies, there are vascular anastomoses or interconnections within the placentas.378 Complications from this shunting can affect one or both fetuses. If one of the co-twins dies, clots or necrotic tissue from the dead twin may enter the circulation of the surviving twin, or alternatively the sudden reduction in vascular pressure of the dying twin leads to an acute and temporary exsanguination and hypovolemia in the surviving twin.379 During the second trimester, vascularization is related to the iliac and umbilical arteries, which explains the frequent distribution of this variant of ACC over the flanks and upper thighs. The surviving twin has ACC, possibly from vascular disruption of the placenta380 but is usually otherwise normal with the rare exception of constricting bands of tight fibrous tissue on the extremities, psychomotor retardation, hydranencephaly, nail dystrophy, and clubbed hands and feet.358 No familial cases have been reported. Cases of ACC in surviving infants of multigestational pregnancies undergoing multifetal reduction procedures have been described.379 To confirm the diagnosis, a complete pathologic study of the placenta and

376. Herron MD, Coffin CM, Vanderhooft SL. Vascular stains and hair collar sign associated with congenital anomalies of the scalp. Pediatr Dermatol. 2005;22:200–205. 377. Mannino FL, Jones KL, Bernischke K. Congenital skin defects and fetus papyraceus. J Pediatr. 1977;91:559. 378. Leaute-Labreze C, Depaire-Duclos F, Sarlangue J, et al. Congenital cutaneous defects as complications in surviving co-twins: aplasia cutis congenita and neonatal Volkmann ischemic contracture of the forearm. Arch Dermatol. 1998;134:1121–1124. 379. Schaffer JV, Popiolek DA, Orlow SJ. Symmetric truncal aplasia cutis congenita following multifetal reduction of a sextuplet pregnancy. J Pediatr. 2008;153:860–863.

There have been at least two families in whom multiple members have had extensive ACC of the lower extremities.358 Some of these patients also had affected feet and hands.

Group 8: Teratogens There have been a few cases of ACC linked to intrauterine infection with herpes simplex virus or varicella and to the medications valproate and methimazole, which were given during pregnancy for the treatment of thyrotoxicosis.358

Group 9: Associated with syndromes of malformation ACC has been reported in association with various syndromes and dysplasias.358 These include trisomy 13, 4p-syndrome, ectodermal dysplasia, Johansson–Blizzard syndrome, focal dermal hypoplasia (Goltz syndrome), and 46 XY gonadal dysgenesis. In Xp22 deletion syndrome, bilateral linear reticulated defects are found on the malar areas of the face.381 In the amniotic band syndrome, a ring-like constriction forms that can surround a limb and cause focal aplasia and amputation.382 Two newborns have been reported with complete absence of the skin, intra­ uterine growth retardation, hypoplastic lungs, syndactyly, skull defects, and early demise in the post-natal period.383,384

Laboratory findings There are no consistent or specific laboratory abnormalities found in ACC, but there may be abnormalities caused by some of the associated findings.

380. Cambiaghi S, Schiera A, Tasin L, et al. Aplasia cutis congenita in surviving co-twins: four unrelated cases. Pediatr Dermatol. 2001;18:511–515. 381. Zvulunov A, Kachko L, Manor E, et al. Reticulolinear aplasia cutis congenita of the face and neck: a distinctive cutaneous manifestation in several syndromes linked to Xp22. Br J Dermatol. 1998;138:1046–1052. 382. Nagore E, Sanchez-Motilla JM, Febrer MI, et al. Radius hypoplasia, radial palsy and aplasia cutis due to amniotic band syndrome. Pediatr Dermatol. 1999;16:217–219. 383. Sugiura T, Kouwaki M, Kiyosawa S, et al. A case of systemic aplasia cutis congenita: a newly recognized syndrome? Eur J Pediatr. 2008;167:409–413. 384. Park MS, Hahn SH, Hong CH, et al. Extensive form of aplasia cutis congenita: a new syndrome? J Med Genet. 1998;35:609–611.

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Pathophysiology and histogenesis

Therapy and prognosis

The histology varies according to the depth of the aplasia and its duration. At birth, deeply ulcerated lesions may show complete absence of skin. After healing, the epidermis, if present, is thinned and flattened, and there may be a proliferation of fibroblasts within the connective tissue stroma. Bullous ACC may show fibrovascular or edematous stroma similar to the histopathological findings of encephaloceles and meningoceles, supporting the theory that ACC is a forme fruste of neural tube defects.363 Because ACC is a clinical finding that occurs in more than one disease state, it is very likely that there is more than one mechanism of pathogenesis. The disruption of skin development occurs in utero, so genetic factors are one mechanism by which the abnormality may be produced. Other proposed mechanisms include trauma, compromised cutaneous vasculature, and teratogens. Stephan et al.361 noted the proximity of scalp ACC to the scalp hair whorl, which is thought to be the point of maximum tensile force during rapid brain growth. They hypothesized that tension-induced disruption of the overlying skin occurs at 10–18 weeks’ gestation, when hair direction, patterning, and rapid brain growth occur. Early rupture of the amniotic membranes is associated with this disorder in several cases.358 Happle and Konig recognized cases of ACC in close proximity to nevus sebaceous as an example of twin spotting which they coined as didymosis aplasticosebacea.385 This theoretical mechanism occurs in an embryo heterozygous for two different recessive mutations on a pair of chromosomes which undergo somatic mutation, resulting in two different cell lineages homozygous for either mutation. The phenotypic outcome is two distinct cutaneous defects in close proximity to each other.

Treatment is rarely necessary in more superficial lesions because the erosions and ulcerations almost always heal spontaneously and the prognosis is usually excellent. Occasionally, patients require skin grafting. If the ACC is associated with other syndromes, the prognosis is dependent on the prognosis associated with the syndrome. Genetic counseling is advised for affected infants. When the ACC is full thickness, meaning the absence of periosteum, skull bone and/or dura, a mortality as high as 50% has been reported.388 If the dura is exposed, the defect needs to be covered early with full-thickness skin flaps and/or frequent moist dressings because if an eschar forms over the exposed dura, there is a high risk of infection or life-threatening hemorrhage from laceration of the sagittal sinus.389–391 Imaging studies may be appropriate if bony defects are palpated under the ACC scalp lesion and prior to surgical intervention.

Differential diagnosis Diagnostic considerations include an encephalocele or a dermoid cyst. ACC must also be differentiated from the erosions of EB; this can be confusing because patients with EB can also have ACC. Neonatal herpes may present with an eroded plaque, not uncommonly on the scalp. Unlike ACC, neonatal herpes is uncommon at birth. In the first few days of life, congenital erosive and vesicular dermatosis healing with reticulated supple scarring386 can look similar to the erythematous erosions or partially healed erosions seen in some infants with ACC. Focal dermal hypoplasia and amniotic band syndrome also need to be differentiated. In early infancy, scalp ACC may be similar to a nevus sebaceous. Use of the dermatoscope to visualize bright yellow dots signifying sebaceous glands may help differentiate nevus sebaceous from ACC which would be devoid of appendages.387 385. Happle R, Konig A. Didymosis aplasticosebacea: coexistence of aplasia cutis congenita and nevus sebaceous may be explained as a twin spot phenomenon. Dermatology. 2001;202:246–248. 386. Cohen BA, Esterly NB, Nelson PF. Congenital erosive and vesicular dermatosis healing with reticulated supple scarring. Arch Dermatol. 1985;121:361. 387. Neri I, Savoia F, Giacomini F, et al. Usefulness of dermatoscopy for the early diagnosis of sebaceous naevus and differentiation from aplasia cutis congenita. Clin Exp Dermatol. 2009;34:e50–e52. 388. Dutra LB, Pereira MD, Kreniski TM, et al. Aplasia cutis congenita: management of large skull defect with acrania. J Craniofac Surg. 2009;20:1288–1292. 389. Abbott R, Cutting CB, Wisoff JH, et al. Aplasia cutis congenita of the scalp: issues in its management. Pediatr Neurosurg. 1991–1992;17(4):182–184.

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FAT ATROPHY (LIPOATROPHY) Atrophy of the subcutaneous fat may be a localized problem, as in the localized annular lipodystrophies; it may be more widespread and involve an entire area of the body, as in partial lipodystrophy; or, it can affect the entire body, as it does in total or generalized lipoatrophy (lipodystrophy). Both partial and total forms can be congenital or acquired. The generalized forms of lipodystrophy are extremely rare and often associated with severe insulin resistance and characterized by diabetes mellitus, acanthosis nigricans, and by hirsutism and virilization in females. In a retrospective review of 23 children with acquired lipodystrophy, Pope et al. found 78% were associated with dermatomyositis with or without additional autoimmune disease and over 50% showed complications including acanthosis nigricans, hypertension, hepatomegaly, and hyperlipidemia, but none of these patients had diabetes mellitus.392

LOCALIZED LIPOATROPHY Several clinical forms of localized lipoatrophy have been described. All are rare. Lipoatrophia semicircularis presents with a circular, band-like depression on the extensor surface of the thigh or lateral arm (Fig. 18.18).393 There is no accompanying epidermal atrophy or color change. The lesions develop rapidly over several weeks. They begin with painless, dusky-red, asymptomatic subcutaneous swelling; arthralgias have been reported in some patients.393 Histologically, there is degeneration of fat cells. A similar lipoatrophy has been reported that involves the ankles.394 These cases have been preceded by a panniculitis with 390. Kim CS, Tatum SA, Rocziewicz G. Scalp aplasia cutis congenita presenting with sagittal sinus hemorrhage. Arch Otolaryngol Head Neck Surg. 2001;127:71–74. 391. Simman R, Priebe CJ, Simon M. Reconstruction of aplasia cutis congenita of the trunk in a newborn infant using acellular allogenic dermal graft and cultured epithelial autografts. Ann Plast Surg. 2000;44:451–454. 392. Pope E, Janson A, Khambalia A, et al. Childhood acquired lipodystrophy: a retrospective study. J Am Acad Dermatol. 2006;55:947–950. 393. Jablonska S, Szczeponski A, Gorkiewicz A. Lipoatrophy of the ankles and its relationship to other lipoatrophies. Acta Derm Venereol (Stockh). 1975;55:135. 394. Shelley WB, Izumi AK. Annular atrophy of the ankles: a case of partial lipodystrophy. Arch Dermatol. 1970;102:236.

Sclerosing and atrophying conditions

B

Figure 18.18  (A) Localized annular lipoatrophy on the leg of a child: no antecedent injections or injuries. (B) Lipoatrophy of the back.

395. Dimson OG, Esterly NB. Annular lipoatrophy of the ankles. J Am Acad Dermatol. 2006;54:S40–S42. 396. Nagore E, Sanchez-Motilla JM, Rodriguez-Serna M, et al. Lipoatrophia semicircularis – a traumatic panniculitis: report of seven cases and review of the literature. J Am Acad Dermatol. 1998;39:879–881. 397. Haas N, Henz BM, Bunikowski R, et al. Semicircular lipoatrophy in a child with systemic lupus erythematosus after subcutaneous injections with methotrexate. Pediatr Dermatol. 2002;19:432–435. 398. Imamura S, Yamada M, Ikeda T. Lipodystrophia centrifugalis abdominalis infantilis. Arch Dermatol. 1971;104:291. 399. Llistosella E, Puig L, Perez F. Lipodystrophia centrifugalis abdominalis infantilis: a case report. Pediatr Dermatol. 1997;14:216–218. 400. Muller S, Beissert S, Metze D, et al. Lipodystrophia centrifugalis abdominalis infantilis in a 4-year-old Caucasian girl: association with partial IgA deficiency and autoantibodies. Br J Dermatol. 1999;140:1161–1169. 401. Caputo R. Lipodystrophia centrifugalis sacralis infantilis: a 15-year follow-up observation. Acta Derm Venereol (Stockh). 1989;69:442. 402. Hagari Y, Sasaoka R, Nishiura S, et al. Centrifugal lipodystrophy of the face mimicking progressive lipodystrophy. Br J Dermatol. 1992;127:407–410. 403. Kagoura M, Toyoda M, Matsui C, et al. An ultrastructural study of lipodystrophia centrifugalis abdominalis infantilis, with special reference to fibrous long-spacing collagen. Pediatr Dermatol. 2001;18:13–16.

adipocytes engulfed in foreign body giant cells on pathology.395 Nagore et al. detected precipitating trauma in seven cases of lipoatrophia semicircularis and avoidance led to resolution in 9 months to 4 years.396 Occasionally, the atrophy may completely encircle the arm and cause distal edema; the disease is then called lipoatrophia annularis (annular lipoatrophy). Panatrophy of Gower is a localized lipoatrophy associated with autoimmune conditions such as systemic lupus erythematosus, nephritis, Sjögren syndrome, or diabetes. A recent report described a girl with systemic lupus erythematosus on sub­ cutaneous methotrexate who developed classic lipoatrophia semicircularis. The authors postulated that her lipodystrophy was caused by the injections, the methotrexate, and/or her lupus, showing that these cases may have multifactorial etiologies.397 Lipodystrophia centrifugalis abdominalis infantilis was originally reported in Japanese children.398 Most patients are of Asian descent,399 but it has now been reported in Caucasian children400 and other racial groups. It usually begins before the age of 3 years. A large depressed area with a slightly erythematous or violaceous and scaling edge is seen on the lower abdomen. The lesion enlarges in a centrifugal fashion. There is no history of preceding trauma. Cases involving areas other than the abdomen have been described.401,402 Regional lymph node enlargement occurs in about half of cases. Corticosteroid therapy is ineffective. The disease tends to remit spontaneously after puberty. Electron microscopy shows a breakdown in fibrillar collagen403 and immunohistochemical staining of mononuclear cells shows apoptosis.404 In a few cases, co-existing morphea has been present.405 Localized lipoatrophy can occur in the subcutis after the injection of medications.406 The most common examples are due to injections of corticosteroids, particularly following injections of triamcinolone acetonide in the deltoid area.407 Parents may not recall the child receiving a local injection to the area. Insulin and penicillin,408,409 heparin, actinomycin, and growth hormone410 have also been implicated.394 The lipoatrophy usually resolves in several months. Repeated insulin injections at the same site may eventually result in atrophy, especially in children and women, 6 months to 2 years after initiation of insulin therapy.411 This problem occurs less frequently with recombinant human insulin.

FAT ATROPHY (LIPOATROPHY)

A

18

404. Okita H, Ohtsuda T, Yamakage A, et al. Lipodystrophia centrifugalis abdominalis infantilis – immunohistochemical demonstration of an apoptotic process in the degenerating fatty tissue. Dermatology. 2000;201:370–372. 405. Ikoma A, Tanaka T, Miyachi Y. A case of lipodystrophia centrifugalis abdominalis infantilis with morphea. J Dermatol. 1999;26:603–607. 406. Dahl PR, Zalla MJ, Winkelmann RK. Localized involutional lipoatrophy: a clinicopathologic study of 16 patients. J Am Acad Dermatol. 1996;35:523–528. 407. Fritsch WC. Deep atrophy of the skin of the deltoid area. Arch Dermatol. 1970;101:585. 408. Kayikcioglu A, Akuyrek M, Erk Y. Semicircular lipoatrophy after intragluteal injection of benzathine penicillin. J Pediatr. 1996;129:166–167. 409. Kuperman-Beade M, Laude T. Partial lipoatrophy in a child. Pediatr Dermatol. 2000;17:302–303. 410. Buyukgebiz A, Aydin A, Dundar B, et al. Localized lipoatrophy due to recombinant growth hormone therapy in a child with 6.7 kilobase gene deletion isolated growth hormone deficiency. J Pediatr Endocrinol. 1999;12:95–97. 411. Huntley AC. The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol. 1982;7:427.

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Localized forms of lipoatrophy must be differentiated from partial lipodystrophy, total lipoatrophy, morphea, atrophoderma, panniculitis, and lupus profundus.

FAMILIAL PARTIAL LIPODYSTROPHY (FPL)

FAT ATROPHY (LIPOATROPHY)

Initially, two main phenotypes of FPL were described and thought to be X-linked dominant because the disorders had only been described in females.412 Male patients are recognized as well and it has been determined that FPL is an autosomal dominant trait for those phenotypes with a known gene mutation. Female patients appear to have more severe disease than their male affected family members.413 Progressive loss of subcutaneous (SQ) tissue begins in childhood for all forms. In type 1 (Kobberling) the loss of SQ tissue is localized to the extremities often with central obesity; in type 2 (Dunnigan), there is loss in the extremities and trunk with increased SQ tissue in the face and neck and muscular hypertrophy in the extremities;412 in type 3, patients experience decreased SQ tissue in the extremities and buttocks, sparing the trunk.414 All three phenotypes have associated insulin resistance, diabetes, hypertriglyceridemia, acute pancreatitis, and, in females, menstrual abnormalities. In one study, 31% of patients with Type 1 FLP experienced early coronary disease.414 Mutations of the laminin A/C gene lead to Type 2 disease415 and mutations in peroxisome proliferator-activated receptor-gamma (PPARG) gene cause the Type 3 phenotype.416 The genetic etiology of Type 1 is yet to be determined. Mapping of heterozygotes indicates that plasma lipid abnormalities precede glucose abnormalities.415 Women with Type 2 FPL suffer higher risk of infertility, miscarriages, gestational diabetes, and increased prevalence of polycystic ovarian syndrome.417

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trophy (APL) a distinctive gaunt appearance. Occasionally, hypertrophy of the subcutaneous fat on the lower part of the body occurs. The disease is much more common in females and primarily affects children between the ages of 5 and 10 years and young adults. It may be preceded by an acute febrile episode. The disease is only ‘progressive’ until all the fat is lost, when the process arrests. Many affected patients eventually have a progressive membranous mesangiocapillary glomerulonephritis (MGN), which can be precipitated by pregnancy, oral contraceptive use, and ergot medications.420 The latter drugs are therefore contraindicated in these patients. The glomerulonephritis is associated with persistently low levels of C3 due to a serum ‘C3 nephritic’ factor that can activate C3 without activating earlier complement components by the alternative pathway.421 In one review of 35 patients with APL, 22% developed MGN a median of 8 years following the onset of the lipodystrophy. Additional associations included systemic lupus erythematosus, dermatomyositis, diabetes, and impaired glucose tolerance.422 Retinitis pigmentosa occurs in rare patients. An autosomal-dominant form of partial lipodystrophy in association with the Rieger anomaly (variable eye and tooth abnormalities), midface hypoplasia, short stature, and hypotrichosis has been reported.423 There is one report of APL associated with a chromosome 10 abnormality.424 Upon re-evaluation of the LMNB2 gene, Hegele et al. discovered novel mutations in four patients with APL They postulated the mutation led to disease susceptibility and that it is likely that there is genetic heterogeneity for APL.425 The differential diagnosis includes facial hemiatrophy and the generalized wasting that may occur in malnutrition or thyrotoxicosis.

ACQUIRED (PROGRESSIVE) PARTIAL LIPODYSTROPHY (BARRAQUER–SIMONS SYNDROME)

PARTIAL LIPODYSTROPHY IN DERMATOMYOSITIS

In the most common variant of this rare disorder, there is complete symmetrical disappearance of the subcutaneous fat from the face that progresses to involve the upper half of the body.418,419 The loss of facial fat gives patients with acquired partial lipodys-

Lipodystrophy has been reported in association with many autoimmune disorders, most commonly with juvenile dermatomyositis (JDM),426 sometimes years after the initial diagnosis, and at times when the disease is clinically in remission.427

412. Kobberling J, Dunnigan MG. Familial partial lipodystrophy: two types of an X-linked dominant syndrome, lethal in the hemizygous state. J Med Genet. 1986;23:120–127. 413. Laudes M, Oberhauser F, Walgenbach K, et al. Comparison of phenotypes in male and female individuals of a new family with Dunnigan type of familial partial lipodystrophy due to a lamin A/C R482W mutation. Horm Metab Res. 2009;41:414–417. 414. Herbst KL, Tannock LR, Deeb SS, et al. Kobberling type of familial partial lipodystrophy: an underrecognized syndrome. Diabetes Care. 2003;26(1819):24. 415. Hegele RA, Anderson CM, Wang J, et al. Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Res. 2000;10:652–658. 416. Argawal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002;87:408–411. 417. Vantyghem MD, Vincent-Desplanques D, DeFrance-Faivre F, et al. Fertility and obstetrical complications in women with LMNA-related familial partial lipodystrophy. J Clin Endocrinol Metab. 2008;93:2223–2229. 418. Senior B, Gellis SS. The syndromes of total lipodystrophy and partial lipodystrophy. Pediatrics. 1964;33:593. 419. Lenane P, Murphy G. Partial lipodystrophy and renal disease. Clin Exp Dermatol. 2000;25:605–607.

420. Bingham A, Mamyrova G, Rother KI, et al. Predictors of acquired lipodystrophy in juvenile onset dermatomyositis and a gradient of severity. Medicine (Balt). 2008;87:70–86. 421. Sissons JG, West RJ, Fallows J, et al. The complement abnormalities of lipodystrophy. N Engl J Med. 1976;294:461. 422. Misra A, Peethambaram A, Garg A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature. Medicine (Balt). 2004;83: 18–34. 423. Aarskoig D, Ose L, Pande H, et al. Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes. Am J Med Genet. 1983;15:29. 424. Martinez A, Malone M, Hoeger P, et al. Lipoatrophic panniculitis and chromosome 10 abnormality. Br J Dermatol. 2000;142:1034–1039. 425. Hegele RA, Cao H, Liu DM, et al. Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy. Am J Hum Genet. 2006;79:383–389. 426. Kavanagh GM, Colaco CB, Kennedy CTC. Juvenile dermatomyositis associated with partial lipoatrophy. J Am Acad Dermatol. 1993;28:348. 427. Quecedo E, Febrer I, Serrano G, et al. Partial lipodystrophy associated with juvenile dermatomyositis: report of two cases. Pediatr Dermatol. 1996;13:477–482.

Sclerosing and atrophying conditions

functional abnormalities of the epidermal growth factor receptor.432,433

CONGENITAL GENERALIZED LIPODYSTROPHY (CGL) (SEIP–BERARDINELLI SYNDROME)

Affected newborns are small due to cessation of growth in utero. The facies has a gnome-like appearance and the infant is severely emaciated. Classic cases have hypertrichosis, acanthosis nigricans, decreased SQ fat and symptomatic hyperglycemia because of insulin resistance. Most die before 1 year of age. Milder variants have been reported.431 The disease is caused by different mutations in the insulin gene receptor and some cases also have

Complete loss of SQ tissue is noticed at birth or before the age of 2 years.418 The children are tall (90th percentile) because of an advanced bone age. The muscles appear to be very prominent, in part because of the loss of subcutaneous tissue. The abdomen protrudes and there is hepatomegaly. The skin may be generally hyperpigmented and acanthosis nigricans may occur. The scalp hair grows luxuriously onto the forehead, almost reaching the eyebrows. Adipose tissue remains in several anatomical sites (orbits, palms, soles),434 suggesting differences in fat metabolism in different body areas. Three subtypes of CGL have been described showing genetic and phenotypic heterogeneity for this disease.435 Type 1 is caused by a mutation in the AGPAT2 gene on chromosome 9;436 type 2 is due to a mutation in BSCL2 gene which encodes seipin,435 and type 3 is attributed to a mutation in the CAV-1 gene encoding caveoloin-1.437 Through MRI studies, all three forms show loss of SQ and visceral adipose tissue but only Types 1 and 2 have loss of adipose tissue in the bone marrow in addition to the other areas. Distinct cohorts with adipose distribution like Type 3 but also showing muscular weakness and atlantoaxial dislocation without mutations in any of the described genes illustrate that other gene mutations are likely to be contributing to phenotypes of CGL.438 Diabetes due to insulin resistance develops by the time the patient reaches adulthood. Younger patients may have glucosuria only after glucose loading, but true hyperglycemia often develops after age 10 years. The hyperglycemia is not associated with significant ketosis, and there is minimal response to insulin; hyperlipidemia from elevated triglycerides also occurs. The disease may be associated with renal abnormalities, cardiomegaly and disturbances of central nervous system function. Multiple pulmonary artery stenoses have been reported in three patients.439 CGL must be differentiated from muscular dystrophy, Cornelia de Lange syndrome, and from leprechaunism. Unlike leprechaunism, there is no mutation of the insulin receptor gene, which makes pregnancy management difficult.440,441 Patients usually survive into adulthood.

428. Huemer C, Kitson H, Malleson PN, et al. Lipodystrophy in patients with juvenile dermatomyositis – evaluation of clinical and metabolic abnormalities. J Rheumatol. 2001;28:610–615. 429. Brambilla P, Bricalli D, Sala N, et al. Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy. AIDS. 2001;15:2415–2422. 430. Vigano A, Mora S, Testolin C, et al. Increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in HIV-infected children. J Acquir Immune Defic Syndr. 2003;32:482–489. 431. al Gazali LI, Khalil M, Devadas K. A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents. J Med Genet. 1993;30:470–475. 432. Psiachou H, Mitton S, Alaghband-Zadey J, et al. Leprechaunism and homozygous nonsense mutation in the insulin receptor gene. Lancet. 1993;342:924. 433. Reddy SSK, Kahn CR. Epidermal growth factor receptor defects in leprechaunism: a multiple growth factor-resistant syndrome. J Clin Invest. 1989;84:1569–1576. 434. David R, Goodman RM. The Patterson syndrome, leprechaunism and pseudo-leprechaunism. J Med Genet. 1981;18:294–298.

435. Agarwal AK, Simha V, Oral E, et al. Phenotypic and genotypic heterogeneity in congenital generalized lipodystrophy. J Clin Endocr Metab. 2003;88:4840–4847. 436. Agarwal AK, Arioglu E, deAlmeida S, et al. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nature Genet. 2002;31:21–23. 437. Kim Ca, Delepine M, Boutet E, et al. Association of homozygous nonsense caveolin-1 mutation with Bernardinelli-Seip congenital lipodystrophy. J Clin Endocr Metab. 2008;93:1129–1134. 438. Simha V, Agarwal AK, Aronin PA, et al. Novel subtype of congenital generalized lipodystrophy associated with muscular weakness and cervical spine instability. Am J Med Genet. 2008;146A:2318–2326. 439. Uzun O, Blackburn ME, Gibbs JL. Congenital total lipodystrophy and peripheral pulmonary artery stenosis. Arch Dis Child. 1997;76: 456–457. 440. Desbois MC, Magre J, Amselsm S, et al. Lipoatrophic diabetes: genetic exclusion of the insulin receptor gene. J Clin Endocrinol Metab. 1995;80: 314–319. 441. Sturley RH, Stirling C, Reckless JP. Generalised lipodystrophy and pregnancy. Br J Obstet Gynaecol. 1994;101:719–720.

LIPODYSTROPHIC SYNDROME IN HIV-INFECTED CHILDREN Peripheral lipoatrophy with an increase in central fat is seen in HIV-infected children treated with highly active antiretroviral therapy (HAART).429 Imaging reveals changes in SQ composition before clinical exams detect such changes, suggesting a higher number of patients are affected. Such changes are associated with higher cardiovascular risks.430 It may be associated with hypertriglyceridemia and/or insulin resistance.

GENERALIZED LIPODYSTROPHY (DONOHUE SYNDROME) (LEPRECHAUNISM)

FAT ATROPHY (LIPOATROPHY)

The lipodystrophy may be partial, localized, or generalized. The largest series is a study of 28 patients with JDM who had developed lipodystrophy.420 The authors concluded that LD is an under-recognized sequela of JDM and that patients with a severe prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for developing LD. Patients with JDM-associated lipodystrophy are also at risk for diabetes and lipid abnormalities. In a study by Huemer et al., four of 20 patients with JDM and lipodystrophy had either diabetes or impaired glucose tolerance, and another eight had abnormal glucose and/or lipid studies.428 It is suggested that JDM patients with lipodystrophy be screened for metabolic abnormalities. Systemic complications of lipodystrophy occur more often in JDM patients with the partial and generalized phenotypes (acanthosis nigricans, hypertrichosis, hyperpigmentation, menstrual irregularities, low leptin levels, abnormal glucose and lipid metabolism, and hyperandrogenism) and the severity correlates with earlier age of onset of JDM and the severity of the JDM.420 A myositis associated antibody, anti-p155, has been associated with the generalized phenotype of lipodystrophy.420

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Reaction Patterns

A FAT ATROPHY (LIPOATROPHY)

Figure 18.19  (A) Oval patches of necrobiosis lipoidica in a child with diabetes mellitus (courtesy of Dr A. Torrelo). (B) These lesions of necrobiosis lipoidica have a distinctive yellow waxy appearance.

ACQUIRED GENERALIZED LIPODYSTROPHY (AGL) (LAWRENCE SYNDROME) Selective loss of large regions of SQ tissue develops during childhood or adolescence in the rare cases of AGL following infection or onset of autoimmune disorders. Unlike cases of Type 1 and 2 CGL, bone marrow fat is not involved in AGL. Patients have associated insulin resistance, diabetes mellitus, and hypertriglyceridemia early in the disease. Cutaneous findings include acanthosis nigricans, hyperpigmentation and less often telangiectasias, thickening of the neck or hyperkeratosis of the palms and soles. Misra and Garg suggested three categories of AGL: panniculitis associated, autoimmune disease associated, and idiopathic.442 When the disease has its onset in adulthood, height is normal, and muscularity and abdominal protuberance are not as marked as in childhood lipoatrophy.443 Adults may have features of acromegaly such as enlargement of the skull, hands, and feet with diabetes. Association of low levels of C4 and subsequent activation of the classical complement pathway (as opposed to low C3 and alterative pathway in APL) have been observed in patients with acquired generalized lipodystrophy and autoimmune hepatitis.444 Death occurs from hepatic failure or hematemesis.

442. Misra A, Garg A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: case reports and review of the literature. Medicine (Balt). 2003;82:129–146. 443. Sasaki T, Ono H, Nakajima H, et al. Lipoatrophic diabetes. J Dermatol. 1992;19:246–249. 444. Savage DB, Semple RK, Clatworthy MR, et al. Complement abnormalities in acquired lipodystrophy revisited. J Clin Endocrinol Metab. 2009;94:10–16. 445. Arioglu E, Duncan-Morin J, Sebring N, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med. 2000;133:263–274.

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Treatment of lipodystrophy Treatment of all forms of lipoatrophy associated with metabolic abnormalities is control of the glucose and lipid abnormalities. An antidiabetic drug troglitazone, which is a ligand for the peroxisome proliferator-activated receptor, was reported to increase insulin sensitivity and promote adipocyte development. It was been used to treat patients with various forms of partial and generalized lipoatrophy.445 There was improved metabolic control and increased body fat, but the drug had a substantial risk of hepatotoxicity and was removed from the market in 2002.445 Newer forms available now include rosiglitazone and pioglitazone, both of which have shown variable results in treating lipodystrophies.446 Therapy with leptin improves glucose and lipid control in patients with various forms of generalized and partial lipodystrophy.447 Intensive plasma exchange therapy dramatically improved triglyceride levels, xanthomata, and hepatomegaly in a 15year-old with acquired generalized lipoatrophy.448 Cosmetic disfigurement has been treated with autologous fat transfer, implants, and poly-L-lactic acid with mixed and often transient results.449

446. Boyd AS. Thiazolidinediones in dermatology. Int J Dermatol. 2007;46:557–563. 447. Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570–578. 448. Bolan C, Oral EA, Gorden P, et al. Intensive, long-term plasma exchange therapy for severe hypertriglyceridemia in acquired generalized lipoatrophy. J Clin Endocrinol Metabol. 2002;87:380–384. 449. Misra 2004 LL72 above; and Burgess CM. Poly-L-lactic acid for correction of localized facial lipoatrophy in an otherwise healthy young woman. Dermatol Surg. 2009;35:881–884.

Sclerosing and atrophying conditions

Necrobiosis lipoidica (NL) is a degenerative disease of the dermal connective tissue characterized by atrophic plaques on the anterior legs. Because the first patients seen with the disease were diabetic, NL was originally considered to be a complication of diabetes mellitus, but some patients with this condition do not have diabetes, and the disease is uncommon in the diabetic population. NL may begin at any age, but it usually develops in young adults or in midlife. It is unusual in early childhood with prevalence rates reported to be 0.06–0.3%; it develops more often in adolescence.450,451 The presence of NL may be a marker for greater risk of renal and retinal disease.452 In most patients, the disease occurs on the shins (Fig. 18.19). Oval plaques with central atrophy are present, beginning with dull red, asymptomatic, rounded papules that slowly enlarge or coalesce with other lesions. The margin of the lesion is brownred or violaceous, while the center atrophies and develops a distinctive yellow waxy hue. Telangiectasias from visible dermal vessels are prominent. Ulceration occurs in 35% of cases,453 mostly in larger lesions and after minor trauma. It is unusual for the ulcerations to become infected, even in diabetic patients.453 Occasionally, lesions occur on other areas of the legs and rarely on other body sites, including the arms, trunk, and head. Sixty-two percent of 171 patients with NL reported in one study were found to have diabetes.454 In this study, nearly half of the non-diabetic patients had abnormal glucose tolerance tests. All patients with NL should be screened for diabetes. One young girl was reported to have granuloma annulare at age 5, necrobiosis lipoidica at age 7, and insulin dependent diabetes at age 12.455 Skin biopsy initially shows a leukocytoclastic vasculitis followed by collagen degeneration and destruction of adnexal structures.411 The dermis becomes necrobiotic, then granulomatous, and finally sclerotic.453 Fatty deposits are present in the

450. deSilva BD, Schofield DMV, Walker JD. The prevalence of necrobiosis lipoidica diabeticorum in children with type I diabetes. Br J Dermatol. 1999;141:593–594. 451. Pavlovic MD, Milenkovic T, Dinic M, et al. The prevalence of cutaneous manifestations in young patients with type I diabetes. Diabetes Care. 2007;30:1964–1967. 452. Verrotti A, Chiarelli F, Amerio P, et al. Necrobiosis lipoidica diabeticorum in children and adolescents: a clue for underlying renal and retinal disease. Pediatr Dermatol. 1995;12:220–223. 453. Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol. 1991;25:735. 454. Muller SA, Winkleman RK. Necrobiosis lipoidica diabeticorum: a clinical and pathological investigation of 171 cases. Arch Dermatol. 1966;93:272. 455. Marchetti F, Gerarduzzi T Longo F, et al. Maturity onset diabetes of the young with necrobiosis lipoidica and granuloma annulare. Pediatr Dermatol. 2006;23:247–250. 456. Pestoni C, Ferreiros MM, de la Torre C, et al. Two girls with necrobiosis lipoidica and type I diabetes mellitus with transfollicular elimination in one girl. Pediatr Dermatol. 2003;20:211–214. 457. Noz KC, Korstanje MJ, Vermeer BJ. Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline. Clin Exp Dermatol. 1993;18:78. 458. Petzelbauer P, Wolff K, Tappeiner G. Necrobiosis lipoidica: treatment with systemic corticosteroids. Br J Dermatol. 1992;126:542. 459. Nguyen K, Washenik K, Shupack J. Necrobiosis lipoidica diabeticorum treated with chloroquine. J Am Acad Dermatol. 2002;46:S34–S36.

upper dermis, which gives the lesions their yellow color clinically. A few patients including children have been reported to have a perforating form of necrobiosis lipoidica with transfollicular elimination of necrotic material in biopsy specimens.456 NL may be a significant cosmetic problem for the affected patient. It is chronic and persistent, with only occasional resolution of the lesions. Control of the hyperglycemia in patients with diabetes does not seem to affect the course of the skin lesions. Numerous medications have been used to treat this disorder, none with uniform success. Those medications that do halt the progression of NL often do not result in complete resolution of the lesions, leaving hyperpigmentation and atrophy. Potent topical steroids are occasionally helpful. Intralesional steroids injected into active areas may cause regression but usually do not clear the atrophic centers. A combination of dipyridamole and aspirin was reported to cause marked improvement in several uncontrolled studies, but controlled studies did not show significant differences.453 Pentoxifylline 400 mg bid457 cleared the condition dramatically in some patients; others showed no response.457 Petzelbauer et al.458 advocated the use of a 5-week course of systemic corticosteroids (1 mg/kg of body weight of methylprednisolone for 1 week, followed by 40 mg/day for an additional 4 weeks) for treating recalcitrant NL in adults. All six patients treated had complete cessation of active disease on the borders of the NL and no recurrence after a follow-up period of 7 months. The already atrophic areas were unchanged. Other treatments include high-dose nicotinamide, clofazimine, antimalarials,459–461 topical tretinoin,462 topical tacrolimus,463 fumaric acid esters,464 tumor necrosis factor inhibitors,465,466 and photodynamic therapy.467 One recent report described resolution of necrobiosis lipoidica following pancreatic transplant and concomitant immunosuppresion.468 The patient should be instructed to minimize trauma to the lower extremities to prevent ulcerations.

NECROBIOSIS LIPOIDICA

NECROBIOSIS LIPOIDICA

18

460. Ling TC, Thomson KF, Goulden V, et al. PUVA therapy in necrobiosis lipoidica diabeticorum, J Am Acad Dermatol. 2002;46:319–320. 461. Durupt F, Dalle S, Debarbieux S, et al. Successful treatment of necrobiosis lipoidica with antimalarial agents. Arch Dermatol. 2008;144:118–119. 462. Boyd AS. Tretinoin treatment of necrobiosis lipoidica diabeticorum. Diabetes Care. 1999;22:1753–1754. 463. Clayton TH, Harrison PV. Successful treatment of chronic ulcerated necrobiosis lipoidica with 0.1% topical tacrolimus. Br J Dermatol. 2005;152:581–582. 464. Krueter A, Knierim C, Stucker M, et al. Fumaric acid esters for necrobiosis lipoidica: results of a prospective noncontrolled study. Br J Dermatol. 2005;153:802–807. 465. Zeichner JA, Stern DW, Lebowohl M. Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol. 2006;54:S120–S121. 466. Hu SW, Bevona C, Winterfield L, et al. Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. Arch Dermatol. 2009;145:437–439. 467. Heidenheim M, Jemec GBE. Successful treatment of necrobiosis lipoidica diabeticorum with photodynamic therapy. Arch Dermatol. 2006;142:1548–1550. 468. Souza AD, El-Azhery RA, Gibson LE. Does pancreas transplant in diabetic patients affect the evolution of necrobiosis lipoidica? Int J Dermatol. 2009;48:964–970.

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Vascular reactions David Orchard and David Burden TRANSIENT ERYTHEMAS

INTRODUCTION The diseases considered to be vascular reactions arise as a result of abnormalities either in the blood vessels of the skin or in the blood that flows through them. These abnormalities, which may be functional or structural, give rise to cutaneous lesions that share the clinical characteristics of a smooth surface (nonscaling, non-eczematous) and varying degrees of red or white color. Classification by gross morphology is preferred. With this system, types of vascular reactions can be divided into two major categories based on the presence or absence of purpura. This determination can be made with considerable accuracy through compression of individual lesions. Compression is best accomplished with a contact dermatoscope or, carefully, two glass microscope slides; the application and quick release of finger pressure alone are inadequate. Non-purpuric lesions blanch completely whereas the presence of even a modest number of extravasated erythrocytes in purpuric lesions results in the retention of some red or violaceous coloration. Biopsy offers even greater accuracy in separating purpuric from non-purpuric lesions and is sometimes required for confirmation of a clinical impression or for the evaluation of equivocal lesions such as occur in urticarial vasculitis. Within the group of non-purpuric lesions, three subdivisions exist (Box 19.1). The transient erythemas are characterized by the evolution and resolution of individual lesions within minutes to hours. The persistent erythemas, characterized by a greater duration of lesions, resolve over days or weeks. The vasospastic lesions are characterized by the presence of pale white patches, a palpable sense of coolness, or a history of development during cold exposure. Within the group of purpuric lesions, two subdivisions exist (Box 19.1). The vasculitic or inflammatory purpuras are characterized by the presence of petechiae and, usually, palpable purpuric papules. The non-inflammatory purpuras are characterized by the presence of larger lesions of purpura (ecchymoses). Ecchymoses are usually not palpable.

1. 2.

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Warin R, Champion RH. Urticaria. Philadelphia: WB Saunders; 1974. Doutre M. Physiopathology of urticaria. Eur J Dermatol. 1999;9:601–605.

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Thus five major morphologic categories exist within the vascular reactions. It is generally easy for a clinician to assign unrecognized, smooth-surfaced, red lesions to one or another of these categories; for this reason, each of the five categories serves as a section heading within this chapter.

TRANSIENT ERYTHEMAS The diseases in this category, as indicated above, are characterized by the presence of smooth red lesions that evolve individually and resolve within minutes or hours. This degree of transience is possible because inflammatory cells are minimal or absent within the lesions. The redness observed in transient erythemas is due to dilation of upper dermal blood vessels, the size and type of blood vessel involved, and the degree of oxygen saturation of hemoglobin in the circulation. The prototype for the transient erythemas is urticaria. Transient erythemas can be subdivided into palpable and flat diseases (Box 19.2).

URTICARIA, ANGIOEDEMA, AND ANAPHYLAXIS Introduction and historical note Urticaria describes a heterogeneous group of diseases characterized by transient wheals (‘hives’). This reaction pattern is commonly seen in children – one in five will have an episode of urticaria before adolescence.1–3 For many children, the urticarial episode is short lived and simply a nuisance. For a few, urticaria may be a sign of a more serious disorder. Although the diseases now recognized as urticaria were described in antiquity, the term, according to Warin and Champion,1 is generally attributed to Johann Peter Frank of Vienna, and in the English literature to William Cullen of Scotland. Angioedema was recognized by Donato in the 16th century but not named until Strubing in the 1880s. The earliest authors reported urticaria as part of a febrile illness. Robert Willan first associated it with other factors such as foods.1

3.

Greaves MW. Chronic urticaria in childhood. Allergy. 2000;55:309–320.

Vascular reactions

Non-purpuric lesions

>> Transient erythemas >> Persistent erythemas >> Vasospastic reactions

genetically determined, angioedema and some rare types of urticaria may be hereditary.8

Presenting history

Although the precise incidence is not known, urticaria in childhood is considered to be common, and most authorities observe that 15–20% of children have at least one episode of urticaria by adolescence.1,4–6 Several large studies indicate that 3% of preschool children and about 2% of older children suffer from urticaria at any given time.3–8 In childhood, acute urticaria is more common than chronic urticaria. Children who have atopic dermatitis in infancy have an increased incidence of acute urticaria to foods such as peanuts, and reactions to latex.6 Although most forms of urticaria are not

A careful history, including a detailed complete review of systems, is the most important aspect of the evaluation of a child with urticaria.1,3–8 Most patients report the sudden onset of a pruritic eruption, with red raised spots scattered over the body.1–4,7 Importantly, the history of an individual urticarial lesion is transient. Although the eruption may have been present for days, a history can usually be obtained of new lesions arriving and older lesions fading. Individual lesions usually resolve within 24 h leaving no mark on the skin. The lesions of urticaria are generally accompanied by pruritus, sometimes of extraordinary severity. It is interesting, however, that the quality of this pruritus is different from that which occurs in eczematous disease. Urticarial itching, even when severe, rarely leads to excoriation. Angioedema, on the other hand, is usually not very pruritic and may instead be accompanied by burning or stinging.8 Angioedema may be associated with dyspnea or dysphagia, but if these symptoms have not occurred within the first few hours of any one urticarial episode, they are not likely to develop during the course of that particular episode. Lesions of angioedema may persist for several days. Events that occurred hours or a few days before the onset of acute urticaria are the most likely associated factors. Specific information should be sought about the most commonly recognized etiologic factors for urticaria and angioedema. These can be remembered by the mnemonic ‘i-i-i-i-i’ (which stands for: infection, ingestion, inhalation, infestation and injection). These categories include the urticaria that may accompany a childhood infection, the ingestion of particular foods or drugs, the inhalation of pollens and other allergens, and the injection of medi­ cations or serum products (Box 19.3). Frequently, a history of a preceding infection, particularly respiratory infection is obtained.1–8 Infections are the most commonly sought cause of urticaria in children.2,3,7 Acute viral infections, often not specifically identified, are the most frequent offenders, but virtually every infectious agent of childhood has been reported to be associated with urticaria. Among bacterial infections, those caused by streptococci are encountered most often. The fungal infections of histoplasmosis and coccidioidomycosis are well-documented causes in certain areas of the USA. In chronic urticaria, parasitic disease, candidiasis of the gut and vagina, and chronic ‘hidden’ foci of bacterial disease (otitis, sinusitis, dental abscesses, and low-grade urinary tract infection) are controversial. Medications in children are probably second in importance to infection.2,3,7–10 Penicillin and its derivatives are by far the medications most likely to cause urticaria. Even when a history of specific penicillin usage cannot be obtained, non-medical sources of penicillin might be considered because up to 25%

4.

7.

Purpuric lesions

>> Vasculitis and inflammatory purpuras >> Non-inflammatory purpuras

BOX 19.2 TRANSIENT ERYTHEMAS Palpable lesions

>> Common urticaria and angioedema >> Anaphylactic reactions >> Serum sickness >> Contact urticaria >> Physical urticarials >> Erythema marginatum Non-palpable lesions

>> Blushing >> Flushing

Urticaria represents transient edema of the dermis. Wheals may arise spontaneously (spontaneous urticaria) or in response to environmental stimuli (physical urticaria). Spontaneous urticaria is traditionally classified into acute urticaria if symptoms resolve within 6 weeks, and chronic urticaria if wheals continue to occur on most days for greater than 6 weeks. Angioedema represents edema of the deep dermis and subcutaneous tissues, or mucosa. Angioedema can occur in isolation or in association with urticaria.

Epidemiology

5. 6.

Zuberbier T, Brindslev-Jensen C, Canonica W, et al. EAACI/GA2LEN/EDF guideline: definition, classification and diagnosis of urticaria. Allergy. 2006;61:316–320. Legrain V, Taieb A, Sagi T. Urticaria in infants: a study of forty patients. Pediatr Dermatol. 1990;7:101–103. Gustafsson D, Sjoberg O, Foucard T. Development of allergies and asthma in infants and young children with atopic dermatitis – a prospective follow-up to seven years of age. Allergy. 2000;55:240–245.

TRANSIENT ERYTHEMAS

BOX 19.1 CLASSIFICATION OF VASCULAR REACTIONS

19

Greaves MW. Chronic urticaria. J Allergy Clin Immunology. 2000;105:664–672. 8. Kwong KY, Maalouf N, Jones CA. Urticaria and angioedema: pathophysiology, diagnosis and treatment. Pediatr Ann. 1998;27:719–724. 9. Knowles S, Shapiro L, Shear NH. Drug eruptions in children. Adv Dermatol. 1999;14:399–415. 10. Bircher AJ. Drug-induced urticaria and angioedema caused by non-IgE mediated pathomechanisms. Eur J Dermatol. 1999;9:657–663.

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BOX 19.3 ETIOLOGIC AGENTS IN URTICARIA AND ANGIOEDEMA: THE MNEMONIC ‘i-i-i-i-i’

Acute urticaria Infection

>> Bacterial – Streptococcal >> Viral – Virtually all, especially enteroviral and adenoviral infections

>> Fungal – Candidiasis – Histoplasmosis – Coccidioidomycosis TRANSIENT ERYTHEMAS

Infestation

>> Virtually all parasites Ingestion

>> Medications – Penicillins – Cephalosporins – Sulfonamides – Aspirin – Non-steroidals >> Foods – Nuts – Shellfish and other seafoods – Chocolate – Strawberries

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– –

Dairy products Grains

Injections

>> Antibiotics >> Immunizations >> Blood products Inhalation

>> Pollens >> Molds Chronic urticaria Collagen vascular disease

>> Lupus erythematosus >> Dermatomyositis >> Juvenile rheumatoid arthritis >> Inflammatory bowel disease >> Immunobullous skin diseases Parasitosis ‘Hidden’ infections

>> Chronic otitis media >> Sinusitis >> Dental infections >> Urinary tract infection >> Candidiasis of gut or vagina Malignancies (Hodgkin’s lymphomas and non-Hodgkin’s lymphomas)

of patients with urticaria have demonstrable antibodies to this substance. Cephalosporins (which occasionally cross-react with penicillin), sulfa-derived antibiotics, and anticonvulsants are other well-established offenders. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are often associated with worsening of urticaria.9,10 Infusion or injection of blood products is also commonly associated with the development of urticaria.2 Rechallenge studies are few, and in suspected urticarial reactions to drugs, only 4% could be reproduced.10 Less often, a history of a specific ingested product, such as a medication or food, is noted.3–11 Food-related products as a cause of urticaria are difficult to evaluate.2–4,12,13 Certainly some foods, such as nuts, seafood, chocolate, dairy products, grains, and berries, are responsible for episodes of acute urticaria, but the role of foods, food dyes, and food preservatives in chronic urticaria is more controversial. Studies that use provocative double-blind oral food challenges rather than skin tests and radio-allergosorbent tests (RAST) are interpreted to show that food allergy is reproducible in only a few instances.12 Injections of medications, immunizations, or allergy desensitization treatments might be found. Most uncommonly, an associated infestation is uncovered.

Physical examination

11. Janniger CK, Schutzer SE, Schwartz RA. Childhood insect bite reactions to ants, wasps, and bees. Cutis. 1994;54:14. 12. Jarisch R, Beringer K, Hemmer W. Role of food allergy and food intolerance in recurrent urticaria. Curr Prob Dermatol. 1999;28:64–73.

13. Friedmann PS. Assessment of urticaria and angio-oedema. Clin Exp Allergy. 1999;29(suppl):109–112.

The initial lesions of urticaria are tense, flat-topped papules known as wheals. The color is usually pink or light red but may occasionally be bright red, and the wheals are usually 2–10 mm in diameter, flat-topped, and have tense edema (Fig. 19.1). The edema can be appreciated by stretching the skin slightly to demonstrate whitish centers. Wheals quickly enlarge to form flattopped, sharply marginated papules and plaques (Fig. 19.2). This rapid change may be dramatized by the placement of ink marks around existing lesions and noting the degree of change a short time later. In many instances, centrifugal enlargement of closely set lesions leads to the formation of very large urticarial plaques with polycyclic borders, the so-called ‘giant urticaria.’ In other instances, the centrifugal expansion is accompanied by central clearing and development of ringed (annular) borders (Fig. 19.3). Giant urticarial lesions are dramatic and these large polycyclic plaques have no special significance but are often misdiagnosed as erythema multiforme (Fig. 19.4). The lesions of urticaria may occur anywhere on the body but are often most prominent at points of pressure, including the belt line and the palms and soles (Box 19.4). Exacerbation may occur as a result

Figure 19.1  Idiopathic urticaria in a 6-year-old child.

19

TRANSIENT ERYTHEMAS

Vascular reactions

Figure 19.3  Annular urticarial lesions with clearing in the center (courtesy of Dr A. Torrelo).

Figure 19.2  Urticaria with different sized and shaped lesions in a child.

Figure 19.4  Gyrate polycyclic giant urticarial lesions with dusky centers in an

(courtesy of Dr A. Torrelo).

infant (courtesy of Dr A. Torrelo).

BOX 19.4 THE WORKUP OF CHRONIC URTICARIA

>> Careful detailed history >> Erythrocyte sedimentation rate >> Antinuclear antibody titer >> Examination for parasites

of vasodilation during body warming. Thus, urticarial lesions may be particularly prominent during exercise, after showering, and under bed coverings at night. In angioedema, light pink to skin-colored, slope-shouldered, large nodules develop. It is most likely to occur as diffuse swelling of the eyelids, lips, tongue, genitalia, hands, feet, and mucous membranes (Fig. 19.5). Mild angioedema may accompany ordinary urticaria in 10% of infants and children.2,8,10 The face,

hands, and feet are involved in 85% and other areas are involved in 15% of children. Angioedema of a more severe type occurs in anaphylaxis, serum sickness, and hereditary angioedema. These conditions are considered separately in the section that follows. Anaphylaxis is a medical emergency characterized by the sudden onset of urticaria, angioedema, dyspnea, and hypotension.8,10,11 The term anaphylaxis came into use more than 80 years ago, when it was recognized that prior exposure to certain agents (e.g., measles virus) offered protection (prophylaxis) against subsequent development of the disease, whereas the reverse was true (anaphylaxis) for other agents such as horse serum. Today, probably because of the less frequent use of foreign proteins and better purification steps in pharmaceutical manufacture, anaphylaxis is less commonly encountered but may occur during allergen desensitization strategies. Patients experiencing anaphylaxis have pruritus within seconds to minutes, followed almost immediately by urticaria and 1099

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Figure 19.5  Urticaria with angioedema of the hand in a toddler. angioedema.8,10,11 Often, these skin changes appear at the site of antigen entrance (intramuscular injection site, envenomization site, or mouth) but rapidly become more widespread. The rapid shift of fluid from the vessel into the connective tissue results in varying degrees of hypotension and may lead to shock. Angioedema of the larynx causes difficulty with breathing and speaking. Bronchospasm is often present, and incontinence of the bladder and the bowel sometimes occur. Mucous membranes of the tongue, soft palate, pharynx, and larynx may rarely be involved, producing acute respiratory distress.8,10,11 The gastrointestinal mucosa of the stomach and intestines may also rarely be involved, resulting in abdominal cramping, vomiting, or diarrhea. It is not clear whether cerebral edema can cause confusion or coma in these disorders. The diagnosis of anaphylaxis is made on a clinical basis because there are no immediately useful associated laboratory findings.

Laboratory findings Routine history and physical examination are by far the most useful approaches to the classification of urticaria and the determination of its cause. In children with acute urticaria, if this approach does not supply a likely cause, laboratory testing will seldom be useful. In chronic urticaria, full blood count and ESR may be helpful but further routine tests are not necessary unless particular symptoms require investigation. In particular, allergy screening by prick testing or measuring specific IgE to ingested or inhalant allergens is not indicated if there is no suggestive history. Physical urticaria may be reproduced by provocation testing. A skin biopsy may be helpful if urticarial vasculitis is suspected based on the duration of the wheals, bruising or associated symptoms.2

Pathophysiology The molecular and cellular mechanisms that produce urticaria are complex and incompletely understood. Histamine release from dermal mastocytes appears to be central and this can be

14. O’Donnell BF, Francis DM, Swana GT, et al. Thyroid autoimmunity in chronic urticaria. Br J Dermatol. 2005;153:331–335.

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associated with activation of components of the innate and acquired skin immune systems. The mechanisms through which urticaria develops can be divided into immunologic and nonimmunologic events. Non-immunologic mechanisms for the development of urticaria include direct pharmacologic degranulation of mast cells and a separate, less well-understood pathway utilized by agents that alter the metabolism of prostaglandins. Both of these non-immunologic mechanisms can be important in the urticaria and angioedema of anaphylactic reactions.2,8 The role of non-immunologic mechanisms in chronic urticaria is less certain. However, aspirin and other non-steroidal antiinflammatory agents (all of which are antagonists of the prostaglandin cyclooxygenase pathway) may worsen chronic urticaria. Antigen attachment to, and activation of, specific immunoglobulin (IgE) antibody bound to the membranes of dermal mast cells is the best-studied immunologic event and is particularly relevant to acute urticaria and anaphylaxis to food allergens in atopic children. Chronic urticaria frequently arises with no clear environmental trigger (chronic idiopathic urticaria) and a substantial proportion of cases are now considered to have an autoimmune basis (chronic autoimmune urticaria). An autoimmune pathogenesis was first suggested by the observation of an association between chronic urticaria and autoimmune thyroid disease. Of patients with chronic urticaria, 10–20% have antithyroid antibodies.14 In the mid-1980s, it was shown that some patients with active urticaria developed a wheal at the site of intradermal injection of autologous serum15 and the serum factor has subsequently been identified as an IgG class antibody directed against the α subunit of the IgE receptor (FcεRI) on mast cells or, less frequently, against IgE itself. Binding of IgG to mast cells activates complement via the classical pathway which may be necessary for activation of the mast cell and the release of inflammatory mediators. It is now considered that about 50% of cases of chronic urticaria are autoimmune and a similar proportion remain idiopathic. Regardless of the specific mechanism through which wheal formation is initiated, the final common pathway is that of mast cell degranulation and release of inflammatory mediators. Histamine, leukotrienes, chemokines and cytokines released from mast cells are responsible for mediating an increase in vascular permeability and also an activation of the vasculature with subsequent extravasation of inflammatory cells into the dermis. In angioedema, the formation and breakdown of kinins such as bradykinin are also involved particularly in hereditary angioedema, and angioedema associated with ACE inhibitors. Kinins are potent vasodilators and increase vascular permeability. They also stimulate sensory nerve endings in the skin to produce the characteristic burning pain of angioedema.

Differential diagnosis Urticaria and angioedema are diagnosed strictly on clinical criteria based on the presence of characteristic wheals, at times accompanied by focal areas of subcutaneous edema, and the transient nature of individual lesions.1–9,11 Anaphylaxis is

15. Grattan CE, Wallington TB, Warin RP, et al. A serological mediator in chronic idiopathic urticaria – a clinical, immunological and histological evaluation. Br J Dermatol. 1986;114:583–590.

Vascular reactions

Therapeutics and prognosis For most children, urticaria is not a serious problem. The most serious complication is acute airway obstruction from edema. Although deaths have been reported, the mortality rate is low. These fatalities are almost exclusively the result of hereditary angioedema and not urticaria with anaphylaxis. Most children with urticaria do not have other conditions that require intervention; even with chronic urticaria, the child’s growth and development are unaffected. Elimination diets, desensitization strategies, and environmental changes are not indicated and may induce malnutrition or severely disrupt a child’s routine. Loss of sleep from itching is rarely a problem for children. In acute urticaria, reassurance of the child and parents, and advice concerning the avoidance of identifiable precipitating factors are important. Most of the symptoms of urticaria are mediated by the H1 receptor and there is good published evidence for the efficacy of second generation non-sedating (or less sedating) antihistamines such as desloratadine, astemizole, fexofenadine and cetirizine.17 Some of these agents are not licenced in younger age groups and the availability of acceptable formulations in children is an important consideration. For severe disease, and when itch at night is disruptive of sleep, the addition of a first generation sedating antihistamine such as chlorphenamine, hydroxyzine, promethazine or trimeprazine can be useful. For severe resistant acute urticaria a short pulse of an oral corticosteroid is effective and is occasionally required. It is important to use the antihistamine until the allergen is removed from the body, to prevent rebound of the urticaria. Usually a week to 10 days is sufficient. The mainstay of treatment of chronic urticaria is also with antihistamines. Ordinarily, one should initiate therapy with a dose that is within the upper level recommended by the manufacturer. This dose can gradually be increased until either improvement occurs or side-effects become troublesome. An amount twice the recommended dose should not be exceeded. Sedation may occur even at rather low doses. In infants and toddlers, paradoxical irritability and hyperactivity may occur, especially with diphenhydramine. In older children, daytime drowsiness can be minimized by administering most of the entire day’s dosage 1 hour before bedtime. A sedating antihista-

16. Weston WL. What is erythema multiforme? Pediatr Ann. 1996;25:106–109.

mine at bedtime and a non-sedating antihistamine in the morning may be useful. Anticholinergic effects secondary to H1 antihistamine are not usually troublesome in children. Once the urticaria has been controlled, the antihistamine dosage should be slowly tapered rather than being discontinued abruptly. This approach reduces the risk of immediate exacerbation. In the event of recurrences, it is safe and appropriate to carry out longer therapy. This may be ongoing for more than 1 year. If there is little response after two or more H1 blockers have been used, the addition of H2 antihistamine (cimetidine or ranitidine) may occasionally be helpful. Alternatively, an agent such as low dose oral doxepin, which is a tricyclic antidepressant, can be used although the perceived toxicity prevents it from being a first line treatment in children. A small proportion of children with chronic urticaria do not respond to adequate doses of antihistamines and can be a challenging management problem. A variety of therapeutic approaches have been reported, although for most the quality of the published evidence is low. These include leukotriene receptor antagonists such as montelukast, calcium channel antagonists, immunosuppressants such as cyclosporine and methotrexate, and other oral therapies including dapsone and hydroxychloroquine. The risk–benefit of these treatments that are prescribed off-label should be carefully considered in the individual patient. Injected epinephrine (adrenaline) is first-line therapy for severe anaphylaxis and severe angioedema reactions (0.01 mg/Kg s.c.). Venous access for the administration of fluids must be established because, even when the clinical appearance of angioedema suggests the presence of excess fluids, intravascular hypovolemic shock is likely to be present.8 Intubation is necessary when there is evidence of significant laryngeal edema. Mild degrees of bronchoconstriction can be treated with asthma aerosol inhalers; intravenous aminophylline should be administered if the problem is more severe. Supplemental oxygen can be added as necessary. If the entry site of the offending agent occurred on an extremity, a tourniquet should be placed proximal to it. Antihistamines and corticosteroids may be administered in addition to (but never in lieu of) the steps outlined above. Anaphylaxis is a frightening event for all concerned. Every attempt should be made to identify the responsible agent and to minimize the chances for subsequent exposure. Appropriate notations of sensitivity should be placed in the patient’s medical record, and patients should wear ‘alert’ tags or bracelets. Anaphylaxis kits (bee sting kits) should be prescribed, and both the patient and parents should be instructed regarding injection of the epinephrine contained therein. Occasionally, the fear of subsequent anaphylaxis reaches that of a neurosis. In such instances, psychiatric counseling should be sought. The outlook for most children with urticaria is excellent.3,7 If laryngeal edema has not occurred during the first several hours of any given episode, it is very unlikely to occur thereafter. Most children with urticaria experience resolution within 14 days. The remainder experience a more chronic course that can be either intermittent or continuous over a matter of weeks or months.

TRANSIENT ERYTHEMAS

diagnosed based on the presence of acute airway obstruction, hypotension and association with urticaria.8,13 In giant urticaria, the large transient wheals may be misdiagnosed as erythema multiforme.16 Insect bite reactions, such as papular urticaria, may mimic common urticaria. Rarely, autoimmune diseases, such as SLE or dermatomyositis, may present as urticaria. Photodistributed urticaria and angioedema may be seen in erythropoietic protoporphyria and variegate porphyria. Immunobullous disease, such as dermatitis herpetiformis and bullous pemphigoid, may present with urticaria. Diffuse cutaneous mastocytosis may present in the early stages with urticaria and dermatographism. Hypocomplementemic vasculitis may also mimic urticaria. Early red papules of guttate psoriasis or pityriasis rosea have also been misdiagnosed as urticaria.

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17. Schad CA, Skoner DP. Antihistamines in the pediatric population: Achieving optimal outcomes when treating seasonal allergic rhinitis and chronic urticaria. Allergy Asthma Proc. 2008;29:7–13.

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These individuals should be followed with symptomatic treatment. There is no way of predicting the expected duration of chronic urticaria but most resolve in about 2 years.18

OTHER TRANSIENT ERYTHEMAS Serum sickness

TRANSIENT ERYTHEMAS

Serum sickness is characterized by the development of urticaria, angioedema, arthralgia, myalgia, lymphadenopathy, and fever 7–20 days after the administration of animal serum or other foreign proteins.19,20 Both the likelihood of developing serum sickness and the level of severity when it occurs are dependent on the dose of the antigen and frequency of administration. The pruritus, urticaria, and angioedema that occur are similar to those observed in anaphylaxis.19 In fact, anaphylaxis itself occasionally occurs during the course of serum sickness. The development of a serpiginous erythematous and purpuric eruption at the edges of the palms and soles is a useful diagnostic feature of serum sickness. Evidence of systemic involvement is usually confined to joints, muscles, and reticuloendothelial tissues. The major pathogenetic mechanism in serum sickness involves immune complex deposition at the basement membrane of blood vessels with subsequent complement activation. Circulating immune complexes can usually be detected, and serum levels of complement are depressed. Reactions essentially identical to those seen in classical serum sickness are occasionally encountered during the use of medications that do not contain animal serum. In these cases, the medication presumably acts as a partial antigen (hapten), which, by attaching to one or more of the patient’s own proteins, subsequently forms a complete antigen. This complete antigen may then cause antibody formation and the development of immune complexes. Serum sickness generally lasts 5–30 days and then slowly resolves. Subsequent readministration of the same antigen results in an accelerated reappearance of the original symptoms and signs. The ‘serum sickness’ frequently observed with Ceclor treatment in children resembles urticaria and angioedema rather than true serum sickness (Fig. 19.6).20 Antihistamines are only moderately effective in the treatment of serum sickness. For this reason, and because the usual duration of illness is short, systemic corticosteroids are appropriately used in all but the mildest cases. Oral prednisone in doses of 1–1.5 mg/kg administered for 2–3 weeks is usually sufficient.

Hereditary angioedema (HAE) Angioedema can be inherited or acquired, allergic or drug induced.21 Hereditary angioedema usually develops for the first time in childhood or adolescence. Attacks may arise spontaneously or following trauma (surgery, dental manipulation, or accidents) and present as repeated attacks of swelling of the extremities, face, and throat, accompanied by abdominal pain.22

18. Calnan CD. Urticarial reactions. BMJ. 1964;2:649–655. 19. Martin-Munoz F, Moreno-Ancillo A, Dominguez-Noche C, et al. Evaluation of drug-related hypersensitivity reactions in children. J Invest Allerg Clin Immunol. 1999;9:172–177. 20. Hebert AA, Sigman ES, Levy ML. Serum sickness-like reactions from cefaclor in children. J Am Acad Dermatol. 1991;25:805–806.

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Figure 19.6  Polycyclic urticarial lesions with angioedema of foot in child with so-called ‘serum sickness’ reaction to Ceclor.

On the skin, it presents as a diffuse, brawny swelling of the extremities in 75% of patients and swelling of the face and throat in 30%. Typical urticarial wheals are not a feature. Individual lesions are of longer duration than common urticaria and pitting of the skin does not occur. Abdominal pain eventually becomes a major complaint for many patients.22 Severe airway edema accounts for the mortality of almost 30% in untreated patients. The angioedema seen in the genetically determined HAE syndrome is different from that associated with common urticaria, anaphylaxis, and serum sickness, in that it is not triggered by readily identifiable antigens or pharmacologic agents; it is mediated through complement activation and kinin release rather than by an IgE mechanism.2,22 HAE is usually due to a mutation in C1 inhibitor (C1NH) and is inherited as an autosomal dominant trait with about a 20% new mutation rate. Two clinically indistinguishable genetic variants are recognized: HAE type 1 (85%) in which deletions or stop codons result in reduced C1NH protein levels, and HAE type 2 (15%) in which point mutations in C1NH result in normal levels of functionally inactive protein. An extremely rare form of HAE (type 3) that occurs almost exclusively in women has normal C1NH activity and in some families is due to gain-of-function mutations in coagulation factor XII. C1NH deficiency may also be acquired either due to consumption of the protein (associated with SLE or lymphoma) or due to auto-antibodies directed against C1NH. The diagnosis of C1NH deficient angioedema should be suspected if the serum C4 level is persistently low in the presence of normal C3 levels. This forms a useful screening test and the diagnosis can be confirmed by functional assay of the C1NH. In acquired forms of the disease C1q levels are also depressed as well as C4. Acute attacks are managed by intravenous fluid replacement,

21. Krishnamurthy A, Naguwa SM, Gershwin ME. Pediatric angioedema. Clin Rev Allergy Immunol. 2008;34:250–259. 22. Laurent J, Guinnepain MT. Angioedema associated with C1 inhibitor deficiency. Clin Rev Allergy Immunol. 1999;17:513–523.

Vascular reactions

Contact urticaria Ordinary urticarial reactions commonly occur by way of mucous membrane exposure to antigens (inhalants or ingestants), but urticaria as a result of skin exposure is also possible.3,25 In contact urticaria, the lesions are usually confined to the precise site of contact (an important diagnostic clue), but on occasion, satellite or even widespread lesions develop. Systemic reactions in the form of anaphylaxis have also rarely been observed. The contactants responsible for these reactions may operate either through pharmacologic or immunologic mechanisms. Some common examples of the former include skin contact to jellyfish, nettles, corals, moths, caterpillars, and certain chemicals.3 Immunologically mediated reactions can occur after exposure to fish, wood dust, latex, cosmetics, epoxy resins, parabens, antibiotics, nickel, and certain animal products, such as dander, hair, and saliva. Allergic contact urticaria to natural rubber latex is a particular problem in health care workers and also in children who have had many medical treatments such as those with spina bifida. Treatment requires identification and elimination of the contactant together with administration of antihistamines. Aquagenic urticaria represents a special variant of contact urticaria.25 This rare condition usually starts at or after puberty and is occasionally familial. Small, uniform urticarial papules develop at the ostia of hair follicles after exposure to water at any temperature. When the reaction is widespread, there are hundreds of minute lesions. The mechanism through which these lesions develop is unknown. Aquagenic urticaria might be analogous to cholinergic urticaria in which sweat is believed to play a similar inciting role. Antihistamine therapy may be tried but is often only marginally helpful.

Physical urticarias The physical urticarias are distinguished from other urticarial reactions because the precipitating factors (heat, cold, ultraviolet light, and pressure) are neither direct antigens nor direct mast cell degranulators.1,3 Nevertheless, these agents appear to induce immunologic mechanisms that eventuate in a final common pathway of histamine (and probably other mediator) release from mast cells.

23. Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359:1027–1036. 24. Bork K, Yasothan U, Kirkpatrick P. Icatibant. Nat Rev Drug Disc. 2008;7:801–802.

Figure 19.7  Dermographism in a child.

Dermographism

TRANSIENT ERYTHEMAS

airway maintenance, and intravenous infusion of plasma inhibitor concentrate.17 Unlike other angioedema states, HAE is not responsive to therapy with steroids, epinephrine, or antihistamines. C1NH replacement (fresh-frozen plasma or ε-aminocaproic acid if plasma is not available) may be useful as prophylaxis before surgical procedures.22 Good control of the disease may be obtained through the regular use of anabolic steroids, such as danazol or stanozolol. These agents increase the levels of C1 esterase inhibitor. Promising therapeutic developments include recombinant human C1 inhibitor, kallikrein inhibitors and bradykinin receptor antagonists.23 Recently icatibant, a bradykinin B2 receptor antagonist, has been licenced for acute attacks of HAE in adults.24

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In virtually all infants younger than 6 months of age, about onehalf of otherwise normal children, 1% of adolescents, and most children that have urticaria, linear stroking of the skin with modest pressure results in the immediate development of a red line at the exact site of stroking, the subsequent replacement of this line with a linear wheal, and development of a surrounding flat red axon flare (Fig. 19.7).1,3 The wheal reaches maximal size in 6–7 min and persists for 10–15 min. This phenomenon is known as the triple response of Lewis. In a smaller proportion of patients, the wheal formation is accompanied by significant local or even generalized pruritus. This pruritic reaction, called symptomatic dermographism, may be troublesome enough to warrant medical attention. The wheal is seen in comatose children (e.g., in encephalitis, meningitis, drug overdose) and has been termed ‘tache cerebrale’. Symptomatic dermographism can be passively transferred, which suggests the presence of an immunologic mechanism, possibly IgE in type. Wheals are commonly found around the belt area and may follow widespread insect bites and transient episodes of urticaria. The presence of symptomatic dermographism may be associated with atopic dermatitis, urticaria, or mastocytosis. In infants with diffuse cutaneous mastocytosis, dermographism is particularly prominent and may precede the characteristic ‘Moroccan leather’ appearance by several months. There is no known specific cause for dermographism, and it is not often a clue to the presence of an underlying systemic disorder. Dermographism may persist for years, but most patients can expect spontaneous regression within 2 years. Treatment with antihistamines, especially concomitant use of low-dose hydroxyzine and cimetidine, may occasionally be warranted. Delayed-pressure urticaria is a variant of dermographism. The lesions, however, do not occur until several hours after the pressure has been applied. The palms and soles are most commonly involved. The lesions are painful and deep. The response to antihistamine therapy is poor.

Cold urticaria There are two distinct forms of cold urticaria: an acquired and a familial type. The former is common and is particularly likely to

25. Wasserman D, Preminger A, Zlotogorski A. Aquagenic urticaria in a child. Pediatr Dermatol. 1994;11:29–30.

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occur in children. In acquired cold urticaria, symptoms of urticaria and angioedema of conventional type develop during or immediately after exposure to cold.26 Either of two mechanisms can be responsible for the pathogenesis of acquired cold urticaria. The more common is that of IgE antibody response to an unknown, but presumably cold-induced, antigen. The second is that due to the presence of cryoproteins. These cold-precipitable proteins activate complement with subsequent release of anaphylatoxins and consequent mast cell degranulation, possibly through a mechanism involving immune complex formation. Many of the patients with cryoproteins have or will have symptoms and signs of infection or connective tissue disease. Antihistamines, particularly cyproheptadine and doxepin, may be helpful. Anaphylactic reactions, particularly during swimming, have been reported in those with acquired cold urticaria. It is important to confirm the diagnosis by cold provocation testing, usually by placing an ice cube on the skin and waiting for a wheal reaction where the ice has been applied. Familial cold urticaria is now considered to be a periodic fever, or autoinflammatory disease and is known as familial cold autoinflammatory syndrome. It is caused by mutation in the gene CIAS1 and is inherited as an autosomal dominant trait.27 In this condition, symptoms are more often caused by cold air than by cold water exposure and are usually delayed until several hours after the cold exposure. Burning or stinging is much more prominent than pruritus and the rash usually consists of erythematous macules rather than wheals. Associated problems include fever, arthralgia, and leukocytosis. Neutrophils are found in lesional skin biopsies.28 Occasional patients develop amyloidosis. Muckle–Wells syndrome is an allelic condition in which there is a higher risk of amyloidosis and sensorineural deafness.

Cholinergic urticaria (heat and exercise urticaria) This type of urticaria occurs commonly in adolescents.1,3,29 It is readily identified when numerous, small (2–3 mm) red macules with a tiny (1 mm) central urticarial papule occur within a matter of minutes after sweating. The individual papules may be grouped. Headache, faintness, pulmonary distress, and gastrointestinal problems may also develop. Exercise-induced broncho­ spasm can accompany cholinergic urticaria. There is a refractory period after an attack when another episode cannot be induced for up to 24 h. Cold urticaria may be seen in some patients with cholinergic urticaria. The pathogenesis of cholinergic urticaria is believed to involve heating of the skin surface. Stimulation of sweating by heating the skin surface or with cholinergic-type pharmacologic agents can also induce lesions in some individuals. The development of lesions may be related to host-determined, heightened reactivity to cholinergic-type chemicals. It has been suggested that there are two subtypes of cholinergic urticaria, distinguishable by

26. Siebenhaar F, Weller K, Mlynek A, et al. Acquired cold urticaria: clinical picture and update on diagnosis and treatment. Clin Exp Dermatol. 2007;32:241–245. 27. Hoffman HM, Mueller JL, et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nature Genet. 2001;29:301–305. 28. Toppe Haas N, Henz BM. Neutrophilic urticaria: clinical features, histological changes and possible mechanisms. Br J Dermatol. 1998;138:248–253.

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intradermal testing with autologous sweat. The first subtype is non-follicular in distribution and shows a strong positive reaction to autologous sweat and a negative reaction to autologous serum. The second subtype is follicular in distribution and shows a weak reaction to autologous sweat and a positive reaction to autologous serum.30 Attacks can be avoided through rapid cooling. This cooling must, of course, occur before the onset of sweating. One can instruct the child to induce attacks when there is optimal antihistamine coverage. Antihistamines, especially hydroxyzine, can be used to control symptoms. Autosomal-dominant inheritance has been reported but most cases are sporadic.29

Solar urticaria Urticaria as a result of exposure to light occurs occasionally in children.1,31 Sunlight, which also contains infrared energy, is the usual source of light exposure. For this reason, cholinergic urticaria (from heat) must also be considered in the differential diagnosis of solar urticaria. Childhood LE, erythropoietic protoporphyria, and polymorphous light eruption may present with sun-induced urticaria. Children with solar urticaria develop lesions within minutes of light exposure.31 Pruritic wheals are similar to those found in common urticaria and are occasionally associated with systemic symptoms. Appropriate blood tests to rule out LE and erythropoietic protoporphyria should be performed. Passive transfer experiments are positive in some children with solar urticaria, which suggests that immunoglobulins (probably of the IgE type) are important in the pathogenesis of this disease. A clinical diagnosis of solar urticaria can be confirmed with controlled light testing. Phototesting with a solar simulator or monochromatic light source can define the action spectrum of light involved. Most patients with solar urticaria are responsive only to UVB (280–320 nm) wavelengths; others react to UVA (320–400 nm) or visible light. A few respond to UV light across its entire spectrum. Treatment depends on the use of sun protection strategies, including sun avoidance, clothing, and sunscreens. Many commercial brands of clothing are available. Unfortunately, the currently available sunscreens, including newer agents with some UVA protection, are still not very effective for those who are sensitive to UVA or visible light. Systemic administration of β-carotene, antimalarials, or antihistamines may be considered, but, in most children, are not often helpful. Attempts to induce ‘hardening’ or ‘hyposensitization’ with UV light therapy may be useful.

Erythema marginatum (erythema circinatum) Up to 10% of children with acute rheumatic fever have transient episodic, asymptomatic, annular erythematous lesions. Erythema marginatum is a major diagnostic criterion of acute

29. Onn A, Levo Y, Kivity S. Familial cholinergic urticaria. J Allergy Clin Immunol. 1996;98:847–849. 30. Fukunaga A, Bito T, Tsuru K, et al. Responsiveness to autologous sweat and serum in cholinergic urticaria classifies its clinical subtypes. J Allergy Clin Immunol. 2005;116:397–402. 31. Monfrecola G, Masturzo E, Riccardo AM, et al. Solar urticaria: a report on 57 cases. Am J Contact Dermatol. 2000;11:89–94.

Vascular reactions

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(termed blushing reactions), those related to certain ingestants, and those related to an underlying systemic disease.

Physiologic flushing and blushing

with acute rheumatic fever.

rheumatic fever, along with carditis, polyarthritis, Sydenham chorea and subcutaneous nodules. Lesions begin as flat or slightly raised reddened papules that clear in the center and rapidly enlarge in a centrifugal manner. These enlarging lesions appear as thin red lines, forming large annular or polycyclic patterns (Fig. 19.8). These lines and circles appear in successive waves over the trunk and proximal extremities. Each lesion evolves, migrates, and then resolves over 1 hour or so. They occur most commonly late in the day and usually appear with fever. Inducing cutaneous vasodilation may make the lesions more visible. The pathogenesis of erythema marginatum is unknown, although it appears to involve the release of vasodilating and permeability-enhancing mediators similar to those responsible for the development of common urticaria. From the lack of itching and the migration of individual lesions one can suggest that the two processes are not identical. A thorough evaluation for acute rheumatic fever is indicated. Erythema marginatum may also be seen following streptococcal infections without evidence of acute rheumatic fever, and also in association with hereditary angioedema. It should be considered in the differential diagnosis of juvenile idiopathic arthritis.

PERSISTENT ERYTHEMAS

The flushing and blushing reactions are characterized by the sudden development of diffuse flat erythema that is most striking over the face and upper trunk.32 There is no associated increase in vascular permeability during these reactions, and urticaria and angioedema are absent. These reactions may be divided into those related to normal physiologic responses

The diseases in this category are characterized by the presence of smooth-surfaced, blanchable red papules and plaques. As such, they are similar to the lesions of the transient erythemas. However, as the name implies, the lesions of the persistent erythemas are considerably more stable and remain at the same skin sites, unchanged in shape or size, for at least 1 week rather than for minutes or hours. The stability of the lesion is explained by its histology. All of the diseases in this group are characterized by the presence of mononuclear (primarily lymphocytic) perivascular dermal infiltrates. The deposition and removal of these cells require a much longer time period than the simple change in vascular permeability that occurs in the transient erythemas. The per­ sistent erythemas are separated from the purpuras because the lymphocytic infiltrates in the persistent erythemas are nonnecrotizing so that the inflammatory infiltrate seldom compromises the integrity of the vascular wall and there is little or no extravasation of red blood cells into the surrounding connective tissue. The color of the erythema present in the lesions of persistent erythemas is variable, depending on the degree of oxygen saturation, the amount of dermal edema, and the size and type of vessels involved. In general, lesions of the persistent erythemas tend to be duskier in color than are the lesions of the transient erythemas. There are a large number of diseases that meet the criteria of the persistent erythemas. To enhance their recognition and to simplify discussion, they are subclassified on the basis of shared

32. Chen WJ, Chen CC, Cheng AT. Self-reported flushing and genotypes of ALDH2, ADH2 and ADH3 among Taiwanese Han. Alcohol Clin Exp Res. 1998;22:1048–1052.

33. Milingou M, Antille C, Sorg O, et al. Alcohol intolerance and facial flushing in patients treated with topical tacrolimus. Arch Dermatol. 2004;140:1542–1544.

Flushing and blushing reactions

PERSISTENT ERYTHEMAS

Figure 19.8  Polycyclic red borders of erythema marginatum in febrile child

The term blushing is usually used for reactions caused by embarrassment and the term flushing for those caused by anger or excitement. Little is known about the mechanisms through which these reactions occur. These are most prominent in fairskinned children. Flushing may occur during the ingestion of hot or spicy food and beverages and may accompany the ingestion of foods containing sulfites, nitrites, monosodium benzoate, certain ‘hot’ spices, and products containing alcohol.32 Familial flushing and racial susceptibility to flushing following alcohol have been associated with inheritance of aldehyde dehydrogenase polymorphisms.32 There are also reports of alcohol flushing induced by topical tacrolimus and pimecrolimus, seen also occasionally in children.33 Episodic flushing occurs in some children with mastocytosis and pheochromocytomas. In mastocytosis, the reactions are probably mediated through prostaglandin D2 mechanisms. In pheochromocytoma, the reactions are believed to be due to catecholamine release.

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morphologic features (Box 19.5). The prototype for the persistent erythemas is erythema multiforme.

ERYTHEMA MULTIFORME Introduction and historical note

PERSISTENT ERYTHEMAS

Erythema multiforme (EM) is an acute, self-limited skin condition characterized by the abrupt onset of symmetrical, fixed red papules, some of which evolve into target lesions. The term erythema multiforme is attributed to the Viennese dermatologist, Ferdinand von Hebra in 1860.34,35 The illness he described was mild, recurrent, and characterized by the evolution of early red papules into ‘target’ lesions. He noted that there was no prodrome and that oral lesions were not present. Since von Hebra’s time, the concept of EM has become confused in the literature, possibly because authors interpreted EM to mean many forms of lesions present at one time. This has resulted in many instances of giant urticaria or lesions with polycyclic borders being reported as EM. Further confusion came when Thomas designated the illness described by von Hebra as EM minor and the severe mucocutaneous reaction described by Stevens and Johnson as EM major.36 This incorrectly linked Stevens–Johnson syndrome (SJS) to EM, and later others linked toxic epidermal necrolysis (TEN) to EM. No author has demonstrated that EM progresses to SJS or TEN.37 Most authorities believe these are distinct conditions.37 A consensus classification of severe mucocutaneous reactions in this group was established in 1993 and has since been found accurately to reflect elements of the diverse biology of these conditions.38 Five clinically distinct entities are recognized; bullous erythema multiforme (detachment below 10% of the body surface area plus localized ‘typical targets’ or ‘raised atypical targets’); Stevens–Johnson syndrome (detachment below 10% of the body surface area plus widespread erythematous or purpuric macules or flat atypical targets); overlap Stevens–Johnson syndrome–toxic epidermal necrolysis (detachment between 10% and 30% of the body surface area plus widespread purpuric macules or flat atypical targets); toxic epidermal necrolysis with spots (detachment above 30% of the body surface area plus widespread purpuric macules or flat atypical targets); and toxic epidermal necrolysis without spots (detachment above 10% of the body surface area with large epidermal sheets and without any purpuric macule or target lesions).

Epidemiology The exact incidence of EM is unknown, but it is believed to be very uncommon in childhood, even less common than SJS.37 Some 20% of all cases of EM occur in childhood. There is a slight male preponderance but no racial bias. Several small studies of histocompatability antigen (HLA) associations with EM reported differing types, such as HLA DQB1*0301.39

34. von Hebra F. Acute Exantheme und Hautkrankheiten. Handbuch der speciellen Pathologie und Therapie. Erlangen: Verlag von Ferdinand von Enke; 1860:198–200. 35. von Hebra F. On diseases of the skin including the exanthemata. London: New Sydenham Society; 1866:285. 36. Thomas BA. The so-called Stevens–Johnson syndrome. BMJ. 1950;1:1393. 37. Assier H, Bastuji-Garin S, Revuz J, et al. Erythema multiforme with mucous membrane involvement and Stevens–Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol. 1995;131:539–543.

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BOX 19.5 CLASSIFICATION OF PERSISTENT ERYTHEMAS Mucocutaneous syndromes

>> Erythema multiforme >> Stevens–Johnson syndrome >> Toxic epidermal necrolysis >> Fixed drug eruption Papular erythemas

>> Papular urticaria (insect bites) >> Pityriasis lichenoides >> Lymphomatoid papulosis >> Erythema elevatum diutinum Nodular erythemas

>> Erythema nodosum >> Subacute nodular migratory panniculitis >> Lobular panniculitis syndromes >> Nodular vasculitis >> Superficial thrombophlebitis Annular and gyrate erythemas

>> Erythema chronicum migrans >> Erythema annulare centrifugum >> Erythema gyratum repens Acral erythemas

>> Erythromelalgia >> Miscellaneous acral erythemas Reticulate erythemas

>> Livedo reticularis >> Erythema ab Igne >> Erythema infectiosum Diffuse and morbilliform erythemas

>> Rubeola and atypical measles >> Rubella >> Roseola >> ECHO and Coxsackie viral exanthems >> Erythema infectiosum >> Infectious mononucleosis >> Scarlet fever >> Staphylococcal toxic erythemas Presenting history There is usually no prodrome. Approximately 50% of the children give a history of a preceding herpes labialis or, rarely, herpes genitalis.40 The preceding herpes simplex virus (HSV) lesion may

38. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme. Arch Dermatol. 1993;129:92–96. 39. Khalil I, Lepage V, Douay C, et al. HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme. J Invest Dermatol. 1991;97:697–700. 40. Weston WL, Morelli JG. Herpes-associated erythema multiforme in prepubertal children. Arch Pediatr Adolesc Med. 1998;151:1014–1018.

Figure 19.9  Classic ‘target’ lesions of erythema multiforme in a boy (courtesy of Dr A. Torrelo).

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PERSISTENT ERYTHEMAS

Vascular reactions

Figure 19.10  Isomorphic phenomenon in erythema multiforme. Linear target lesions appear within a prior animal scratch on the arm of an 11-year-old child.

still be present at the onset of the EM skin lesions but, more often, precedes the onset of EM skin lesions by 3–14 days.40 A history of an abrupt onset of skin lesions is obtained, with almost all the lesions appearing within 24 h and completely by 72 h. Itching or burning sensations may be described. The eruption usually clears within 2 weeks but is frequently recurrent.

Physical examination The primary lesion is a round, red papule that remains fixed at the same skin site for 7 days or more. At least some of the red papules evolve into target lesions. A target lesion consists of concentric zones of color change with evidence of damage of the epidermis in the central zone such as bulla formation or crust (Fig. 19.9). Early target lesions will have a central dusky zone and a red outer zone, but may evolve to three zones of color change, sometimes referred to as an iris lesion. (Fig. 19.9) Lesions that contain less than three concentric color changes are currently named ‘raised atypical targets’ whereas ‘typical target lesions’ contain three or more.41 The forearms are the most frequently affected skin sites, but palms, neck, face, and trunk are also often involved. Although there is considerable variation from individual to individual, usually over 100 lesions are present. The Koebner phenomenon may be observed, with target lesions appearing within areas of cutaneous injury such as scratches (Fig. 19.10). The injury precedes the onset of the other EM skin lesions and cannot occur once EM lesions are present.42 EM lesions may also be found within areas of sunburn. Cuticular redness and swelling are observed. Lesions tend to be grouped, especially around the elbows and knees. The diagnosis of EM requires the presence of symmetrical fixed red papules, at least some of which evolve into typical target lesions. Oral erosions are present in less than one-half of children with EM and, when present, are few in

41. Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129:92. 42. Huff JC, Weston WL. Isomorphic phenomenon in erythema multiforme. Clin Exp Dermatol. 1983;8:409–413. 43. Weston WL, Morelli JG, Rogers M. Target lesions on the lips: Childhood herpes simplex associated erythema multiforme mimics Stevens–Johnson syndrome. J Am Acad Dermatol. 1997;37:848–850.

Figure 19.11  Vesicular lesions of the lips in erythema multiforme (courtesy of Dr A. Torrelo).

number and mildly symptomatic.43 Involvement of the lips, buccal mucosa, and tongue is seen. Occasionally, large bullous target lesions may involve the lips and mimic the crusted lips seen in Stevens–Johnson syndrome (Fig. 19.11).43,44 Recurrent oral erythema multiforme without skin target lesions has been described but this condition is not universally accepted.44 Recurrent episodes of shallow mouth ulcers mimic aphthous ulcers and these conditions may be impossible to distinguish. Other mucosal sites are not involved. Fever, lymphadenopathy, and organomegaly are absent. Atypical forms of herpes simplexassociated EM have been described.45 Large, solitary and asymmetrical target lesions are seen on the skin.

44. Farthing PM, Maragou P, Coates F, et al. Characteristics of the oral lesions in patients with recurrent erythema multiforme. J Oral Pathol Med. 1995;24:9–11. 45. Weston WL, Brice SL. Atypical forms of herpes-simplex associated erythema multiforme. J Am Acad Dermatol. 1998;39: 124–126.

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Laboratory findings There are no characteristic laboratory changes in EM.

Pathophysiology and histogenesis

PERSISTENT ERYTHEMAS

The value of histopathologic examination is to exclude conditions such as LE or vasculitis that may mimic EM. The earliest pathologic change of EM is keratinocyte apoptosis.46 A perivascular infiltrate of mononuclear leukocytes with exocytosis into the epidermis is seen. Spongiosis and focal liquefaction degeneration of basal keratinocytes are observed with edema of the superficial dermis.37,46 Immunofluorescent findings are non-specific. Granular deposits of IgM and C3 around superficial blood vessels and at focal areas of the dermal–epidermal junction have been described. Most childhood EM cases are HSV-associated (HAEM).40,47 HSV genomic DNA has been detected by polymerase chain reaction amplification of skin biopsy samples in 36–75% of cases40,48 and on in situ hybridization, HSV DNA is seen primarily within basal keratinocytes.48 The rate of HSV positivity by PCR of skin biopsy is higher in those with recurrent EM than in those with a single episode.49 The overall rates of PCR positivity are similar in those with preceding clinically apparent HSV infection and in those without, suggesting a high rate of subclinical HSV preceding the onset of EM.40 Fragments of HSV DNA have also been detected in circulating CD34+/CLA+ Langerhans cell progenitors following HSV reactivation in patients with HAEM. It seems likely that these cells are involved in transporting HSV DNA fragments to lesional skin.50 The presence of HSV DNA within the skin lesions and the expression of virally encoded antigens on keratinocytes may be interpreted as evidence for replicating HSV within affected skin sites. The inflammation within skin lesions is believed to be a part of the HSV-specific host response.48 Mycoplasma pneumoniae infection is the only other common infectious trigger for EM, and has also been reported in association with SJS.51 Other infections definitely associated with EM are histoplasmosis and Orf.52 Histoplasmosis in endemic areas has occasionally been responsible for EM, especially when both EM and erythema nodosum lesions are present together. Orf is a rare cause of EM.

Differential diagnosis In clinical practice, EM is frequently misdiagnosed. Giant urticaria is most often confused with EM in pediatric patients. The lesions of urticaria are transient and not persistent; they usually have a clear central zone, not a dusky one. In children with

46. Howland WW, Golitz LE, Huff JC, et al. Erythema multiforme: Clinical, histopathologic and immunologic study. J Am Acad Derm. 1984;10:438–446. 47. Léauté-Labrèze C, Lamireau T, Chawki D, et al. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Childh. 2000;83:347–352. 48. Brice SL, Leahy MA, Ong L, et al. Examination of non-involved skin, previously involved skin and peripheral blood for herpes simplex virus DNA in patients with recurrent herpes associated erythema multiforme. J Cutan Pathol. 1994;21:408–412. 49. Ng PP, Sun YJ, Tan TH, et al. Detection of herpes simplex virus genomic DNA in various subsets of erythema multiforme by polymerase chain reaction. Dermatology. 2003;207:349,.

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systemic LE (SLE), individual lesions may mimic true target lesions, but other lesions characteristic of SLE are present. Early lesions of vasculitis, particularly urticarial vasculitis, may mimic target lesions of EM. In the case of both SLE and vasculitis, a skin biopsy, elevated ESR, and low complement level help in the differential diagnosis. Juvenile spring eruption, a form of polymorphous light eruption, may mimic herpes-associated EM.47 Morbilliform drug rashes with atypical target and contact reactions can mimic EM.

Therapeutics and prognosis There are no double-blind or open trials of therapy for the acute episodes of EM. For the usual attack of EM, symptomatic treatment will suffice. Oral antihistamines for three or four days reduce the stinging and burning of the skin. Oral antacids may be useful for discrete oral ulcers. In children receiving oral steroids, it is advisable to discontinue the steroids, despite the likelihood of an EM flare, as prolonged steroid use may result in more frequent or continuous episodes.53 There are no trials that support the use of oral steroids in EM. A double-blind, placebocontrolled study in young adults demonstrated efficacy of acyclovir prophylaxis in chronic or frequently recurrent EM.53 In children with HAEM with frequent recurrences, 6- to 12-month prophylaxis with oral acyclovir at 10 mg/kg per day may be considered. Acyclovir started after signs are present is ineffective.52 A few individuals have attacks precipitated by factors other than reactivation of HSV, and in these cases acyclovir will be of no benefit. All children affected by EM have an uncomplicated course, except when immunosuppressive drugs are used; in these cases, secondary infections and more frequent and longer episodes may occur. For most children with untreated EM, the episode lasts 2 weeks and heals without sequelae.40 Except for burning and stinging of the skin, the child is usually otherwise healthy. Recurrences are the rule in HAEM. Most children have one or two recurrences per year, typically each spring and, after 2–3 years, stop having recurrences.

STEVENS–JOHNSON SYNDROME Introduction and historical note In 1922, two physicians in the USA, Stevens and Johnson, described an acute mucocutaneous syndrome in two young boys.54 The condition was characterized by severe purulent conjunctivitis, stomatitis with extensive mucosal necrosis, and ‘EMlike’ skin lesions. This became known as SJS and was recognized

50. Ono F, Sharma BK, Smith CC, et al. CD34+ cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM). J Investig Dermatol. 2005;124:1215–1224. 51. Forman R, Koren G, Shear NH. Erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis in children: a review of 10 years’ experience. Drug Safety. 2002;25:965–972. 52. Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema multiforme: Clinical features and treatment in a large series of patients. Br J Dermatol. 1993;128:542–545. 53. Tatnall FM, Schofield JK, Leigh IM. A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol. 1995;132:267. 54. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia. Am J Dis Child. 1922;24:526–533.

Vascular reactions

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as a severe mucocutaneous disease with a prolonged course and occasional fatalities. SJS is usually preceded by a prodrome of a respiratory illness, followed in 1–14 days by severe erosions of at least two mucosal surfaces with extensive necrosis of the lips and mouth and a purulent conjunctivitis.50–52 A varied extent of skin involvement is described, with red macules evolving within hours into bullae and large areas of skin necrosis and denudation rapidly developing. SJS may have mucosal lesions only or both mucosal and skin lesions.50–52 Fever, lymphadenopathy, and toxicity virtually always accompany the mucocutaneous involvement.

The exact incidence of SJS is not known, in part because there is considerable confusion over a definition and significant clinical and histologic overlap with other forms of acute epidermal necrolysis such as toxic epidermal necrolysis (TEN).41,55,56 Chan et al. estimated the incidence as 0.8 cases per 1 million inhabitants per year.56 The peak incidence of all cases is in the second decade of life with the majority of patients being pediatric. SJS is more common in childhood than EM.41,55,56 Spring and summer prevalence has been observed for SJS. Recurrences have been described, but are quite unusual. There is no sex or racial predilection.

Figure 19.12  Stevens–Johnson syndrome. Hemorrhagic crusts of lips and red macules on face of 2-year-old infant treated with trimethoprim-sulfonamide combination.

PERSISTENT ERYTHEMAS

Epidemiology

Presenting history Most children have a distinct prodrome of an upper respiratory illness with fever, cough, rhinitis, sore throat, headache, vomiting, diarrhea, and malaise.41,55,56 During the prodrome, children are often treated with antipyretics or antibiotics or both. After 1–14 days, there is an abrupt onset of the skin eruption.

Physical examination The child with SJS is febrile and appears acutely ill. The lips develop hemorrhagic crusts with denudation of the mucosa, and severe stomatitis ensues (Fig. 19.12). Unlike EM, mucosal involvement is confluent and widespread, rather than focal.43,41 There is a purulent conjunctivitis with photophobia and pseudomembrane formation. The eyelids are adherent to one another. Genital involvement with pain, redness, and erosions accompanied by bleeding may occur. Anal erosions may be seen; uncommonly, the esophagus, respiratory epithelium, and nasal mucosa are involved. In girls, severe vulvovaginal pain may be observed. The skin eruption consists of symmetrical red macules, which progress to central blister formation and extensive areas of epidermal necrosis. The skin is tender. Involved areas may blister or show central desquamation (Fig. 19.13). All children with SJS have two or more mucosal sites involved; some, in addition, have skin involvement. Skin involvement tends to affect the trunk and proximal limbs and may be limited or extensive. Some children develop red macules, which rapidly enlarge and may become confluent. Frequently, the child is unable to eat or drink and appears dehydrated at presentation. Generalized lymphad-

55. Leaute-Labreze C, Lamireau T, Chawki D, et al. Diagnosis, classification and management of erythema multiforme and Stevens–Johnson syndrome. Arch Dis Child. 2000;83:347.

Figure 19.13  Discrete bullous lesion in a child with SJS (Courtesy Dr A. Torrelo).

enopathy is usually present, and enlargement of the liver and spleen may be found. Arthritis and arthralgias are sometimes seen, and hepatitis is common. Myocarditis, pneumothorax, and nephritis are rare associations. Gastrointestinal bleeding can be observed. The diagnosis of SJS can be made by the characteristic prodrome followed by an abrupt onset of extensive areas of mucocutaneous necrosis with at least two mucosal sites involved.41,55,56 A biopsy that shows extensive areas of epidermal necrosis is useful. Because there may be significant overlap with TEN in those children with SJS and skin involvement, the presence of two or more mucosal sites of injury is a critical diagnostic feature. In SJS, the areas of epidermal necrolysis involve less than 10% of the body surface whereas in TEN over 30% is affected. An SJS/ TEN overlap is described, in which there is 10–30% involvement of the skin.

56. Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis: A population based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol. 1990;126:43.

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Laboratory findings In addition to fluid and electrolyte imbalance, a number of other laboratory abnormalities may be observed. An elevated ESR is found in every child with SJS, with leukocytosis in 60%, eosinophilia in 20%, anemia in 15%, elevated liver enzyme levels in 15%, leukopenia in 10%, and proteinuria and microscopic hematuria in 5%.41,55–57

Pathogenesis

PERSISTENT ERYTHEMAS

Extensive epidermal necrosis with a paucity of inflammatory cells is characteristic.41,55,56 The severity of epidermal necrosis is accompanied by incontinence of melanin pigment, colloid bodies, and subepidermal blister formation. The cellular and molecular pathogenesis of SJS (and TEN) is incompletely understood but seems to involve dysregulation of cell mediated immune mechanisms in response to exogenous agents in genetically predisposed individuals. Lesional skin contains CD8+ T cells, neutrophils and macrophages. Soluble mediators of inflammation including TNF-α, IFN-γ, IL-2, IL-5 and IL-13 are overexpressed.58 It has been proposed that keratinocyte apoptosis may be triggered via activation of Fas which is overexpressed on lesional keratinocytes in TEN, and that activation of Fas by binding Fas ligand may be inhibited with high dose human immunoglobulin, with therapeutic benefits in TEN.59 Drugs predominate as the major precipitant of SJS with occasional cases related to infection, usually with Mycoplasma pneumoniae.51 Of the drugs implicated, the most frequent are oxicam-type non-steroidal anti-inflammatory drugs, antiinfective sulfonamides, allopurinol, aromatic anticonvulsants (carbamazepine, phenobarbital, phenytoin), and lamotrigine. Among more recently marketed drugs, nevirapine, sertraline, pantoprazole and tramadol have demonstrated strong associations in a case-control study.60 The onset of mucosal lesions usually follows the drug ingestion by 1–3 weeks and occasionally by as much as 2 months.61 Drugs administered a few days prior to the onset of SJS are usually not implicated.62 Rechallenge studies are naturally few unless by oversight, but reproduction of SJS upon rechallenge has been reported.63 Strong genetic associations between HLA antigens and risk of drug-induced SJS and TEN have been reported. These include the association between HLA-B*5801 and SJS/TEN related to allopurinol, HLA-B*1502 and carbamazepine (the latter restricted to patients of Asian ancestry),64,65 and HLA-DRB1*01 and nevirap-

57. Wong KC, Kennedy PJ, Lee S. Clinical manifestations and outcomes of 17 cases of Stevens–Johnson syndrome and toxic epidermal necrolysis. Australas J Dermatol. 1999;40:131. 58. Caproni M, Torchia D, Schincaglia E, et al. Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol. 2006;155:722–728. 59. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282:490–493. 60. Mockenhaupt M, Viboud C, Dunant A, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128:35–44. 61. Rasmussen JE. Erythema multiforme: a practical approach to recent advances. Pediatr Dermatol. 2002;19:82–84. 62. Rzany B, Correia O, Kelly JP, et al. Risk of Stevens–Johnson syndrome and toxic epidermal necrolysis during the first weeks of antiepileptic therapy. Lancet. 1999;353:2190.

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ine.66 These genetic findings may have implications for treatment selection in relatives of patients with SJS/TEN. NSAIDs, sulfonamides, and anticonvulsants are metabolized by the liver and epithelium through similar mechanisms, including the cytochrome P450 system generated aromatic drug metabolites, which form arene oxides.62 Epoxide hydrolases have been reported to be deficient in children susceptible to SJS, resulting in accumulation of arene oxides that bind to and inhibit RNA and shut off cell protein synthesis.67 In M. pneumoniae-associated disease and other infectious-related disease, the pathogenesis remains unknown.

Differential diagnosis There are many problems with terminology regarding SJS and TEN.41,55,56 It is clear that some children have features of SJS with extensive skin lesions, which mimic those observed in TEN; some have a limited cutaneous involvement; and others have only mucosal involvement. This confusion has resulted in many controversies in the literature. All forms have overlapping features and share in common the presence of large areas of epithelial necrosis, and all forms of SJS and TEN may be precipitated by the same factors. If two or more mucosal sites are involved with or without accompanying skin lesions, most authorities consider the condition to be SJS; if large sheets of skin are denuded with little mucosal involvement, TEN is frequently diagnosed Unfortunately, there are children with overlapping features whose conditions are difficult to classify. Kawasaki disease is sometimes confused with SJS in children. In Kawasaki disease, the lips are red and dry and the hemorrhagic crusts and mucosal denudation observed with SJS are absent. The bulbar conjunctivae are red in Kawasaki disease, but there is no exudate as seen in SJS. The skin lesions of Kawasaki disease are transient red macules and bullous lesions or target-like lesions are not seen as would be expected in SJS with the exception of perineal peeling and peeling of the fingertips. Paraneoplastic pemphigus may also mimic SJS.68 Although rare, similar severe necrosis of the lips, eyes, and oral mucosa may be observed in paraneoplastic pemphigus. Biopsy will demonstrate epithelial acantholysis and indirect immunofluorescence of serum or immunoblotting will distinguish from SJS. Search for an associated lymphoma or Castleman’s tumour is indicated.

63. Azinge O, Garrick GA. Stevens–Johnson syndrome [erythema multiforme] following ingestion of trimethoprim-sulfamethoxazole on two separate occasions in the same person. J All Clin Immunol. 1978;62:125–126. 64. Chung WH, Hung SI, Hong HS, et al. Medical genetics: A marker for Stevens-Johnson syndrome. Nature. 2004;428:486. 65. Lonjou C, Borot N, Sekula P, et al. RegiSCAR study group. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics. 2008;18:99–107. 66. Vitezica ZG, Milpied B, Lonjou C, et al. HLA-DRB1*01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz. AIDS. 2008;22:540–541. 67. Sullivan JR, Shear NH. The drug hypersensitivity syndrome. What is the pathogenesis? Arch Dermatol. 2001;137:357–364. 68. Lemon A, Huff JC, Weston WL. Childhood paraneoplastic pemphigus associated with Castleman’s tumour. Br J Dermatol. 1977;136:115–117.

Therapeutics and prognosis

Differential diagnosis

Treatment involves discontinuation of the precipitating drug, hospitalization and intensive supportive care. There is no good evidence for a disease-modifying effect of any specific intervention. This is described more fully below in the section concerning TEN.

Differentiation from staphylococcal scalded skin syndrome (SSSS) is necessary. High fever and occurrence in older children favor TEN, whereas evidence of preceding rhinitis and localization to intertriginous areas, and occurrence in newborns or infants favors SSSS. Definitive diagnosis depends on the histologic location of the blister. In TEN, it is subepidermal with overlying epidermal necrosis; in SSSS, separation of skin is at the granular portion of the mid-epidermis with a viable overlying epidermis. The histologic location can be rapidly determined microscopically with a shave skin biopsy and frozen-section examination.41 Involvement of mucous membranes does not occur with SSSS. The predominance of mucosal lesions over skin lesions generally distinguishes SJS from TEN.41,55–57 In the appropriate setting, graft versus host disease should be considered in the differential diagnosis and can be particularly difficult to differentiate.

TOXIC EPIDERMAL NECROLYSIS Introduction and historical note The term ‘toxic epidermal necrolysis’ is attributed to the Scottish dermatologist, Alan Lyell, who in 1956 described a condition that resembled a ‘scald.’69 Since Lyell’s original description, the classification of TEN has been confused. It is recognized that there is considerable overlap between TEN and SJS in clinical features, etiology, pathogenesis and response to treatment.41,55–57 TEN develops in the form of blistered erythematous patches and plaques, which evolve rapidly to extensive areas of skin necrosis, with loss of sheets of epidermis (Fig. 19.14).41,56,69 In some, an acute sunburn-like appearance with evolution into extensive epidermal necrosis is seen. Many skin areas denude when the child is handled during the examination. The cutaneous features may be similar to those of SJS, but individual lesions may evolve more rapidly.41,56,57 Complications and associated cutaneous findings are similar to those of SJS. The precipitating factors appear to be similar for both SJS and TEN, although infection may be even less frequent as a precipitant of TEN.55,56,62

Epidemiology TEN is less common in children than SJS, although the exact prevalence is unknown. It appears to occur more frequently in HIV infection and possibly connective tissue disease.

Figure 19.14  Large sheets of necrotic skin in child with toxic epidermal necrolysis.

69. Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of skin. Br J Dermatol. 1956;68:355–361. 70. Prendiville JS, Hebert AA, Greenwald MJ, et al. Management of Stevens– Johnson syndrome and toxic epidermal necrolysis. J Pediatr. 1989;115:881–887. 71. Garcia-Doral I, LeCloach L, Bocquet H, et al. Toxic epidermal necrolysis and Stevens–Johnson syndrome: Does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol. 2000;136:323–327.

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Management The mainstay of management is admission to a burn unit or a pediatric intensive care unit, and the child is managed as if a burn has occurred from the ‘inside out.’55,57,70–72 If an offending drug is suspected, it should be discontinued.71 The child should undergo correction of fluid and electrolyte imbalance and monitoring of urinary output and serum osmolality and electrolyte levels; protection from secondary infection; good ophthalmologic care; pulmonary toilet to include postural drainage, sputum cultures, and prompt treatment of pulmonary infections; periodic cultures of the skin, eyes, and mucosal sites; caloric replacement; the use of biologic dressings or early skin grafting of large denuded areas; physical therapy to prevent contractures; use of antacids and mouth rinses; and general skilled nursing care.55,57,70–72 TEN is frequently complicated by dehydration; electrolyte imbalance; secondary cutaneous, oral, or pulmonary bacterial infection.55,57,70 Severe pneumonitis and pneumothorax may develop. Large areas of denuded skin may scar with contractures if they are over joints. Ocular sequelae are serious and include pseudomembrane formation with immobility of the eyelids, symblepharon, entropion, trichiasis, corneal scarring, and permanent visual impairment.73 Lacrimal scarring with subsequent excessive tearing, anterior uveitis, and panophthalmos are complications. Although mouth and lip lesions usually heal without sequelae, esophageal strictures, anal strictures, vaginal stenosis, and urethral meatal stenosis may occur and cutaneous scarring with dyspigmentation is common. Shedding of the nails may result in permanent anonychia.57 The use of disease modifying drugs is controversial and currently none can be recommended based on the published literature. No satisfactory clinical trials have been reported and, given

72. Roujeau JC. Treatment of severe drug eruptions. J Dermatol. 1999;26:718–724. 73. Lehman SS. Long term ocular complications of Stevens–Johnson syndrome. Clin Pediatr. 1999;38:425.

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the rarity of TEN, the evidence of effectiveness of treatments is based on small case series only. Because of its inhibitory effect on TNFα, thalidomide was selected for study in one of the only placebo-controlled trials in TEN. The study was stopped because of an excess mortality in the thalidomide group. Ten of 12 patients in the active group died compared with three of ten in the placebo group.74 This has tempered enthusiasm for the use of biological therapy targeting TNFα, although there are case reports suggesting efficacy.75 Similarly there are contradictory reports of the efficacy of systemic corticosteroids (prednisolone 1 mg/kg) with some authors reporting benefit if treatment is given early in the course of the disease and others reporting an excess mortality in those treated with steroids.72,76 Cyclosporin is potentially of benefit and several case reports and small case series have been reported.77 All 20 reported cases describe arrest of the disease within 24–36 h of administration of cyclosporin 3–5 mg/kg daily. Treatment was complicated by non-fatal infection in 12 of these 20 individuals. Most recently, intravenous immunoglobulin (IVIG) treatment has been championed based on its ability to inhibit Fas-mediated apoptosis and encouraging results in a small open study.59 Subsequent small studies have given contradictory results including a study of 20 patients with TEN, in whom no improvement in mortality could be demonstrated when known prognostic factors were controlled for.78 A working group in Europe has suggested that the dose of IVIG be increased to provide a better prognosis (see Ch. 30).

Prognosis Various prognostic factors for mortality in TEN have been identified. A prognostic score (SCORTEN) that combines seven clinical and laboratory variables measured on the third day of hospitalization has been developed largely in an adult population and found to predict outcome accurately.79 The independent prognostic variables are age (>40 years), heart rate (>120 beats/min), cancer, involved body surface area (>10%), serum urea (>10 mmol/L), serum bicarbonate (14 mmol/L). Mortality ranges from 3% with only one adverse prognostic factor to 90% with five or more.

FIXED DRUG ERUPTION In children with fixed drug eruptions, the oral ingestion of the causative agent is followed minutes to hours later by the appearance of one (or sometimes several) sharply marginated round or oval patches.80 A single lesion occurs in half the affected children but those with multiple lesions may have dozens. These smooth, dusky red, or violaceous patches quickly thicken, taking on an

74. Wolkenstein P, Latarjet J, Roujeau JC, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet. 1998;352:1586–1589. 75. Hunger RE, Hunziker T, Buettiker U, et al. Rapid resolution of toxic epidermal necrolysis with anti-TNF-alpha treatment. J Allergy Clin Immunol. 2005;116(4):923–924. 76. Stables GI, Lever RS. Toxic epidermal necrolysis and systemic corticosteroids. Br J Dermatol. 1993;128:357. 77. Chave TA, Mortimer NJ, Sladden MJ, et al. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol. 2005;153(2):241–253.

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Figure 19.15  Fixed drug eruption. Multiple lesions (courtesy of Dr A. Torrelo).

edematous appearance (Fig. 19.15). In many instances, the severity of the inflammation is such that blisters arise from within one or more areas of these plaques. The lesions may be found anywhere on the skin or mucous membranes, but the most common sites are the lips and genitalia.80 When more than one lesion develops, clustering is sometimes observed. Itching or burning may be present. In a few instances, associated systemic symptoms and signs have been reported. Several instances of a generalized bullous eruption, intermediate in severity between classical fixed drug eruption and TEN, have been described.41 The lesions of fixed drug eruption resolve over 10–14 days, leaving a remarkable degree of post-inflammatory hyperpigmentation. Thereafter, following a refractory period of days to weeks, readministration of the same medication is followed by a recurrent episode. The recurrent episode may be more severe than the first. The fact that these recurrent lesions occur in exactly the same skin sites as the original eruption explains the use of the word ‘fixed’ in the name of the disease. The pathogenesis of fixed drug eruption is unknown, but the histology mimics that of EM. Many medications have been reported to cause fixed drug eruptions. The most commonly implicated have been trimethoprim-sulfonamide combinations, the acetaminophen (paracetamol) antipyretics, and ibuprofen anti-inflammatory agents.80 Other drugs that are implicated include phenolphthalein, previously used in laxatives, and tetracycline and its derivative minocycline. Fixed drug eruptions have occasionally been reported to have been caused by foods, including strawberries, cheese-flavored snacks, and the food additive tartrazine.81 A clinical diagnosis can be confirmed by

78. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson and toxic epidermal necrolysis. Arch Dermatol. 2003;139:33. 79. Bastuji-Garin S, Fuchard N, Bertocchi M, et al. SCORTEN: A severity-ofillness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115:149–153. 80. Morelli J, Tay YK, Rogers M, et al. Fixed drug eruptions in children. J Pediatr. 1999;134:365–367. 81. Orchard DC, Varigos GA. Fixed drug eruptions to tartrazine. Australas J Dermatol. 1997;38:212–214.

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oral rechallenge with the suspected medication, but this is rarely indicated. Patch testing at the site of the reaction with the suspected drug gives a positive result in up to a half of cases.82 No specific therapy is described.

PAPULAR ERYTHEMAS The individual lesions of papular erythemas share some clinical characteristics with early lesions that occur in EM. In both cases, the papules are red and smooth surfaced. They differ in that the lesions in the papular erythemas tend to be smaller (1 cm or less), are dome shaped rather than flat topped, and never progress to form target lesions.

Figure 19.16  Papular urticaria. Three-millimeter red papule surrounded by red urticarial flare in child with hypersensitivity to dog fleas.

The cutaneous reaction to bites and stings is frequently that of urticarial papule formation.83 Generally, this is a short-lived reaction, but in some children these lesions persist for weeks or months. These long-lived reactions may occur as a result of allergic sensitization to antigens deposited at the time of the bite or perhaps to impairment in the production of regulatory cytokines such as IL-6 and IL-10 in these patients.84 Because sensitization requires repetitive bites over many months, this reaction is generally not seen until after the first year of life. It is most frequent in toddlers.83 Likewise, long-term re-exposure to the antigen eventually results in hyposensitization. This allows for eventual spontaneous resolution of the problem. It is important to recognize that not all members of a family will become sensitized. Thus, the eruption may appear in a single member of a household, even though others are also bitten. Mites or fleas from dogs or cats are most common, but mites from birds, rats, or mice may also be responsible. A history of pets and birds or rodents around the residence should be sought. IgG directed against salivary gland proteins from bedbugs has been demonstrated in a portion of patients.85 The characteristic lesions of papular urticaria are 5–10 mm, dome-shaped, red papules that tend to occur in crops (Fig. 19.16). At times, a punctum, representing the site of the bite, may be observed at the summit of the papule, but usually excoriation has obscured this helpful diagnostic sign.83 When numerous lesions are present, specific bites may be responsible for only a portion of them. Others may arise as a result of autosensitization. The lesions usually occur on the non-clothed areas of skin. Therapy (and sometimes proof of causation) depends on the prevention of subsequent bites. Where possible, protective clothing, such as long sleeves and long pants, should be worn. Insect repellents may be helpful, but removal of the source is preferable. The most commonly used products contain DEET. The American Academy of Pediatrics suggests a DEET containing product can be used on exposed skin in a concentration that should not exceed 30%. Pets, especially dogs and cats, should be examined and should be treated if infested. Individual lesions

82. Lee AY. Fixed drug eruptions. Incidence, recognition, and avoidance. Am J Clin Dermatol. 2000;1:277–285. 83. Howard R, Frieden IJ. Papular urticaria in children. Pediatr Dermatol. 1996;13:246–249.

PERSISTENT ERYTHEMAS

Papular urticaria and insect bites of papular urticaria may be treated with potent topical cortico­ steroids. The oral administration of antihistamines is useful if scratching persists. Other non-specific treatments of itching may help, such as wet dressings and methol-containing lotions. Antibiotics may be administered if secondary bacterial infection has developed.

Pityriasis lichenoides Traditionally, both an acute type (Mucha–Habermann disease or acute parapsoriasis) and a chronic type of pityriasis lichenoides (pityriasis lichenoides chronica, chronic parapsoriasis, or digitate dermatosis) have been recognized and are considered under papulosquamous eruptions (see Ch. 15). It should be remembered that in acute pityriasis lichenoides the characteristic lesions are dome-shaped red papules 3–10 mm in diameter and may initially mimic a number of conditions characterized by red papules.

Lymphomatoid papulosis Lymphomatoid papulosis is a primary cutaneous CD30+ lymphoproliferative disorder with some similarities to pityriasis lichenoides. The clinical appearance is similar to acute pityriasis lichenoides, although the papules in lymphomatoid papulosis are generally larger and more necrotic. The diagnosis is based on biopsy where, against an inflammatory background similar to that seen in pityriasis lichenoides, marked atypicality of individual lymphocytes is noted. Despite this worrisome histologic appearance, few children develop malignant lymphoma. Lymphomatoid papulosis is extremely rare in children, but it is occasionally encountered in adolescents.

Erythema elevatum diutinum Clinically, the most prominent skin lesions are non-purpuric, persistent erythematous papules. The initial papules are small

84. Cuellar A, Garcia E, Rodriguez A, et al. Functional dysregulation of dendritic cells in patients with papular urticaria caused by fleabite. Arch Dermatol. 2007;143:1415–1419. 85. Abdel-Naser MB, Lofty RA, Al-Sherbiny MM, et al. Patients with papular urticaria have IgG antibodies to bedbug (Cimex lectularius) antigens. Parasitol Res. 2006;98(6):550–556.

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dusky brown-red or even orange-red lesions that gradually enlarge and, through confluent growth, form plaques that are frequently polycyclic in outline. Resolution sometimes occurs in the center of these plaques so that annular lesions are formed. Rarely, bullae develop from the surface of the plaques. These papules and plaques are usually symmetrically located on the dorsal aspects of the hands. The elbows, knees, and buttocks may also be involved. Arthralgia, fever, and malaise often accompany the appearance of the skin lesions. A suspected clinical diagnosis can be confirmed on biopsy in which a vasculitis involving neutrophils (and sometimes eosinophils and mononuclear cells) is found. Leukocytoclasis and fibrinoid deposits are present, but extravasation of erythrocytes is only rarely seen. The course of erythema elevatum diutinum is chronic. Oral treatment with dapsone is the treatment of choice. Unresponsive cases may require prednisone or other immunosuppressive agents. Another, similar-appearing papular disease, granuloma faciale, sometimes develops on the face in children. The histology may be similar to that of erythema elevatum diutinum, but the disease is less chronic and is not associated with systemic symptoms and signs.

Miscellaneous papular erythemas Many other diseases are characterized by the presence of smoothsurfaced small red papules. Most of these are not true vascular reactions. However, the following should be considered in the clinical differential diagnosis of the vascular papular erythemas: secondary syphilis, pityriasis rosea, miliaria rubra, scabies, papular acrodermatitis (Gianotti–Crosti syndrome), a variety of enteroviral infections, Langerhans cell histiocytosis, and atypical forms of granuloma annulare.

NODULAR ERYTHEMAS The nodular erythemas are characterized by the presence of one or more smooth-surfaced, erythematous nodules 2–10 cm in diameter. The deep dermal or subcutaneous location of these lesions generally results in margins that are ‘slope-shouldered’ and poorly defined. This deep location and large diameter also cause some lesions to appear as flat-topped plaques rather than as nodules. The nodular erythemas are not usually pruritic. They are usually painful and tender on palpation. The presence of lesional pain is unique among the various categories of persistent erythema. The presence of discomfort is due in part to the frequent location of lesions on the lower legs where the skin is tightly stretched, leaving little room for inflammatory distention. Histologic examination of the diseases in this group requires a deep elliptical excision to include the subcutaneous fat; conventional punch biopsies are almost always inadequate. The prototype of nodular erythemas is erythema nodosum. (The nodular erythemas are discussed in detail in Chapter 17.)

Annular and gyrate erythemas The conditions considered in this section have in common the presence of erythematous, ringed plaques with prominent central clearing. The adjacent red border of the lesions is narrow (generally > Raynaud syndrome >> Acrocyanosis >> Pernio >> Acrodynia Non-acral reactions

>> Cutis marmorata >> Nevus anemicus

The diseases considered in this section (Box 19.6) have an element of vascular constriction as part of their pathogenesis. Whiteness or paleness is an important part of their presentation. This is true in the case of nevus anemicus, but more often cyanosis (as a result of vascular stasis) or redness (as a result of ‘compensatory’ vasodilation) dominates the clinical appearance. Vasospastic changes can be divided into acral and non-acral types.

ACRAL REACTIONS Raynaud syndrome (RS) and related conditions Raynaud syndrome is characterized by the development of coldor stress-induced painful vasospastic changes in the digits.107 Historically, the term Raynaud ‘disease’ was used when these changes were idiopathic, whereas Raynaud ‘phenomenon’ was used when these changes occurred in association with some other underlying disease. The distinction cannot be made with certainty in many patients; for this reason, it seems reasonable to use the term Raynaud syndrome for all patients presenting with this condition. RS occurs predominantly in young women; children are not often affected. As this condition frequently occurs in association with collagen vascular disease, it suggests that at least some of the individuals who develop RS are genetically predisposed.107 The onset of RS is insidious. Generally, patients first note that their fingers chill more quickly and easily than in the past. Subsequently, they find that considerable discomfort accompanies cold exposure, especially as the fingers start to warm.107 Patients observe that, with chilling, the fingers first turn white (Fig. 19.19) and that this is followed by the appearance of a blue cyanosis over all but the fingertips. During the warming phase, the hand may redden as a result of reactive hyperemia. These color changes compose the triphasic color response of RS.107 The hands alone are affected in about one-half of the patients; both feet and hands are involved in the remainder. Initially, the hands appear

107. Kahaleh B, Matucci-Cerinic M. Raynaud’s phenomenon and scleroderma: dysregulation of neuroendothelial control of vascular tone. Arthritis Rheum. 1995;38:1–4. 108. Cooke JP, Marshall JM. Mechanisms of Raynaud’s disease. Vasc Med. 2005;10(4):293–307.

Figure 19.19  Raynaud phenomenon. Vasoconstrictive (white phase) of

VASOSPASTIC REACTIONS WITH ACRAL ERYTHEMA

VASOSPASTIC REACTIONS WITH ACRAL ERYTHEMA

characteristic blue, white, then red triphasic color response in a 17-year-old.

normal between attacks, but later, the episodes may be almost continuous as a result of constant triggering by minimal temperature variations or emotional stress. In these later stages, atrophic changes develop on the distal fingers. In such cases, the skin becomes shiny, periungual telangiectasias appear, and often features of sclerodactyly (skin tightness and finger tapering) develop. In the worst circumstances, small infarcts, 1–2 mm in diameter, appear on the fingertips. These heal slowly with eventual development of pitted scarring. Finally, in the most unfortunate individuals, the disease eventuates in considerable gangrenous loss of soft tissue. The diagnosis of RS is usually based on historical evidence. The serologic presence of anti-centromere antibodies is considered useful in the diagnosis.101 Confirmation of the diagnosis can, if necessary, be obtained by provocative cold testing. All patients with RS should be queried regarding the use of provocative medications and a search should be carried out for evidence of underlying, associated disease (Box 19.7). Particular attention should be paid to symptoms and signs of early scleroderma.107,101 The mechanisms of RS include increased activation of the sympathetic nerves, in response to cold or emotion; an impaired habituation of the cardiovascular response to stress may contribute. In addition, there appears to be a local fault, which is likely multifactorial. This local fault is due to an alteration in vascular function rather than vascular structure. The alteration in vascular function may be related to increased sensitivity to cold of the adrenergic receptors on the digital artery vascular smooth muscle. In some cases, locally released or systemically circulating vasoconstrictors may participate, including endothelin, 5-hydroxy­ tryptamine and thromboxane. A deficiency or increased degradation of nitric oxide, possibly due to increased oxidative stress, may be involved in some cases.108 Prior infection with parvovirus B19 has been implicated in some children with transient RS.109

109. Harel L, Straussberg R, Rudich H, et al. Raynaud’s phenomenon as a manifestation of parvovirus B19 infection: case reports and review of parvovirus B19 rheumatic and vasculitic syndromes: Clin Infect Dis. 2000;30:500–503.

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BOX 19.7 CONDITIONS ASSOCIATED WITH THE DEVELOPMENT OF RAYNAUD SYNDROME Autoimmune collagen vascular disease

VASOSPASTIC REACTIONS WITH ACRAL ERYTHEMA

>> Scleroderma >> Lupus erythematosus >> Dermatomyositis >> Rheumatoid arthritis >> Sjögren syndrome >> Various ‘mixed’ and ‘overlap’ syndromes >> Cryoproteins >> Cryoglobulins >> Cold agglutinins >> Cold fibrinogens Medications

>> Ergot derivatives >> Methysergide maleate >> Histamine blockers >> Intra-arterial injection of any drug Vascular obliterative diseases

>> Thromboangiitis obliterans >> Arteriosclerosis obliterans >> Embolus and thrombus formation Miscellaneous conditions

>> Carpal tunnel syndrome >> Thoracic outlet syndromes >> Reflex sympathetic dystrophy >> Postchemotherapy for certain malignancies >> Parvovirus B19 infection

Elimination of provocative factors and induction of coldprotection strategies are the mainstays of therapy for Raynaud syndrome. The softball windup exercise (a whirling motion of the extended arm) may be useful in some. Prostacyclins are a therapeutic option in patients with RS. Modest benefits have also been shown with alpha1-antagonists and calcium channel blockers, while the effect of ACE inhibitors has been variable. Some data suggest some benefits to the use of the phosphodiesterase inhibitor sildenafil, the serotonin uptake inhibitor fluoxetine and the angiotensin receptor inhibitor losartan.110 New therapies including RhoA/Rho kinase (ROCK) pathway inhibitors may be beneficial in treating Raynaud’s phenomenon.111

11-year-old girl with pernio.

the digits, predominantly the toes (Fig. 19.20). They are remarkable in that, even without further cold exposure, individual lesions may persist for months. Pain or pruritus may be the predominant symptom. Occasionally, diffuse swelling of a digit is observed; rarely, hemorrhagic blister formation or ulceration may ensue. When ulceration of the toes occurs it is called kibes.112 Several conditions have been described as predisposing subjects to pernio, including the presence of cryoproteins, excessive cold exposure, anorexia nervosa, systemic lupus erythematosus and antiphospholipid antibodies.113 Most sufferers however are healthy, although usually thin. Protecting the digits from cold, wet conditions is the mainstay of therapy, although nifedipine, which produces vasodilation, has been demonstrated to be effective in reducing pain, facilitating healing, and preventing new lesions of pernio.

Acrocyanosis Patients with acrocyanosis present with cool, sometimes sweaty and dusky red or cyanotic hands and fingers or feet and toes. Acrocyanosis is seen predominantly in adolescent girls but may occasionally be observed in childhood. Rarely, edema of the affected extremity is seen. The pathogenesis is unknown, although cold sensitivity may be a prominent feature in some. Arterial constriction plus capillary dilation is involved. The progression to skin changes, as described for Raynaud syndrome, is not seen, and the overall prognosis is good.

Acrodynia

Prolonged cold exposure, when associated with dampness, results in the characteristic skin lesions known as pernio or chilblains.112 Dusky red or violaceous discrete swellings develop on

Diffuse painful swelling and redness of the digits, hands, and feet characterize acrodynia.114 The involved areas are palpably cool, presumably as a result of arterial constriction. The overlying redness occurs as a result of the capillary reactive hyperemia that accompanies the deeper vasoconstriction. These changes are accompanied by tachycardia and excess sweating, which suggests that sympathetic stimulation plays a role in the pathogenesis of the disease. This is recognized as the result of chronic mercury exposure and toxicity.114 Epidemics in children were originally described as ‘pink disease.’ Restlessness and irritability, often to

110. Henness S. Wigley FM. Current drug therapy for scleroderma and secondary Raynaud’s phenomenon: evidence-based review. Curr Opin Rheumatol. 2007;19(6):611–618. 111. Flavahan NA. Regulation of vascular reactivity in scleroderma: new insights into Raynaud’s phenomenon. Rheum Dis Clin North Am. 2008;34(1):81–87; vii.

112. Weston WL, Morelli JG. Childhood pernio and cryoproteins. Pediatr Dermatol. 2000;17:97–99. 113. Simon TD, Soep JB, Hollister JR. Pernio in pediatrics. Pediatrics. 2005;116(3):e472–e475. 114. Boyd AS, Seger D, Vanucci S, et al. Mercury exposure and cutaneous disease. J Am Acad Dermatol. 2000;43:81–90.

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Figure 19.20  Dusky purple nodules of the toes and side of the foot in an

Vascular reactions

RETICULATE ERYTHEMAS The reticulate erythemas are characterized by a flat network of intersecting, reticulated, red lines that enclose small patches of pale or normal-colored skin. The red lines vary in width from several millimeters to as much as 1 cm. These lines are not sharply demarcated but blend into the adjacent normal skin. This lack of sharp margination gives a mottled or blotchy appearance to the involved areas. The red colors that make up the lines vary in color but are generally dusky or violaceous. The lesions have no substance and are non-palpable. The conditions con­ sidered in this section share nothing in common except their similarity in clinical appearance.

Livedo reticularis The basic appearance is of dissecting reticulated violaceous lines (Fig. 19.21). The condition can be widespread, involving most of the body, or it can occur in one or more smaller patches. There is a predilection for distribution on the legs and lower trunk.116,117 Two forms of livedo reticularis exist. The primary (idiopathic) form is most common in adolescent girls. In this form, the distribution tends to be generalized and symmetrical. The course of the condition, although of long duration, is associated with a good prognosis. The lesions in the secondary form tend to be patchier and are more likely to be associated with ulcerations or nodules. Chronic cutaneous or systemic periarteritis nodosa, LE, antiphospholipid antibody syndrome, other thrombophilias

Figure 19.21  Livedo reticularis. Lacy pattern of red-purple discoloration on the arm of a 9-year-old boy.

115. Beck C, Krafchik B, Traubici J, et al. Mercury intoxication: it still exists. Pediatr Dermatol. 2004;21(3):254–259. 116. Frances C, Piette JC. The mystery of Sneddon syndrome: relationship with antiphospholipid syndrome and systemic lupus erythematosus. J Autoimmun. 2000;15:139–143. 117. Lao M, Setty S, Foss C. Antiphospholipid syndrome. A literature review. Minn Med. 2001;84:42–46.

and collagen vascular diseases should be considered. Embolic disease may occasionally be responsible. The eruption is usually asymptomatic and, although similar to cutis marmorata, does not clear when the skin is warmed. Biopsy of secondary forms of livedo lesions often demonstrates vasculitis of small- and large-caliber vessels, most often arteries.117

Cutis marmorata Cutis marmorata is encountered in virtually all newborns and infants and with considerable frequency in children and adolescent girls. It consists of symmetrical reticular mottling of the skin after exposure to cold temperatures. The color changes are identical in appearance to those found in livedo reticularis, but in contrast, they are variable in intensity from minute to minute and disappear entirely on warming. Generally, cutis marmorata is most prominent on the legs. It is an asymptomatic condition. In infants, cutis marmorata must be distinguished from the congenital vascular malformation known as cutis marmorata telangiectasia congenita. Cutis marmorata clears with warming of the skin, which is not the case with cutis marmorata telangiectasia congenita. Cutis marmorata telangiectasia congenita also exhibits sharp midline cut-offs. In most infants, cutis marmorata clears by 6–12 months. It is important to exclude congenital hypothyroidism (which does not disappear on skin warming and, in older individuals, should be differentiated from livedo reticularis).

VASOSPASTIC REACTIONS WITH ACRAL ERYTHEMA

a marked degree, are also present. Acrodynia may be mistaken for Kawasaki disease because of redness of palms, soles, and digits. The hypertension may prompt investigation for pheochromocytomas.115 There is a small but significant mortality rate when the disease remains untreated for prolonged periods. Treatment consists of removing the source of mercury exposure and, in severe cases, the administration of chelating agents.114

19

Antiphospholipid antibody syndrome Antiphospholipid syndrome is a systemic autoimmune disorder characterized by a combination of arterial or venous thromboses and recurrent fetal loss, accompanied by elevated titers of antiphospholipid antibodies. Antiphospholipid syndrome has been recognized as the leading cause of vascular thrombosis in children.118 Originally called Sneddon syndrome, this has also been known as the anticardiolipin syndrome and the lupus anticoagulant syndrome.116,117 The anticardiolipin antibodies were first described in the setting of false positive testing for syphilis. These antibodies are directed against the anionic phospholipid, cardiolipin, which was used in the Wasserman assay for syphilis. It is now known that these antibodies are directed against beta2-glycoprotein I (β2-GPI) as well as other proteins. The term ‘lupus anticoagulant’ often proves to be a misnomer because the patients who test positive for the lupus anticoagulant rarely meet the criteria for the diagnosis of SLE. The antiphospholipid antibodies found in this syndrome are directed against a variety of phospholipid binding proteins, of which β2glycoprotein and prothrombin are considered to be common antigens.119 Antiphospholipid antibodies, particularly lupus anticoagulant, are an independent risk factor for first and possibly recurrent ischemic stroke in young adults120 although the vast majority of elevated levels of antiphospholipid antibodies in

118. Ravelli A, Martini A. Antiphospholipid syndrome. Pediatr Clin North Am. 2005;52:469–491. 119. Briones M. Abshire T. Lupus anticoagulants in children. Curr Opin Hematol. 2003;10(5):375–379. 120. Brey RL. Antiphospholipid antibodies in young adults with stroke. J Thromb Thrombolysis. 2005;20(2):105–112.

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Erythema infectiosum (fifth disease)

VASOSPASTIC REACTIONS WITH ACRAL ERYTHEMA

Erythema infectiosum occurs primarily in infants and young children. It is characterized by the presence of reticulated erythematous patches. The lesions, however, are distinctly pink, with no violaceous or brown hues present, and are fine and lacy. They may occur anywhere but are most often seen on the proximal extremities. The eruption begins after several days of incubation with human parvovirus B19 and lasts approximately 10 days. Once present, episodes of exacerbation and remission may occur for up to 3 months. The development of a reticular eruption, and the presence of flat malar erythema (the ‘slapped cheek’ sign) usually allow for easy clinical identification. The slapped cheeks may precede or accompany the onset of other skin lesions. The child usually appears healthy at the time of the rash. The eruption of erythema infectiosum follows the viremic phase and corresponds to the onset of immunity so that the family can be reassured the child is no longer infectious. (Erythema infectiosum and other viral exanthems are discussed in detail in Chapter 25.) Figure 19.22  Erythema ab igne. Dusky red-brown pattern involving mid-back of 15-year-old girl using heating pad for back pain.

the pediatric population are transient and carry no significant clinical risk.121 The antiphospholipid antibody syndrome can present to the dermatologist as cutaneous infarcts, livedo and ulcerations. Prophylactic therapy with hydroxychloroquine is reported to be efficacious.117 After a thrombotic episode, warfarin is usually given, and antiplatelet therapy such as aspirin is recommended by some. Systemic steroids may predispose to more thromboses. Avoidance of oral contraceptives and smoking is beneficial.

ERYTHEMA AB IGNE Children with erythema ab igne have a localized, dusky red, persistent, patchy livedo pattern. Erythema ab igne looks very much like localized livedo reticularis, except that the hues are brown-red rather than violaceous (Fig. 19.22).122 The lesions are asymptomatic. Erythema ab igne evolves insidiously after repeated exposure of the skin to high (but not burning) temperatures. It usually has developed as a result of habitual heating pad use although there have been a number of reports secondary to laptop computers.123 Biopsy shows vasodilation, mild basal layer vacuolization, and incontinent pigment in dermal macrophages.122 These changes reflect heat-induced toxic damage to both epithelial and vascular structures. In some ways, it may be considered to be a heat analogue to cold-induced pernio (see Vasospastic reactions, above). Discontinuation of heat exposure leads to slow resolution of the red hues, but the reticular postinflammatory hyperpigmentation may persist for years.

121. Male C, Lechner K, Eichinger S, et al. Clinical significance of lupus anticoagulant in children. J Pediatr 1999, 134:199–205. 122. Cavallari V, Ciccarello R, Torre V, et al. Chronic heat-induced skin lesions (erythema ab igne): ultrastructural studies. Ultrastruct Pathol. 2001;25:93–97. 123. Levinbook WS, Mallett J, Grant-Kels JM. Laptop computer–associated erythema ab igne. Cutis. 2007;80(4):319–320.

1120

Miscellaneous reticulate erythemas Angioma serpiginosum is a nevoid vascular hamartoma in which patches of bright red punctate reticulation may be seen. It primarily affects older children and adolescents and is progressive. Poikiloderma may sometimes be confused with reticulate erythemas, especially when first presenting in the photosensitive genodermatoses. It is characterized by fine wrinkling of the epidermis, hyper- and hypopigmentation and atrophy.

DIFFUSE AND MORBILLIFORM ERYTHEMAS Two types of diffuse erythemas can be recognized: morbilliform eruptions and toxic erythemas. Morbilliform eruptions have closely set pink macules or very slightly raised papules that are distributed diffusely over large portions of the body. During the evolution of morbilliform eruptions, areas of coalescence may develop, but on the periphery, discrete individual lesions are always recognizable. On the other hand, in toxic erythemas, there are large areas of flat homogeneous redness, which lack peripheral discrete lesions. As a general rule, morbilliform erythemas occur as a result of drug reaction or viral infection,124 whereas toxic erythemas occur in bacterial infections secondary to the release of toxins. (Additional information about these infections can be found in Chapters 24 and 25.)

NON-ACRAL REACTIONS Nevus anemicus Nevus anemicus is an uncommon condition that first presents in infancy or early childhood with one or more flat patches of uniformly pale white skin (Fig. 19.23).125 The skin, with the

124. Hogan PA, Morelli JG, Weston WL. Viral exanthems. Curr Probl Dermatol. 1992;4:35. 125. Katugampola GA, Lanigan SW. The clinical spectrum of naevus anaemicus and its association with portwine stains: report of 15 cases and review of the literature. Br J Dermatol. 1996;134:292–295.

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BOX 19.8 VASCULITIDES Capillaritis (non-palpable petechiae)

>> Benign pigmented purpuras – Schamberg’s progressive pigmented purpura – Lichen aureus – Purpura annularis telangiectodes – Lichenoid pigmented purpura >> Drug-induced inflammatory petechiae Venulitis (palpable petechiae)

rubbing induced erythema (courtesy of Dr A. Torrelo).

exception of this white color, is otherwise normal on inspection and palpation. Most lesions of nevus anemicus are sharply marginated, but sometimes the border is indistinct or ‘feathered’. The skin surrounding the affected pale area can appear hyperemic. Generally, the lesions are only several centimeters in diameter, but larger lesions can occur. The trunk is the most common site of involvement. Once present, the patches remain stable indefinitely, in both size and configuration. Biopsy of affected skin shows a normal histology; the diagnosis is established by two clinical maneuvers instead. Diascopy of the adjacent normal skin causes a blanching that obliterates the margin between normal and abnormal skin. This indicates that the pale color of the lesion is due to decreased vascularity rather than to the absence of pigment, Firm stroking of the involved skin does not reveal the normally present red axon flare. The absence of the flare indicates that decreased vascularity has occurred as a result of neurally regulated vasoconstriction. There is an association with capillary vascular malformations,125 which may be explained by the phenomenon of twin spotting.126 Nevus anemicus may be linked with certain genodermatoses, including neurofibromatosis and phakomatosis pigmentovascularis.127 Rarely cosmetic coverups may be used and vascular laser to the surrounding skin may be attempted to ‘blur’ the margin if desired.

VASCULITIS AND INFLAMMATORY PURPURAS The diseases considered in this category share in common the presence of non-blanchable purpuric lesions, but, in contrast to the non-inflammatory purpuric diseases considered in the next section, the purpuric lesions of the vasculitic group are usually petechial. Ecchymoses and hematomas are rarely encountered. Histologically, the vasculitic purpuras are characterized by the presence of inflammatory infiltrates located within the blood vessel walls. In all instances, these inflammatory reactions cause sufficient disruption of the vascular wall to allow for the extravasation of erythrocytes. It is the extravascular location of these 126. Happle R, Koopman R, Mier OD. Hypothesis: vascular twin naevi and somatic recombination in man. Lancet. 1990;1:376.

Arteritis (petechiae, erythematous nodules, and ulcers)

VASCULITIS AND INFLAMMATORY PURPURAS

Figure 19.23  Nevus anemicus. petaloid white patches are readily visible after

>> Leukocytoclastic vasculitis – Henoch–Schönlein purpura – Urticarial vasculitis >> Polyarteritis nodosa >> Chronic cutaneous polyarteritis nodosa >> Granulomatous vasculitis >> Churg–Strauss vasculitis

red blood cells that causes the clinically characteristic feature of non-blanchability. When a lesion is blanched by pressure on the skin surface, the red blood cells containing oxyhemoglobin are pushed from superficial vessels into deeper vessels and are non-blanchable. When the red blood cell is outside the vessel wall, it cannot be pushed into deeper vessels. The diseases in this section are subdivided on the basis of the type and size of vessel involved: capillaritis, venulitis, and arteritis (Box 19.8). The prototype of vasculitis in childhood is Henoch-Schönlein purpura.

CAPILLARITIS The diseases in this group are characterized by the presence of non-palpable petechiae. These petechiae are 1–2 mm in diameter, uniform in appearance, and large in number. Histologically, a lymphocytic infiltrate surrounds and infiltrates the walls of those capillaries, which lie within the upper (papillary) dermis. The small size of involved vessels and relative sparsity of inflammatory cells account for the fact that these lesions are not elevated or palpable. Through mechanisms that are not well understood, this lymphocytic vasculitis also produces sufficient vessel wall destruction to result in extravasation of red blood cells. There is no breakup of the inflammatory cell nuclei (leukocytoclasis), and there is little or no fibrinoid deposition. Two types of capillaritis are recognized: a primary (idiopathic) type termed benign pigmented purpura and a secondary type associated with the use of certain medications (Box 19.8).

Benign pigmented purpuras This group of closely related conditions is characterized by the appearance of petechiae that are grouped in distinctive patterns. The histology and course of these conditions are similar. They 127. Ahkami RN. Schwartz RA. Nevus anemicus. Dermatology. 1999;198(4):327–329.

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implies, there is often an overall golden background color to the patch. Histologically, lymphocytes are present both in a bandlike (lichenoid) and in a perivascular pattern. The individual lesions of lichen aureus are similar to suction-type petechiae, such as those seen in ‘hickeys’ and in suction cup applications. In most cases, the lesions will resolve in two to four years.130 Usually, therapy is not requested although pimecrolimus has been reported to be successful.134 Children often induce lesions that mimic lichen aureus (in appearance, although not in duration) through oral suction on their own arms.

Purpura annularis telangiectodes of Majocchi Figure 19.24  Old (brown) and new (red) petechiae in Schamberg’s VASCULITIS AND INFLAMMATORY PURPURAS

pigmented purpura (courtesy of Dr A. Torrelo).

differ in clinical appearance but have in common the presence of both new and old petechiae at the time of examination.

Schamberg’s progressive pigmented purpura This is the most common pigmented purpura and is one of the most common causes of chronic petechiae in children. Multiple distinct annular patches of closely set, but non-confluent, petechiae are found on the legs and occasionally elsewhere (Fig. 19.24). Each of the nummular patches is 2–5 cm in diameter; clear areas of normal skin separate adjacent patches. Within each patch, the complete life cycle of individual petechiae is demonstrated. That is, some of the petechiae are bright red, others are violaceous, and some have disappeared, leaving brown dots of hemosiderin pigmentation. This latter change accounts for the term ‘pigmented’ in the name of the disease. Individual patches come and go and the process tends to last for years with eventual spontaneous resolution in most.128 The lesions are asymptomatic and may be asymmetrical or unilateral.129,130 For any progressive eruption, biopsy is indicated with the differential diagnosis being cutaneous T cell lymphoma.131 Phototherapy is reported to be to be effective.132

Lichen aureus This differs from Schamberg’s purpura as only one or, at most, a few patches of closely set petechiae are present126 although a zosteriform distribution has been reported.133 Moreover, each patch remains stable in size and location for long periods. In this sense, the patch (or patches) remains ‘fixed’ to one skin site for the entire course of the disease. Within each patch, individual petechiae are continually evolving and resolving. As the name

128. Torrelo A, Requena C, Mediero IG, et al. Schamberg’s purpura in children: a review of 13 cases. J Am Acad Dermatol. 2003;48(1):31–33. 129. Mar A, Fergin P, Hogan P. Unilateral pigmented purpuric eruption. Australas J Dermatol. 1999;40:211–214. 130. Gelmetti C, Cerri D, Grimalt R. Lichen aureus in childhood. Pediatr Dermatol. 1991;8:280–283. 131. Ugajin T, Satoh T, Yokozeki H, et al. Mycosis fungoides presenting as pigmented purpuric eruption. Eur J Dermatol. 2005;15(6):489–491. 132. Lasocki AL, Kelly RI. Narrowband UVB therapy as an effective treatment for Schamberg’s disease. Australas J Dermatol. 2008;49(1):16–18. 133. Aoki M, Kawana S. Lichen aureus. Cutis. 2002;69(2):145–148. 134. Bohm M, Bonsmann G, Luger TA. Resolution of lichen aureus in a 10-year-old child after topical pimecrolimus. Br J Dermatol. 2004;151(2):519–520.

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This is similar to Schamberg’s purpura, but within each patch, there is a predilection for the appearance of telangiectasia. Moreover, individual patches undergo centrifugal spread with central clearing. This results in an annular configuration. Benign pigmented purpuras are usually asymptomatic, but rarely, an appreciable degree of pruritus is present. In these instances, small lichenoid papules and mild eczematization may occur secondary to chronic rubbing. The term lichenoid pigmented purpura of Gougerot and Blum is applied to such lesions. The term eczematous-like purpura of Ducas and Kapetenakis is used when eczematous lesions predominate. The cause and pathogenesis of the benign pigmented purpuras are unknown, with all of them being chronic conditions that generally last for months to years.

Drug-induced petechiae Medications can cause purpuric lesions through at least three different mechanisms: lymphocytic capillaritis, thrombocytopenia, and immune complex venulitis. Lymphocytic capillaritis is the least common of these types and is a reaction generally associated with four classes of medications: barbiturates, sulfarelated medications, carbamate muscle relaxants and anxiolytic agents. Capillaritis has also been associated with interferonalpha therapy for hepatitis C.135 The petechiae in these capillaritic drug reactions are widely and randomly distributed. Moreover, they usually do not occur in well-defined patches. These two features help separate capillaritic drug reactions from the benign pigmented purpuric eruptions. The pathogenesis of drug-induced lymphocytic capillaritis is unknown. Immunemediated thrombocytopenia is unlikely to be drug-induced unless it is sudden and severe.136 The differential diagnosis of pigmented purpuric eruption includes pigmented purpuric clothing dermatitis and mycosis fungoides. A number of reports of mycosis fungoides in its early stages have been reported to resemble a capillaritis.137,138

135. Gupta G, Holmes SC, Spence E, et al. Capillaritis associated with interferon-alpha treatment of chronic hepatitis C infection. J Am Acad Dermatol. 2000;43:937–938. 136. Warkentin TE. Drug-induced immune-mediated thrombocytopenia – from purpura to thrombosis. N Engl J Med. 2007;356(9):891–893. 137. Barnhill RL, Braverman IM. Progression of pigmented purpura-like eruptions to mycosis fungoides: a report of three cases. J Am Acad Dermatol. 1988;19:25–31. 138. Georgala S, Katoulis AC, Symeonidou S, et al. Persistent pigmented purpuric eruption associated with mycosis fungoides: a case report and review of the literature. J Eur Acad Dermatol Venereol. 2001;15: 62–64.

Vascular reactions

During the course of many common acute bacterial and viral infections of childhood, petechiae may appear.124 These include streptoccocal infections and numerous viral diseases (the enteroviruses, herpes-group viruses and parvovirus B19). Severe systemic infections due to meningococci and rickettsiae may also result in acute petechiae. The petechiae often appear within a 24-hour period and clear over 5–10 days. A specific clinical entity termed ‘papular-purpuric gloves and socks syndrome’ has been described.139 It presents as pruritic erythematous papules occurring in a gloves-and-socks distribution associated with acral lesions and possibly fever. The lesions rapidly develop petechial purpura and clear within 2 weeks, although may be more prolonged in the setting of HIV.140 Most cases are due to parvovirus B19 with PCR identification of the virus within lesions and serological conversion demonstrated.141 The histology is not specific and may show a mild interface dermatitis and a superficial lymphocytic vasculitis. Other viruses have been implicated in causing the eruption including rubella,142 human herpesvirus 6,143 hepatitis B,144 cytomegalovirus,145 and measles.146

LEUKOCYTOCLASTIC VASCULITIS (VENULITIS) Introduction Petechial diseases in this group are characterized by the presence of small purpuric lesions. These petechiae differ considerably from those in capillaritis. They are palpable, are more variable in size, ranging from 2 to 10 mm in diameter, and are more randomly spread, with little evidence of grouping. Finally, they may be accompanied by other non-petechial lesions, such as urticarial papules and small hemorrhagic vesicles, infarcts, or ulcers. Venulitis-associated petechiae are microscopically characterized by the presence of a neutrophilic infiltrate in and around the venules of the upper dermis. The vessel walls are visibly damaged, with associated leukocytoclasis, erythrocyte extravasation, and fibrinoid deposition. Older lesions may contain scattered lymphocytes in the inflammatory infiltrate, but neutrophils still predominate. The pathogenesis for the venulitic type of vasculitis is usually that of immune complex deposition with consequent complement activation and endothelial injury.

139. Harms M, Feldmann R, Saurat JH. Papular-purpuric ‘gloves and socks’ syndrome. J Am Acad Dermatol. 1990;23:850–854. 140. Ghigliotti G, Mazzarello G, Nigro A, et al. Papular-purpuric gloves and socks syndrome in HIV-positive patients. J Am Acad Dermatol. 2000;43:916–917. 141. Grilli R, Izquierdo MJ, Farina MC, et al. Papular-purpuric ‘gloves and socks’ syndrome: polymerase chain reaction demonstration of parvovirus B19 DNA in cutaneous lesions and sera. J Am Acad Dermatol. 1999;41:793–796. 142. Segui N, Zayas A, Fuertes A, et al. Papular-purpuric ‘gloves and socks’ syndrome related to rubella virus infection. Dermatology. 2000;200(1):89. 143. Ruzicka T, Kalka K, Diercks K, et al. Papular-purpuric ‘gloves and socks’ syndrome associated with human herpesvirus 6 infection. Arch Dermatol. 1998;134:242–244. 144. Guibal F, Buffet P, Mouly F, et al. Papular-purpuric gloves and socks syndrome with hepatitis B infection. Lancet. 1996;347:473. 145. Carrascosa JM, Bielsa I, Ribera M, et al. Papular-purpuric gloves-and-socks syndrome related to cytomegalovirus infection. Dermatology. 1995;191:269–270. 146. Perez-Ferriols A, Martinez-Aparicio A, Aliaga-Boniche A. Papular-purpuric ‘gloves and socks’ syndrome caused by measles virus. J Am Acad Dermatol. 1994;30:291–292.

The nomenclature historically applied to the diseases that share these histologic features has been most confusing. All of the following have been used to describe essentially similar conditions: leukocytoclastic vasculitis, necrotizing angiitis, hypersensitivity angiitis, allergic vasculitis, immune complex vasculitis, anaphylactoid purpura, and palpable purpura. The most common form in childhood is Henoch–Schönlein purpura.

Henoch–Schönlein purpura Definition Henoch–Schönlein purpura represents the clinical presentation of a small vessel vasculitis whose major manifestations include arthritis, non-thrombocytopenic purpura, abdominal pain, and renal disease. This is reflected in the diagnostic criteria established by the American College of Rheumatology, whose criteria would have all small vessel vasculitis in children diagnosed as Henoch–Schönlein purpura.147 However, diagnostic criteria provided by the Chapel Hill Consensus conference suggest that IgA deposition is an imperative component148 and this has been reiterated by diagnostic criteria produced by the European League against Rheumatism and Paediatric Rheumatology society.149 It is therefore difficult to compare and assess historical clinical trials without the assessment of presence of IgA. It would appear that the presence of IgA, which separates Henoch– Schönlein purpura from hypersensitivity vasculitis, does convey a poorer longer-term renal prognosis.150

VASCULITIS AND INFLAMMATORY PURPURAS

Petechiae with acute infection

19

Epidemiology including genetics and statistics This common condition occurs at all ages and equally in both sexes. Approximately 10% of the cases occur in children.151

Presenting history The eruption is frequently preceded by symptoms of fever, malaise, arthralgia, and gastrointestinal upset. The onset in children is usually acute, although may be more insidious on occasion. Upper respiratory tract infections precede Henoch– Schönlein purpura in 30–50% of cases and are often group A Streptococcus.152 A detailed history should be sought, looking for symptoms of conditions that may be associated with other causes of leukocytoclastic vasculitis, listed in Box 19.9.

147. Mills JA, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura. Arthritis Rheum. 1990;33:1114–1121. 148. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an International Consensus Conference. Arthritis Rheum. 1994;37:187–192. 149. Ozen S, Ruperto N, Dillon MJ, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65:936–941. 150. Aalberse J, Dolman K, Ramnath G, et al. Henoch Schönlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria. Ann Rheum Dis. 2007;66(12):1648–1650. 151. Asherson RA, Cruz DD, Stephens CJ, et al. Urticarial vasculitis in connective tissue disease: clinical patterns, presentations and treatment. Semin Arthritis Rheum. 1991;20:285. 152. Masuda M, Nakanishi K, Yoshizawa N, et al. Group A streptococcal antigen in the glomeruli of children with Henoch–Schönlein nephritis. Am J Kidney Dis 2003, 41:366–370.

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BOX 19.9 COMMON CAUSES AND ASSOCIATED UNDERLYING DISEASES IN LEUKOCYTOCLASTIC VASCULITIS Infections

>> Streptococcal and neisserial bacterial infections >> Hepatitis B >> Cytomegalovirus >> Epstein–Barr virus Medications and related substances

>> Sulfa-antibiotics >> Thiazides, phenothiazines, sulfonylureas, and other sulfarelated products

VASCULITIS AND INFLAMMATORY PURPURAS

>> Quinidine >> Phenytoin >> Injected illicit drugs >> Allopurinol >> Radiographic contrast media >> Non-steroidal anti-inflammatory agents Autoimmune diseases

>> Lupus erythematosus >> Rheumatoid arthritis >> Wegener’s granulomatosis >> Giant cell arteritis >> Mixed and overlap collagen vascular diseases >> Sjögren syndrome >> Chronic inflammatory bowel disease

Figure 19.25  Discrete petechial papules on the leg of an 8-year-old girl with Henoch–Schönlein purpura.

Dysproteinemias

>> Cryoglobulinemia >> Monoclonal and polyclonal gammopathies Malignancies

>> Myeloma >> Leukemia >> Lymphoma Food products

>> Food dyes and preservatives

Physical examination The major presentation is that of palpable petechiae. Individual lesions vary in size from 2 to 7 mm in diameter; most of them are slightly elevated and palpable. The individual petechiae may be surrounded by a 2–3 mm, flat red halo or collar. These petechial lesions may occur anywhere but are most commonly found on the lower legs (Fig. 19.25). Other types of lesions may be intermixed with the petechiae. Dusky red macules and flat-topped papules are the most common lesions, but small hemorrhagic vesicles, infarcts, and ulcers may also be seen (Fig. 19.26).151 The mucous membranes are not often involved. Leukocytoclastic vasculitis should be considered to be a systemic disease involving blood vessels in many organs. Some 50% of affected children also have involvement of joints, peripheral nervous system, gastrointestinal tract, and lungs.151 1124

Figure 19.26  Purpuric papules, ecchymoses and brown old petechiae in a 12-year-old girl with Henoch–Schönlein purpura.

Laboratory findings Investigation of leukocytoclastic vasculitis can be subcategorized into: confirmation of diagnosis; assessment of other organs involved; and investigation for underlying cause. Confirmation of a vasculitic pathogenesis can best be obtained through skin biopsy. The light microscopic changes are essentially those described in the introductory paragraph on venulitis. The severity of the histopathological skin changes is not predictive

Vascular reactions

Pathophysiology and histogenesis The pathogenesis of leukocytoclastic vasculitis is mediated through immune complex formation and deposition. The ability to form circulating immune complexes requires the presence of antigen and antibody in roughly equivalent amounts. Outside of this equivalency ratio, binding sites on either the antigen or antibody are saturated such that interconnecting lattice formation occurs very inefficiently. When circulating immune complexes are formed, they are ordinarily quickly removed by phagocytic cells of the reticuloendothelial system before they can do any harm. However, in leukocytoclastic vasculitis, the reticuloendothelial system is partially blocked or overloaded, and immune complexes are not efficiently removed. These immune complexes do no harm while circulating, but when endothelial cells are separated or the blood vessels are otherwise damaged,

153. Cribier B, Couilliet D, Meyer P, et al. The severity of the histopathological changes of leukocytoclastic vasculitis is not predictive of extracutaneous involvement. Am J Dermatopathol. 1999;21:532–536. 154. Narchi H. Risk of long term renal impairment and duration of follow up recommended for Henoch-Schönlein purpura with normal or minimal urinary findings: a systematic review. Arch Dis Child. 2005;90(9):916–920.

they attach to exposed vascular basement membrane. This attachment results in the activation of complement. Complement activation occurs through the classical pathway if the complexes contain IgG or IgM; it occurs through the alternative pathway when they contain IgA. In either case, activation of the complement cascade releases anaphylatoxins (C3a and C5a) that, among other actions, are chemotactic for neutrophils. The neutrophils accumulate and initiate phagocytosis of the deposited complexes. This removal process is appropriate and desirable, but during phagocytosis, excess neutrophilic lysosomal enzymes are released. These proteolytic enzymes cause basement membrane destruction, leukocytoclasis, and resultant erythrocyte extravasation. The entire chain of events from initial immune complex deposition to removal requires only 24–72 h. After this point, an influx of mononuclear cells signals the initiation of the reparative process.

VASCULITIS AND INFLAMMATORY PURPURAS

of internal organ involvement.153 However, immunofluorescent studies are also often helpful, particularly if IgA deposits are detected around blood vessels, indicating the likelihood of Henoch–Schönlein purpura. Commonly, IgM, C3, and fibrin are present in and around the blood vessels. IgG rather than IgM is more likely to be present when there is an underlying collagen vascular disease. Decreased serum levels of C3 and C4 complement components are often noted in leukocytoclastic vasculitis. Testing to exclude internal organ involvement generally includes urinalysis, chest radiograph, stool guaiac, renal function, and liver function studies. With normal urinalysis up to 6 months, there is no requirement to continue testing for longterm renal damage.154 A specific cause or a responsible underlying disease is found in > Disseminated intravascular coagulation >> Thrombotic thrombocytopenic purpura >> Idiopathic thrombocytopenic purpura >> Thrombocytopenic purpura caused by medications, transfusions, and other diseases

>> Deficiencies in non-platelet coagulation factors >> Miscellaneous intravascular purpuras Extravascular purpuras

>> Scurvy >> Ehlers–Danlos syndrome >> Gardner–Diamond syndrome >> Miscellaneous extravascular purpuras

or more points in the circulating components of the coagulation cascade. The extravascular purpuras, on the other hand, occur because of fragility of the vascular wall basement membrane or weakened extravascular connective tissue does not provide adequate structural support for the cutaneous blood vessels. Clinical differentiation between the intra- and the extravascular purpuras is often possible. Patients with intravascular purpura bleed very easily and cease bleeding only with difficulty. Clinically, this is reflected by ‘spontaneous’ bleeding without a history of specific trauma; oozing from the mucous membranes of the nose, gingiva, and gastrointestinal tract; and cutaneous bleeding brisk enough to form nodular hematomas and flat ecchymoses. In contrast, bleeding in children with extravascular purpura is less troublesome. It usually requires recognizable trauma for initiation, rarely affects mucous membranes, and seldom leads to hematoma formation.

DISSEMINATED INTRAVASCULAR COAGULATION

The diseases considered in this section are characterized by the presence of large areas of purpura. Petechiae are usually present, but ecchymoses dominate the clinical presentation. These ecchymoses, which consist of large, non-inflammatory depositions of blood within the skin, are usually not elevated or palpable and neither are the petechiae The non-inflammatory petechial and ecchymotic purpuras are subdivided into two groups: intra- and extravascular purpuras (Box 19.10). The intravascular purpuras are so named because they are caused by a disturbance at one

Disseminated intravascular coagulation (DIC) is characterized by the sudden unexpected activation of the coagulation cascade secondary to the presence of an underlying disease process. The triggering of this thrombotic process, together with consequent activation of the fibrinolytic process, depletes the blood of platelets and other clotting factors. This depletion results in the rapid development of a state of hypo- or non-coagulability. The clinical presentation in DIC is highly variable. In mild cases, only a few cutaneous petechiae and ecchymoses are present. Usually, this is recognized as prolonged bleeding at venipuncture sites and at other sites of skin-piercing trauma. In more severe cases, soft tissue hematomas, hemorrhagic bullae, and skin necrosis are encountered. It is common to find evidence of gastrointestinal, genitourinary, and other internal organ

175. Kallenberg CG. Churg–Strauss syndrome: just one disease entity? Arthritis Rheum. 2005;52:2589–2593. 176. Davis MD, Daoud MS, McEvoy MT, et al. Cutaneous manifestations of Churg–Strauss syndrome: a clinicopathologic correlation. J Am Acad Dermatol. 1997;37:199–203.

177. Keogh KA. Leukotriene receptor antagonists and Churg-Strauss syndrome: cause, trigger or merely an association? Drug Safety. 2007;30(10):837–843. 178. Saech J, Owczarczyk K, Roesgen S, et al. Successful use of rituximab in a patient with Churg-Strauss syndrome and refractory CNS involvement. Ann Rheum Dis. 2009;[Epub ahead of print].

NON-INFLAMMATORY PETECHIAL AND ECCHYMOTIC PURPURAS

NON-INFLAMMATORY PETECHIAL AND ECCHYMOTIC PURPURAS

formation. Circulating immune complexes are found in about one-half of patients, but evidence for their deposition in vessel walls is generally lacking. Antineutrophilic cytoplasmic antibody (c-ANCA) is seen in almost all patients and the level is useful in monitoring disease progress.174 Children with untreated disease may die within several years. Steroid therapy is only partially effective, but 90% of children respond to cyclophosphamide administered in a daily dosage of 1–2 mg/kg with complete remission. A combination of steroids and cytotoxic agents, used concomitantly, is necessary in some.

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NON-INFLAMMATORY PETECHIAL AND ECCHYMOTIC PURPURAS

bleeding. Almost always, the signs and symptoms of hypocoagulability (bleeding) overshadow those due to the primary hypercoagulability (thromboses). The diagnosis of DIC usually can be accomplished through the use of screening tests, although there is no single laboratory test sensitive and specific enough to allow a definitive diagnosis.179 Specifically, platelet counts are usually (but not always) decreased, and there is prolongation of the prothrombin and partial thromboplastin times. Fibrinogen levels are usually decreased, and the presence of fibrin split products can be ascertained. Examination of a blood smear generally reveals the presence of schistocytes from erythrocyte damage caused during passage through partially thrombosed vessels. DIC may be triggered by a variety of underlying disease processes. Those of importance in pediatric settings include snake bite envenomation, burns, blood transfusions, leukemic malignancies, vascular hamartomas, and, most commonly, various types of infection.180 Treatment of DIC is directed towards removal or reduction of the triggering process including a thorough investigation for underlying sepsis. The next step involves replacement of depleted clotting factors through administration of fresh-frozen plasma, platelets, or cryoprecipitates containing fibrinogen. Determination of the amount and ‘mix’ of these substances is difficult and requires the assistance of an experienced hematologist. Early fears that the addition of these clotting factors would only exacerbate the condition are unwarranted.180 The use of heparin to impede the clotting process and decrease consumption of coagulation factors remains controversial. Some authorities would use it in most cases, but most would withhold it until there was evidence that simple replacement of clotting factors proves inadequate.180 The use of heparin seems particularly helpful when fibrinogen levels are found to be extremely low. There is consensus that heparin should not be administered to patients with hypertension, to those with evidence of central nervous system bleeding, and to those in the immediate postoperative period. The administration of aminocaproic acid might be helpful because of its inhibitory effect on fibrinolysis, but some authorities are hesitant to use it because of the risk of thrombosis. The role of other modalities such as antithrombin concentrates, protein C concentrates, and cytokine modifiers may be of value depending on the clinical situation and highlight the need to manage this clinical situation in conjunction with hematological experts.180 In sepsis patients with DIC, administration of antithrombin concentrate may increase overall survival.181 Interferon alfa may also be useful in children with Kasabach–Merritt syndrome, but the response is slow, occurring over weeks to months, and reported neurological complications restrict its use.

179. Dalainas I. Pathogenesis, diagnosis, and management of disseminated intravascular coagulation: a literature review. Eur Rev Med Pharmacol Sci. 2008;12(1):19–31. 180. Bick RL, Arun B, Frenkel EP. Disseminated intravascular coagulation: clinical and pathophysiological mechanisms and manifestations. Haemostasis. 1999;29:111–134. 181. Wiedermann CJ, Kaneider NC. A systematic review of antithrombin concentrate use in patients with disseminated intravascular coagulation of severe sepsis. Blood Coagul Fibrinolysis. 2006;17(7):521–526. 182. Edlich RF, Cross CL, Dahlstrom JJ, et al. Modern concepts of the diagnosis and treatment of purpura fulminans. J Environ Pathol, Toxicol Oncol. 2008;27(3):191–196.

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Purpura fulminans Purpura fulminans is a rare syndrome of intravascular thrombosis and hemorrhagic infarction of the skin that is rapidly progressive and accompanied by vascular collapse and disseminated intravascular coagulation. It usually occurs in children, but has also been noted in adults. There are three forms of purpura fulminans that are classified by the triggering mechanisms. Neonatal purpura fulminans is associated with a hereditary deficiency of the natural anticoagulants protein C and protein S as well as antithrombin III. Idiopathic purpura fulminans usually follows an initiating febrile illness that manifests with rapidly progressive purpura. Deficiency of protein S is considered to be central to the pathogenesis of this form of the disease. The third and most common type is acute infectious purpura fulminans.182 This occurs in children during or just after a bacterial (most often meningococcal or streptococcal) or viral (most often varicella) infection.183 Persons who are heterozygous for protein C deficiency have levels of circulating protein C that are 50% that of normal and usually do not have symptoms from thrombosis until early adult life.184 These persons are also predisposed to coumarin-induced skin necrosis. Persons who are homozygous or doubly heterozygous for the defect have levels of protein C that are > Infantile hemangiomas >> Congenital hemangiomas (RICH and NICH) >> Tufted angioma (with or without KMP) >> Kaposiform hemangioendothelioma (with or without KMP) >> Spindle cell hemangioendothelioma >> Other, rare hemangioendotheliomas (epithelioid, composite, Dabska tumor, lymphangioendotheliomatosis, etc.)

>> Dermatologic acquired vascular tumors (pyogenic granuloma,

targetoid hemangioma, glomeruloid hemangioma, microvenular hemangioma, etc.)

VASCULAR TUMORS

Vascular malformations

>> Slow-flow vascular malformations: – Capillary malformation (CM) (port-wine stain, telangiectasia, angiokeratoma)

Figure 20.1  Coexistence of a nevus simplex (salmon patch) and a mixed



Venous malformation (VM) (common sporadic, familial venous malformation, cutaneous and mucosal syndrome (VMCM), glomuvenous malformation, Maffucci syndrome and blue rubber bleb nevus (Bean) syndrome

infantile hemangioma of the occipital scalp (Courtesy Dr A. Torrelo).



Lymphatic malformation.

>> Fast-flow vascular malformations: – Arterial malformation (AM) – Arteriovenous fistula (AVF) – Arteriovenous malformation (AVM) (Parkes Weber

Although the precise events leading to the formation of IH are not known, research in blood vessel development (vasculogen-

esis) and proliferation (angiogenesis) have provided some clues. During their proliferative phase, IH are composed of densely packed endothelial cells, forming small sinusoidal channels. Cellular markers of angiogenesis, such as basic fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), proliferating-cell nuclear antigen, and E-selectin, are increased. Immunohistochemical stains confirm blood vessel markers such as CD31, von Willebrand factor, and VE-cadherin. Additional studies have shown that IH have a unique vascular phenotype which most closely resembles that of placental microvasculature, rather than normal cutaneous vasculature, demonstrated by staining markers such as glucose transporter 1 (GLUT-1), merosin, and Lewis Y antigen.18 Other studies have demonstrated that hemangioma cells cultured in vitro behave more like fetal than neonatal endothelial cells. This includes attaining a spindle-shape rather than epithelioid morphology, lower levels of expression of platelet–endothelial cell adhesion molecule-1, von-Willebrand factor, and production of interstitial type I collagen rather than epithelium-specific type IV collagen.19 Recent evidence also suggests that IH may originate from the growth of vascular progenitor cells.20 Several pieces of evidence, at molecular, cellular and clinical levels, suggest a possible role for hypoxia in hemangioma development. Hypoxia inducible factor 1A (HIF-1α) is upregulated in patients with hemangiomas.21 GLUT-1 and insulin-like growth factor 2 (IGF-2), two protein products implicated in hemangioma pathogenesis, are present in hemangiomas at relatively high levels, and are both under the

17. Berg JN, Walter JW, Thisanagayam U, et al. Evidence for loss of heterozygosity of 5q in sporadic haemangiomas: are somatic mutations involved in haemangioma formation? J Clin Pathol. 2001;54:249–252. 18. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137:559–570. 19. Dosanjh A, Chang J, Bresnick S, et al. In vitro characteristics of neonatal hemangioma endothelial cells: similarities and differences

between normal neonatal and fetal endothelial cells. J Cutan Pathol. 2000;27:4. 20. Ritter MR, Butschek RA, Friedlander M, et al. Pathogenesis of infantile haemangioma: new molecular and cellular insights. Expert Rev Mol Med. 2007;9:1–19. 21. Kleinman ME, Greives MR, Churgin SS, et al. Hypoxia-induced mediators of stem/progenitor cell trafficking are increased in children with hemangioma. Arterioscler Thromb Vasc Biol. 2007;27:2664–2670.

syndrome)

>> Complex-combined vascular malformations – CVM, CLM, LVM – CLVM, capillary–lymphatic–venous malformation (most common type seen in limbs with Klippel–Trenaunay syndrome)



AVM-LM, CM-AVM

Adapted from the International Society for the Study of Vascular Anomalies updated classification.4

may play a role and approximately 10% of affected patients have a positive family history, although there is no obvious pattern of Mendelian inheritance in most cases. The exception is in rare families with an autosomal dominant inheritance pattern for hemangiomas and other vascular anomalies, with a putative localization to 5q.17

Etiology/pathogenesis

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B

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A

Figure 20.2  Hemangioma precursors. (A) Area of blanching with superimposed telangiectasias.   (B) Extensive stain and telangiectasias resembling a port-wine stain. (C) Bruise-like area.

C

control of HIF-1A and are induced by hypoxia.22,23 Other evidence points to mutations in vascular endothelial growth factor receptor-1 (VEGFR1) leading to VEGF-dependent activation of VEGFR2 and downstream signaling pathways.24 An animal model retaining phenocopy in immunodeficient nude mice has recently been described leading to hopes of a better understanding of the phases of development and involution as well as in vitro assays for therapies.25 The pathogenesis of involution of hemangiomas is not well understood. IH demonstrate characteristic histologic changes including dilatation of vascular lumina, flattening of endothelial cells, presence of fibrous tissue and mast and CD8+ T-cell infiltrates.20 Programmed cell death (apoptosis) is believed to be an important mechanism of hemangioma involution. Markers of apoptosis become evident before 1 year of age and reach the highest levels by 2 years.26

22. Feldser D, Agani F, Iyer NV, et al. 1999. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59, 3915–3918. 23. Loike JD, Cao L, Brett J, et al. Hypoxia induces glucose transporter expression in endothelial cells. Am J Physiol. 1992;263:C326–C333. 24. Jinnin M, Medici D, Park L, et al. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med. 2008;14:1236–1246. 25. Khan ZA, Boscolo E, Picard A, et al. Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. J Clin Invest. 2008;118:2592–2599.

Clinical characteristics Approximately 30–50% of hemangiomas are heralded by a precursor lesion. The varied appearances of these lesions include a focal or large area of pallor, often with fine thread-like telangiectases (Fig. 20.2A), a telangiectatic or macular erythematous stain (Fig. 20.2B), a bruise-like area (often erroneously attributed to perinatal trauma) (Fig. 20.2C), or a small ‘scratch’ or ulceration.27 Most precursor lesions go on to develop a fully formed hemangioma, but occasionally no proliferation or only a small amount of proliferation occurs at the periphery. These types of hemangioma have been termed abortive, or minimal growth hemangiomas. Although they do not proliferate, they are GLUT 1 positive and are considered to be within the spectrum of true IH.28 Uncommonly, fully formed ‘congenital’ hemangiomas are present at the time of birth; in rare instances, these are

26. Razon MJ, Kraling BM, Mulliken JB, et al. Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation. 1998;5:189–195. 27. Hidano A, Nakajima S. Earliest features of the strawberry mark in the newborn. Br J Dermatol. 1972;87:138–144. 28. Corella F, Garcia-Navarro X, Ribe A, et al. Abortive or minimal-growth hemangiomas: Immunohistochemical evidence that they represent true infantile hemangiomas. J Am Acad Dermatol. 2008;58: 685–690.

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Figure 20.4  Deep hemangioma. Many deep hemangiomas in the preauricular Figure 20.3  Superficial hemangioma. The color and the texture resemble a

area involve the parotid gland.

strawberry (Courtesy Dr A. Torrelo).

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diagnosed in utero. These congenital hemangiomas have distinct clinical and growth characteristics (see discussion below). The appearance of the proliferative phase of cutaneous hemangiomas depends on which levels of the skin are affected. Superficial hemangiomas (Fig. 20.3) (also called ‘strawberry’ marks) involve the superficial dermis and appear as lobulated, bright red lesions with a thin, delicate surface epithelium. Deep hemangiomas (Fig. 20.4) involve the deep dermis and subcutis. In these cases, the epidermis retains its normal thickness and, instead of a superficial red color, the surface of the tumor has a bluish cast or normal skin color. Telangiectases, tortuous vessels, or a few vascular papules may be visible on the surface, and draining veins may be noted at the periphery. Deep hemangiomas were formerly called ‘cavernous hemangiomas,’ a term that should be avoided, since it has been used to refer to several disparate vascular anomalies, rather than one single disease. Superficial and deep hemangiomas are also referred to as ‘mixed hemangiomas.’ They involve both the dermis and subcutis. All IH, regardless of their location, are benign neoplasms of capillaries; terms such as combined capillary–cavernous hemangiomas are confusing and should be avoided.29 Hemangiomas are rarely painful, unless they ulcerate. Many, especially large ones, are warm to palpation and occasionally have enough blood flow to produce a bruit. This warmth and high blood flow subside as the tumor undergoes involution. Although rapid growth is a common characteristic during the proliferative phase, some fluctuation of size may be observed even once the tumor growth has ceased, when some parents report a temporary increase in size after the child has a crying episode or an upper respiratory infection.

Specific morphologic patterns of hemangiomas can be recognized, and have significant clinical implications. Based on the known timing of some of their associated structural defects, segmental hemangiomas (those that occupy a region or territory) appear to have their origin as early as 4–8 weeks’ gestation.30 In addition to marked variations in size and location, some present as discrete papules or nodules, whereas others are small or large plaques. Some plaque-type hemangiomas appear as numerous small papules coalescing into a plaque of involvement. Larger plaques may involve broader segments of the skin. The concept of localized (Fig. 20.5) and segmental (Fig. 20.6) hemangiomas has demonstrable clinical correlates. Large segmental hemangiomas in specific locations have been associated with underlying structural anomalies, including posterior fossa abnormalities, arterial and aortic anomalies, spinal dysraphism, genitourinary anomalies, and subglottic hemangiomas (see discussion below). Segmental hemangiomas in the preauricular area often involve the parotid gland and/or facial nerve without compromising function. Large preauricular segmental hemangiomas often have an associated hemangioma within the parotid gland that does not compromise facial nerve function. Large segmental hemangiomas of the face have a non-random distribution which has been carefully mapped into commonly affected regions or segments (Fig. 20.6).12 Segment 1 corresponds to the frontotemporal segment (forehead and temple); Segment 2 to the maxillary segment (encompassing the malar cheek); Segment 3 to the mandibular segment (so-called ‘beard’ distribution); and Segment 4 to the frontonasal segment (central forehead, nose and philtrum in a linear distribution). Some of these segments, particularly those in the lower face, correspond to previously described

29. Mulliken JB, Young AE. Vascular birthmarks: hemangiomas and malformations. Philadelphia: WB Saunders; 1988.

30. Hersh JH, Waterfill D, Rutledge J, et al. Sternal malformation/vascular dysplasia association. Am J Med Genet. 1985;21:177–186, 201–202.

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20

Most hemangiomas are solitary, but a significant percentage of patients (up to 15%) have multiple lesions. Multiple focal hemangiomas have a higher risk of visceral hemangiomas (Fig. 20.7) (see ‘hepatic hemangioma’ and ‘hemangiomatosis’, below).

Sites of involvement

VASCULAR TUMORS

A

Anatomic location plays a critical role in determining whether complications might occur; in these cases, extra concern and vigilance during the growth phase are necessary. Although any area of the body may be affected, approximately 60% occur on the head and neck. The distribution of facial hemangiomas does not appear to be random but appears to have a predilection for embryologic fusion lines and facial developmental subunits or segments.12,32 Less common anatomic sites include the trunk (25%) and extremities (15%).8 Hemangiomas can also develop in almost any internal organ. Table 20.1 outlines the risks associated with hemangiomas in several anatomic locations.

Natural history

B

Figure 20.5  Localized hemangioma. (A) Appearance at 3 months of age. (B) Appearance after oral steroid treatment at 2 years of age (Both Courtesy Dr A Torrelo).

embryologic facial prominences.12 The segment, or region, involved often heralds potential complications; for example, in one study, 85% of patients with S1 hemangiomas were found to meet criteria for PHACE syndrome (PHACE syndrome is the term applied to the association of posterior fossa brain abnormalities, hemangiomas, arterial anomalies in the cranial vasculature, coarctation of the aorta/cardiac defects, and eye abnormalities),31 while patients with S3 hemangiomas are more likely to have cardiac anomalies. The S3 distribution of hemangioma is highly associated with airway involvement (Fig. 20.6C).

31. Haggstrom AN, Lammer EJ, Schneider RA, et al. Large facial hemangiomas: what is the risk of PHACE? Abstract, ISSVA Meeting, Boston; 2008. 32. Waner M, Waner A, North P, et al. 2000. Identification of two distinct types of hemangioma. Presented at the 13th International Workshop on Vascular Anomalies, Montreal; 2000. 33. Chang LC, Haggstrom AN, Drolet BA, et al. Growth characteristics of infantile hemangiomas: implications for management. Pediatrics. 2008;122:360–367. 34. Jacobs AH. Strawberry hemangiomas. The natural history of the untreated lesion. Cal Med. 1957;86:8–10.

The natural history of hemangiomas has been well documented.29,33–35 Historically, hemangioma growth was categorized into proliferative, plateau and involution phases. However, recent evidence suggests that the growth and involution of hemangiomas may be better viewed as a continuous or dynamic process rather than one with stable, discrete phases.33 Hemangiomas ‘mark out their territory’ early on in their development and thereafter proliferate within their defined anatomic area and grow volumetrically rather than with a true radial growth phase. During the first 3–5 months, superficial hemangiomas proliferate rapidly. In 80% of cases, growth is complete by 5 months of age.33 Deep hemangiomas are often noted about 1 month later than superficial lesions and proliferate for about 1 month longer.33 Despite these general parameters, the early growth characteristics of any individual hemangioma can be very difficult to predict, because some hemangiomas barely proliferate beyond their nascent phase, whereas others, particularly large hemangiomas with both a superficial and deep component, continue to grow for longer periods, occasionally up to 1–2 years.33,36,37 The involution phase of hemangiomas is usually much slower than the proliferation phase. Involution of superficial lesions typically begins by about 1 year of age, occasionally sooner, and its onset is heralded by a color change from bright cherry red-to-dull redto-purple, beginning at the central portion of the tumor and eventually developing a grayish-white color that extends peripherally (Fig. 20.8). In some cases, proliferation actually continues at the margins of the lesion or in deeper components, despite signs of regression in the superficial central portions of the

35. Bivings L. Spontaneous regression of angiomas in children. J Pediatr. 1954;45:643–647. 36. Blei F, Isakoff M, Deb G. The response of parotid hemangiomas to the use of systemic interferon alfa-2a or corticosteroids. Arch Otolaryngol Head Neck Surg. 1997;123:841–844. 37. Williams EF III, Stanislaw P, Dupree M, et al. Hemangiomas in infants and children. An algorithm for intervention. Arch Facial Plast Surg. 2000;2:103–111.

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1

2

A B

3

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Di

C

Dii

Figure 20.6  Segmental hemangioma. (A) Segmental hemangioma on the face. (B) Facial segments (1–4). Hemangiomas tend to favor distinct regions which are predictive of possible complications; e.g., S1 segmental facial hemangiomas carry a high risk of underlying PHACE association.11 (From Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr. 2007;150:291–294.) (C) Segmental hemangioma on the trunk and limb. (Di) Segmental hemangioma on the face. (Dii) Same patient after steroid treatment. (A, C, Di and Dii, courtesy Dr A. Torrelo).

Table 20.1  Location and morphology of infantile hemangioma and associated risks ANATOMIC LOCATION, MORPHOLOGY

ASSOCIATED RISK

Large segmental facial

PHACE syndrome (see text)

Nasal tip, ear, large facial Permanent scarring and (especially with prominent dermal disfigurement component) Periorbital and retrobulbar

Ocular axis occlusion, astigmatism, amblyopia, tear-duct occlusion

Segmental mandibular (beard area)Airway hemangioma and central neck

Figure 20.7  Multiple disseminated hemangiomas. These may be associated with hepatic hemangiomas.

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Perioral, lips

Ulceration, disfigurement

Lumbosacral spine

Tethered spinal cord, genital and vesicorenal anomalies

Perianal, axilla, neck

Ulceration

Multiple hemangiomas

Hepatic involvement with risk of congestive heart failure and hypothyroidism

Vascular birthmarks: tumors and malformations

A

B

20

C

Figure 20.8  Plaque-type hemangioma. Natural involution of a large plaque-type hemangioma of the leg at ages (A) 2; (B) 4; and (C) 5 years. Although some

hemangioma. As the hemangioma involutes and is replaced by fibrofatty tissue, its volume decreases and it becomes softer and more easily compressible. Deeper lesions become less blue, softer, and less warm. Disappearance occurs at a rate of approximately 10% per year, so that approximately 50% have involuted by 5 years of age; 70% by 7 years, and 90% by 9 years.34,38 Involution may not leave completely normal skin. Exact estimates of the percentage of hemangiomas that leave significant residual skin changes are a matter of great controversy, with estimates varying widely, from 20–50%.9,39 Even when present, the residua in mild cases can be fairly inconspicuous, characterized by focal telangiectases, atrophic wrinkling, slight hypopigmentation, and subtle textural changes. In more severe cases, anetoderma-like scarring or fibrofatty swelling with marked distortion of anatomic structures may be evident. Most small hemangiomas do not result in significant disfigurement, but in certain locations such as the glabella, nose, lips, and ears, the risk of scarring is greater. Segmental hemangiomas, particularly those with a significant superficial dermal component, have a high risk of complications including scarring (Fig. 20.9). Ulceration always causes some degree of scarring, with the severity depending on the size and depth of the ante­ cedent ulcer such as the location and thickness of the hemangioma.6,10

PATHOLOGY Diagnosis and differential diagnosis In most cases, the diagnosis of hemangioma is a clinical one, based on appearance and typical growth characteristics. In a

38. Bowers RE, Graham EA, Tomlinson KM. The natural history of the strawberry nevus. Arch Dermatol. 1960;82:667–680. 39. Waner M, Suen JY, eds. Hemangiomas and vascular malformations of the head and neck. In: The Natural History of Hemangiomas. New York: Wiley-Liss; 1999:13–46. 40. Paltiel HJ, Burrows PE, Kozakewich HP, et al. Soft-tissue vascular anomalies: utility of US for diagnosis. Radiology. 2000;214:747–754.

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pigment and texture remain, the overall result is satisfactory.

small minority of patients, diagnosis is less obvious and ancillary tests are necessary. Deep hemangiomas, in particular, can be difficult to differentiate from other soft-tissue tumors. Tables 20.2 and 20.3 list the diagnoses that can resemble or mimic IH; imaging studies such as magnetic resonance (MRI), computed tomography (CT), and ultrasound can be helpful in differentiating hemangiomas from many of these conditions, but biopsy may be necessary in very atypical cases. In the proliferative phase, CT and MRI both demonstrate well-circumscribed densely lobulated, uniformly enhancing lesions with dilated feeding and draining vessels either at the center or periphery. On MR, the lesions are isointense or hypointense to muscle on T1-weighted images, and hyperintense on T2-weighted images. Flow voids are seen within and around the mass. Sonography with Doppler interrogation usually demonstrates a well-circumscribed parenchymal mass, often containing anechoic channels.40 Although true arteriovenous shunting is usually absent (except in hepatic hemangiomas), hemangiomas are fast-flow lesions with numerous high-flow vessels around and within the soft tissue mass; decreased arterial resistance is evident during both the prolifer­ ating and the involuting phases.41 During the proliferative phase, ultrasound demonstrates non-specific echogenicity and numerous vessels with high Doppler shift (>2 kHz) and low resistance.42 The histopathology of IH in the early proliferative phase is characterized by well-defined unencapsulated aggregates of plump endothelial cells with closely associated pericytes. Mast cells are numerous. Normal mitotic figures are often present and may be numerous. Deeper hemangiomas may involve skeletal muscle, salivary gland tissue, and nerves, not by invasion but by insinuating themselves between individual cells.

41. Burrows PE, Laor T, Paltiel H, et al. Diagnostic imaging in the evaluation of vascular birthmarks. Dermatol Clin. 1998;16:455–488. 42. Dubois J, Garel L, Grignon A, et al. Imaging of hemangiomas and vascular malformations in children. Acad Radiol. 1998;5:390–400.

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A B

Figure 20.9  (A) Large hemangioma of the face with superficial ulceration C

When hemangiomas start involuting, proliferating vessels decrease in number and loose fibrous or fibrofatty tissue begins to separate the vessels.43 GLUT-1, found in all phases of hemangioma growth, can be extremely helpful in differentiating IH from other tumors.18

Complications Most complications of IH develop during the first 4 months, in the proliferative phase; these include ulceration, compromise of vital functions, and, in rare instances, congestive heart failure. Significant bleeding and infection can also rarely occur.

Ulceration Cutaneous ulceration is the most common complication, occurring in 16% of hemangiomas in a referral setting (Fig. 20.10).10

43. North PE, Mihm MC. The surgical pathology approach to pediatric vascular tumors and anomalies. In: Waner M, Suen JY, eds. Hemangiomas and vascular malformations of the head and neck. New York: Wiley-Liss; 1999:93–170.

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(B). Same patient as (A): Partial regression with scarring. (C) Good result   after surgical excision of the partially regressed hemangioma (All Courtesy   Dr A. Torrelo).

Rarely, the ulceration occurs very early in the development of a hemangioma preceding the growth phase or the hemangioma may be masked by the ulceration.44 Ulceration is more common in larger, segmental hemangiomas and in those located on the lip, neck and anogenital regions.10 It usually presents as crusting that appears on the surface of the tumor. Early white/gray discoloration of the hemangioma at about 2 months can sometimes herald ulceration. If ulceration is mild, it can often be managed with topical therapies, including antibiotics such as metronidazole gel45 or petrolatum ointment; this is covered with an occlusive dressing such as a thin hydrocolloid dressing or petrolatum-impregnated gauze.45 Pain, which is often a major feature of ulcerated hemangiomas, is usually diminished with the use of occlusive dressings; if the pain is severe, it can be helped by the oral administration of acetaminophen (paracetamol), acetaminophen with codeine, or the conservative application of topical lidocaine ointment.45 Other second-line agents useful in the management of ulceration include topical

44. Liang MG, Frieden IJ. Perineal and lip ulcerations as the presenting manifestation of hemangioma of infancy. Pediatrics. 1997;99:256–259. 45. Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical characteristics and response to therapy. J Am Acad Dermatol. 2001;44: 962–972.

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20

DISEASE

AGE OF ONSET (USUAL)

Vascular anomalies: tumors and malformations   Congenital hemangiomas     Rapidly involuting Present fully formed at congenital birth hemangioma (RICH)

    Non-involuting congenital hemangioma (NICH)

Present fully formed at birth

  Tufted angioma and kaposiform hemangioendothelioma (KHE)

Occasionally at birth as brown-red stain (especially KHE). Can develop de novo during infancy or later. Growth can be gradual or rapid (especially if Kasabach–Merritt (K–M) develops

  Eccrine angiomatous hamartoma

Usually solitary, fully formed nodule or plaque present often at birth or may have onset later in life Any age including early infancy but onset prior to age 3 months is uncommon, except for multifocal form

  Pyogenic granuloma (lobular capillary hemangioma)

CLINICAL (SKIN)

USUAL LOCATION

OTHER MANIFESTATIONS

Exophytic tumor, few to 10 cm or larger. Often dome-shaped, occasional central ulcer, bluish tinge or overlying telangiectasia with radiating veins and/or halo of pallor at periphery Sharply demarcated patch or plaque, with overlying telangiectasias, feels warm, halo of pallor at periphery, radiating veins common Subtle stain-like area thickens into plaque or can be solitary nodule. Dull red-to-dusky purple or blue color. Size from few cm to large extensive areas. Firm, variably tender. May have increased overlying hair growth. If K–M is present, petechiae, dusky purple color and bruising at periphery may become prominent Vascular nodule, typically blue-red color. Hyperhidrosis may be present

Extremities especially thigh, post-auricular skin, scalp, but may occur at any site

High flow demonstrated on ultrasound or MRI

Extremities especially thigh, but may occur at any site

High flow demonstrated on ultrasound or MRI

Any site but preauricular skin, neck, leg, upper arm somewhat more common sites

If Kasabach–Merritt phenomenon is present, low platelets, fibrinogen, elevated D-dimers. MR shows involvement multiple tissue planes, poorly defined margins, cutaneous thickening, and edema which differ from IH

Acral site most often, but other sites such as torso and scalp may be affected

May be associated with underlying vascular malformation in some cases

Exophytic pedunculated or sessile bright red papule or nodule with friable surface; may have collarette of scale at rim

Face most common site but upper torso, neck, acral, or other skin sites may occur

Profuse and recurrent bleeding out of proportion to size of lesion is common, more so than in typical IH. Rare congenital multifocal form May be associated with soft-tissue hypertrophy, syndromes, including Sturge–Weber, Klippel–Trenaunay, Proteus syndrome, and others Family history may be present, especially in multifocal forms of VM

  Capillary malformation (port-wine stain)

Present at time of birth in vast majority of cases

Pale pink to red patch usually confluent color but reticulated CM can be confused with IH precursor or abortive/ reticular IH

Can occur at any site, but most often face or extremities

  Venous malformation

Often evident at birth but may appear later. Growth variable, usually slow commensurate with child but can enlarge though typically without rapid growth first 3 months

Usually soft, compressible blue soft tissue mass or plaque. Can involve mucosal surfaces, extend across multiple tissue planes. Faint pink stain with telangiectasias may be present. VMs typically enlarge with dependent position, exercise, Valsalva

Any site: Face, extremities most common sites; Size variable from localized nodule to involvement of entire limb or even larger

VASCULAR TUMORS

Table 20.2  Differential diagnosis of infantile hemanigomas – solitary lesions

Continued

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Table 20.2  Differential diagnosis of infantile hemanigomas – solitary lesions (continued) DISEASE

AGE OF ONSET (USUAL)

CLINICAL (SKIN)

USUAL LOCATION

OTHER MANIFESTATIONS

  Glomuvenous malformation (GVM)

May be present at birth, especially segmental plaque type; smaller nodules (often multifocal) more commonly develop childhood or later Macrocystic and extensive LMs often present at the time of birth

At birth, larger, segmental GVM is usually flat or nearly-flat, pink, blue or lilac color, with minimal/no evidence of nodularity. Smaller nodules are firm blue, often tender, a few mm to several cm Soft-tissue mass, typically skin-colored, unless superficial microcysts ‘blebs’ are present

Can occur at any skin site; Unlike venous malformations do not invade muscle or affect visceral tissues

Autosomal dominant inheritance but new mutations common

Head and neck often affected but can occur at any skin site including mucous membranes

  Verrucous ‘hemangioma’

Birth

Most often on extremity

  Capillary-lymphaticvenous malformation (CLVM; Klippel– Trenaunay syndrome)

Birth

Vascular patch or plaque, sharply demarcated red-purple, often rough surface even in infancy becoming more keratotic/ verrucous over time Stain, often geographic with superimposed small ‘blebs’; more blebs appear over time; venous varicosities variably present in infancy

May mimic deep IH, but rapid growth in infancy is uncommon. MRI can easily distinguish from IH. Large macrocysts may transilluminate Despite being called ‘hemangioma’, these are most often lymphatic malformations with a keratotic surface

  Arteriovenous malformations

Sometimes evident as vascular stain at time of birth; much less commonly presents as vascular soft-tissue mass

Pseudo-port-wine stain or soft-tissue fullness with overlying stain

Any site

Solitary XGs mimicking IH are typically nodules up to several centimeters which may appear flesh-colored, red, purple, or bluish Skin-colored, white or gray-blue nodule, rarely red or purple; usually grow slowly but occasionally expand quickly Firm nodules, may be fast-growing and exophytic, may ulcerate and bleed; often surface telangiectasias; color usually red or purple Solitary lesions usually nodular and fast-growing, yellow/brown-to-red in color Painless skin colored (less commonly erythematous) soft tissue mass

Any site

Tend to crust and then indent centrally as they begin to resolve

Most often on face, neck or upper body

Hard, knobbly consistency. Calcification demonstrated by posterior shadow on ultrasound May have other small indented lesions elsewhere. Imaging demonstrates vascularity to be primarily peripheral Often initially presents as a vesicular lesion. Resolves spontaneously over weeks May be subtle small indented lesions elsewhere. Imaging demonstrates vascularity to be essentially peripheral

  Lymphatic malformation (LM) VASCULAR TUMORS

Benign growths and developmental anomalies   Juvenile Majority in first years xanthogranuloma of life; occasionally present at birth

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  Pilomatricoma

Onset typically first few years of life; exceptionally present at birth

  Infantile myofibromatosis and infantile hemangiopericytoma

At birth or first few months of life

  Solitary reticulohistiocytoma

Rarely present in early weeks of life

  Lipoblastoma

Occasionally at birth; one-third less than age 1, most 1 year of age. Neurotoxicity in older children is less common.98,99

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giomas.84,85 They may be considered for treatment of very early hemangiomas that are not causing overt functional impairment and are small and superficial enough to allow adequate percutaneous penetration of the medication. Potential risks of this treatment, although unlikely, include cutaneous atrophy and systemic absorption affecting the hypothalamic–pituitary axis.

20

Surgery Indications for surgical removal of hemangiomas can be divided into those appropriate in early infancy and those to be considered later in the course of the hemangioma, usually after 3 or 4 years of age. Early surgical intervention should be considered for sharply demarcated and localized exophytic and pedunculated hemangiomas, which have such a prominent epidermal component that they are extremely likely to leave permanently stretched skin and fibrofatty residuum after involution. Other reasonable indications include those with ulceration and bleeding that are unresponsive to other modalities of treatment and upper eyelid hemangiomas that have not responded to pharmacologic therapy.9,100

93. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. 1992;326: 1456–1463. 94. Chang E, Boyd A, Nelson CC, et al. Successful treatment of infantile hemangiomas with interferon-alpha-2b. J Pediatr Hematol Oncol. 1997;19: 237–244. 95. Rampini E, Rampini P, Occella C, Bleidl D. Interferon alpha 2b for treatment of complex cutaneous haemangiomas of infancy: a reduced dosage schedule. Br J Dermatol. 2000;142:189–191. 96. Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr. 1998;132:527–530. 97. Dubois J, Hershon L, Carmant L, et al. Toxicity profile of interferon alfa-2b in children: A prospective evaluation. J Pediatr. 1999;135: 782–785. 98. Jiménez-Hernández E, Dueñas-González MT, Quintero-Curiel JL, et al. Treatment with interferon-alpha-2b in children with life-threatening hemangiomas. Dermatol Surg. 2008;34:640–647. 99. Michaud AP, Bauman NM, Burke DK, et al. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope. 2004;114:1231–1236. 100. Aldave AJ, Shields CL, Shields JA. Surgical excision of selected amblyogenic periorbital capillary hemangiomas. Ophthalmic Surg Lasers. 1999;30:754–757.

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Figure 20.12  (A) A large hemangioma on the face. (B) Response to 20 weeks of oral propranolol (Both courtesy Dr A. Torrelo).

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Surgery can also be considered for children around 3–5 years who continue to have prominent and disfiguring hemangiomas (Table 20.4). At this age, enough involution has usually occurred to make the ultimate outcome more predictable (although there are exceptions). Children at this age become aware of facial differences, and may develop low self-esteem because of their hemangioma. The surgical scar that results must be weighed against the child’s emotional distress, as well as the likely outcome if the lesions were left to involute spontaneously. Excision at this age should be seriously considered if resection will be inevitable at some point, if the result of surgery will ultimately be the same whether or not excision is postponed, and in situations where the scar can be easily hidden.9 In cases with a high degree of uncertainty about ultimate prognosis, it may be best to postpone surgery until later in childhood, in order to allow maximal involution prior to determining how much skin needs to be removed. A multidisciplinary vascular anomalies team can be helpful in decisionmaking in these cases. Staged resections may be necessary for larger defects. A purse-string type closure has recently been shown to minimize scar length and give improved results for exophytic focal hemangiomas.101 Laser surgery (see below) may be helpful for removing residual erythema and superficial telangiectases. Several kinds of laser modalities have been used to treat hemangiomas. The pulsed dye laser (PDL) has been utilized since the early 1990s and several case series have emphasized its

use in the treatment of superficial hemangiomas as well as for residual lesions after involution.102,103 Treatment of an actively growing hemangioma is typically performed every 2–3 weeks until control of proliferation has been achieved. Although this modality has a low risk of scarring when used for treating port-wine stains, there is some evidence that it may cause ulceration and scarring when used for treating proliferating hemangiomas.104,105 Paradoxically, PDL at relatively low fluences ~6.6 J/cm2 has also been used successfully for treating ulcerated hemangiomas, resulting in decreased pain and possibly accelerating re-epithelialization.47,106 Deep hemangiomas are not effectively treated with PDL because of its limited depth of penetration. Other laser systems including intralesional bare-fiber Nd:YAG (neodymium–yttrium aluminum garnet) that have been used for this purpose appear to be effective, but with some risk of cutaneous ulceration and scarring.107 Sclerosing agents and embolization may be helpful in serious, life-threatening hemangiomas. They are not used for routine management. Cryotherapy has been used successfully to treat hemangiomas and is popular in some parts of Europe and South America.108,109 The risks of scarring, hypopigmentation and epidermal atrophy have limited the popularity of this modality in the USA. Radiation therapy, a treatment option of the past, is no longer considered an acceptable therapeutic modality unless there are life-threatening complications, because of the risk of effects on bone growth and/or late complications such as malignant change.110,111

101. Mulliken JB, Rogers GF, Marler JJ. 2001. Circular excision of hemangioma and purse-string closure – the shortest possible scar. Plast Reconstr Surg 109:1544–1555. 102. Hohenleutner S, Badur-Ganter E, Landthaler M, et al. Long-term results in the treatment of childhood hemangioma with the flashlamp-pumped pulsed dye laser: an evaluation of 617 cases. Lasers Surg Med. 2001;28: 273–277. 103. Haywood RM, Monk BE, Mahaffey PJ. The treatment of early cutaneous capillary haemangiomata (strawberry naevi) with the tunable dye laser. Br J Plast Surg. 2000;53:302–307. 104. Waner M, Adams D, North P, et al. 2000. A rare complication of pulsed dye laser treatment of hemangiomas. 13th International Workshop of Vascular Anomalies, Montreal; 2000. 105. Witman P, Frieden IJ. Complications following pulsed dye laser treatment of superficial hemangiomas. Lasers Surg Med. 2006;38:116–123.

106. David LR, Malek MM, Argenta LC. Efficacy of pulse dye laser therapy for the treatment of ulcerated hemangiomas: a review of 78 patients. Br J Plast Surg. 2003;56:317–327. 107. Achauer BM, Celikoz B, VanderKam VM. Intralesional bare fiber laser treatment of hemangioma of infancy. Plast Reconstr Surg. 1998;101: 1212–1217. 108. Cremer H. Cryosurgery for hemangiomas. Pediatr Dermatol. 1998;15: 410–411. 109. Reischle S, Schuller-Petrovic S. Treatment of capillary hemangiomas of early childhood with a new method of cryosurgery. J Am Acad Dermatol. 2000;42:809–813. 110. Talmi Y, Kalmanovitch M, Zohar Y. Thyroid carcinoma, cataract and hearing loss in a patient after irradiation for facial hemangioma. J Laryngol Otol. 1988;102:91–92. 111. Scerri L, Navaratnam AE. Basal cell carcinoma presenting as a delayed complication of thorium X used for treating a congenital hemangioma. J Am Acad Dermatol. 1994;31(5 Pt 1):796–797.

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Table 20.4  Therapies for infantile hemangiomas

Corticosteroids   Topical (Class I) corticosteroids

  Intralesional corticosteroids (10 mg/mL)

  Imiquimod 5% cream

Systemic therapies   Systemic corticosteroids (1–4 mg/kg per day)

  Propranolol (2–3 mg/kg/day) (newly described)

  Vincristine (1–1.5 mg/m2/week)

CLINICAL SITUATION

POSSIBLE SIDE-EFFECTS

Superficial IH or precursor lesions in attempt to prevent/alter proliferative phase IH on accessible sites such as the lip, cheek, nasal tip glabellar and periocular* areas (*only by a pediatric ophthalmologist)

Thinning of skin, telangiectasias, possible HPA suppression

Superficial IH in ‘cosmetically sensitive’ areas

Life or function threatening hemangiomas, i.e., airway, hepatic, periorbital Persistent ulceration, those where significant disfigurement is highly likely

Life or function threatening hemangiomas Those where significant disfigurement is highly likely Life or function threatening hemangiomas resistant to treatment with systemic steroids

  Interferon-α2a, b (3 µm/m2/day or QOD)

Life or function threatening IH in older children (particularly in infants >1 year of age when risk of neurotoxicity is lower)

  Surgical excision/debulking

Function threatening IH (i.e., periorbital) IH where scarring/anetoderma are expected (i.e., large, pedunculated or painfully ulcerated IH)

Laser ablation   Pulsed dye laser (595 nm)

  Bare-fiber (Nd:YAG)

Ulcerated hemangiomas Superficial IH later in course as treatment for residual superficial IH to accelerate involution or treat residual skin changes. (Should be avoided in the early proliferative phase) Deep IH in life or function threatening areas

Bleeding Ulceration Atrophy Infection HPA suppression (when large volumes injected) Anaphylaxis Rare potential for retinal artery occlusion Crusting Inflammation Ulceration Flu-like illness (theoretical)

VASCULAR TUMORS

TOPICAL TREATMENTS

Irritability Sleep disturbance Gastrointestinal upset Weight gain Hypertension Growth delay, HPA suppression, immunosuppression Infection Hirsutism Iatrogenic Cushing’s syndrome Hypoglycemia Bradycardia Hypotension Potential asthma exacerbation Constipation Abdominal pain Ileus Bone pain Immunosuppression Neurotoxicity Myalgia Flu-like symptoms Cytopenias Transaminitis Thyroiditis Neurotoxicity, i.e., spastic diplegia (more common in younger infants 150) have been reported. HTH has been observed as both a congenital and acquired vascular neoplasm and there are some reports of this entity occurring after trauma.155 HTT presents as a solitary, annular, pink to violaceous and sometimes hyperpigmented plaque, favoring the trunk and extremities. It has a tendency to fill with blood and then resolve over weeks leaving a hemosideric pattern. The differential diagnosis can include benign and malignant neoplasms, such as IH, fibrous histiocytoma, dermatofibroma, melanocytic nevi, Kaposi’s sarcoma and dermatofibrosarcoma protuberans. Histologically, it is characterized by a dermal vascular neoplasm with a single layer of endothelial cells having an epithelioid or ‘hobnail’ appearance as they line the vascular lumina and intraluminal papillary projections are sometimes observed within the vascular spaces. In the deeper dermis, vascular spaces become more slitlike. Extravasated erythrocytes, hemosiderin deposition, a lymphocytic infiltrate, and intravascular thrombi may be present.155,156 The origin of these benign vascular tumors is controversial; however recent studies suggest a lymphatic origin due to the nature of the histopathology and the positive staining for D2– 40, a marker of lymphatic differentiation leading some to view HTH as part of the spectrum of hobnail hemangiomas.157 There are some reports of episodic or cyclic morphologic changes in HTH, which can help to differentiate them from other entities such as angiokeratomas.158

hemangiopericytoma-like pattern is not distinctive, but seen in many benign and malignant neoplasms (synovial sarcomas, mesenchymal chondrosarcomas, infantile fibrosarcomas and others). Some authors believe that the hemangiopericytoma pattern represents a clinical spectrum of myofibroblastic tumors with pericytic origin, although there are many reports of ‘true hemangiopericytoma’.160 Clinically, these soft tissue tumors resemble infantile myofibromas. While controversial, some pathologists suggest that hemangiopericytoma may be a true entity or a histologic pattern.161

VASCULAR MALFORMATIONS Vascular malformations are congenital lesions composed of anomalous blood vessels and/or lymphatics lined by a quiescent endothelium without cellular hyperplasia.2 Although it is believed that all vascular malformations are present at birth, many only become evident in infancy and a minority appear in childhood or later. Rarely, they may present after episodes of trauma or with hormonal influences of puberty or pregnancy (see below) but the anomalous vessels are present from birth. Depending on their flow characteristics, vascular malformations are defined as either slow or fast flow. The slow-flow anomalies include capillary, venous, and lymphatic malformations and combinations thereof. Fast flow malformations include arterial malformations, arteriovenous malformations (AVMs) and arteriovenous fistulae (AVF). Vascular malformations persist lifelong, unchanged, growing proportionate to the child’s growth, or slowly expanding over many years. They never regress spontaneously and only rarely go through a rapid growth phase such as is seen with IH. Growth in vascular malformations may be stimulated by trauma, clotting, the effects of hormones during puberty and/or pregnancy, or may occur in the absence of any known triggering factor.

Pathogenesis

Described in 1942 by Stout and Murray, hemangiopericytoma was originally thought to be a distinct neoplasm due to its characteristic histologic findings of ‘staghorn’ branched vascular spaces.159 It became clear that this characteristic

Vascular malformations represent errors in the development of blood vessels, most likely caused by dysfunction in pathways regulating vascular embryogenesis, especially the molecular events responsible for vascular remodeling.162 Over the past several years, the genetic basis for many vascular malformations and some corresponding syndromes have become well elucidated. The study of rare families with Mendelian inheritance of their vascular malformations has enhanced our understanding of molecular genetics in this field.163 Mutant genes responsible

152. Nakatsui C, Schloss E, Krol A, et al. Eccrine angiomatous hamartoma: report of a case and literature review. J Am Acad Dermatol. 1999;41: 109–111. 153. Requena L, Sangueza OP. Cutaneous vascular anomalies. Part I. Hamartomas, malformations, and dilation of preexisting vessels. J Am Acad Dermatol. 1997;37:523–549. 154. Santa Cruz DJ, Aronberg J. Targetoid hemosiderotic hemangioma. J Am Acad Dermatol. 1988;19:550–558. 155. Christenson LJ, Stone MS. Trauma-induced simulator of targetoid hemosiderotic hemangioma. Am J Dermatopathol. 2001;23:221–223. 156. Mentzel T, et al. Hobnail hemangioma (’targetoid hemosiderotic hemangioma’): clinicopathologic and immunohistochemical analysis of 62 cases. J Cutan Pathol. 1999;26:279–286. 157. Franke FE, Steger K, Marks A, et al. Hobnail hemangiomas (targetoid hemosiderotic hemangiomas) are true lymphangiomas. J Cutan Pathol. 2004;31:362–367.

158. Carlson JA, Daulat S, Goodheart HP. Targetoid hemosiderotic hemangioma – a dynamic vascular tumor: report of 3 cases with episodic and cyclic changes and comparison with solitary angiokeratomas. J Am Acad Dermatol. 1999;41(2 Pt 1):215–224. 159. Gengler C, Guillou L. Solitary fibrous tumour and haemangiopericytoma: evolution of a concept. Histopathology. 2006;48:63–74. 160. Mentzel T, Calonje E, Nascimento AG, et al. Infantile hemangiopericytoma versus infantile myofibromatosis. Study of a series suggesting a continuous spectrum of infantile myofibroblastic lesions. Am J Surg Pathol. 1994;18: 922–930. 161. Nappi O, Ritter JH, Pettinato G, et al. Hemangiopericytoma: histopathological pattern or clinicopathologic entity? Semin Diagn Pathol. 1995;12:221–232. 162. Chiller KG, Arbiser IJ, Frieden IJ. Vasculogenesis and angiogenesis in the development of cutaneous vascular birthmarks. Submitted; 2001. 163. Vikkula M, Boon LM, Mulliken JB. Molecular basis of vascular anomalies. Trends Cardiovasc Med. 1998;8:281–292.

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VASCULAR MALFORMATIONS

with increased hair and sweating at the site of the lesion.152,153 The extremities and abdomen are the usual sites of involvement. Pain may be present. The diagnosis is established by the characteristic histologic findings of closely packed eccrine sweat glands in association with dilated capillaries and venous channels within a dense collagenous matrix. These congenital hamartomas tend to persist and some become more prominent with time.

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for familial venous malformations, glomuvenous malformations, arteriovenous malformations, lymphedema, cerebral cavernomas, hereditary hemorrhagic telangiectasia (HHT), and ataxia-telangiectasia have been identified. The functions of these mutations, and how they affect signaling pathways between endothelial cells and other mural cells, are currently being investigated. Although the literature and nosology of vascular anomalies are still confusing to those not familiar with the field, the establishment of the simple and clinically useful classification framework by Mulliken and Glowacki for vascular malformations has made the understanding and natural history of these lesions far easier. In the past, the heterogeneous yet similar presentations of vascular anomalies made classification difficult. Emerging research on the genetic and molecular basis of several types of vascular malformations helps to explain the incomplete penetrance, variable expressivity and multifocality of lesions in inherited and sporadic cases of venous, glomuvenous and arteriovenous malformations.164

CAPILLARY MALFORMATIONS Capillary malformations are the most common vascular malformation. They involve vessels of the capillary network in skin and mucous membranes. Capillary malformations may be isolated and innocuous, may cause disfigurement and stigmatization, and, in some cases, may herald the presence of an extracutaneous disease.

Salmon patches The most common vascular lesion in infancy is the salmon patch, also known as nevus simplex, erythema nuchae, angel’s kiss, and stork-bite. The term nevus flammeus is synonymous with port-wine stain (PWS) and should not be used to describe a salmon patch. Salmon patches are best classified as a superficial vascular malformation, although its course is typically different from that of the PWS. They consist of ectatic capillaries that represent the persistence of fetal circulatory patterns in the skin. Hypothetically, their disappearance may be based on maturation of the autonomic innervation of the vessels in early infancy. The salmon patch is present at birth in about 40% of infants and appears as a pink-to-red macule on the nape or the neck, glabella, forehead, and upper eyelids. The nasolabial region, the parietal and occipital scalp and overlying the thoracic or lumbosacral spine (Fig. 20.20) are less commonly affected and disappear more slowly. In contrast to a PWS, salmon patches are usually located in the central portion of the face and do not follow a dermatomal distribution. Many infants have salmon patches in several locations. Of those infants born with salmon patches, 81% have lesions at the nape of the neck, 45% on the eyelids, and 33% on the glabella.165,166 Some authors believe that radiographic studies of the lumbosacral area are not indicated when a butterfly-shaped salmon

164. Brouillard P, Vikkula M. Genetic causes of vascular malformations. Hum Mol Genet. 2007;16:R140–R149. 165. Leung AK, Telmesani AM. Salmon patches in Caucasian children. Pediatr Dermatol. 1989;6:185–187. 166. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics. 1976;58:218–222.

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Figure 20.20  Salmon patch (nevus simplex). Note that in addition to the glabella and upper eyelids – the most common sites of involvement – the nose and upper lip are often affected (Courtesy of Howard Pride).

patch is present while others suggest routine imaging studies of the lumbar spine in patients with a midline cutaneous vascular malformation, because it can be a marker of occult spinal dysraphism.167,168 Salmon patches of the face are, in rare instances, a manifestation of other diseases. Prominent and persistent salmon patch (often referred to as a midline facial nevus flammeus) has been described in the Beckwith–Wiedemann syndrome and macrocephaly–capillary malformation syndrome (formerly known as M-CMTC, macrocephaly-cutis marmorata telangiectatica congenita). In Nova syndrome, glabellar salmon patches are reported as an autosomal dominant trait in association with posterior fossa brain malformations.169 Usually, no treatment of salmon patches is necessary, as most of those on the face fade by 1–2 years.165 The nuchal lesions tend to be more persistent and are present in many adults. If salmon patches do not fade completely, they can be effectively treated with a pulsed dye laser (PDL). Nuchal salmon patches may occur in association with a hemangioma, as an overlap between vascular malformation and vascular tumor (Fig. 20.1)3 and it is not uncommon for infants to develop a superimposed eczematous dermatitis within the affected areas, particularly the nuchal area.

Port-wine stains (PWS, nevus flammeus) Port-wine stains are a common form of capillary malformation, occurring in 0.3% of all newborns; they have an equal sex distribution.166 They are present at birth and do not undergo

167. Metzker A, Shamir R. Butterfly-shaped mark: a variant form of nevus flammeus simplex. Pediatrics. 1990;85:1069–1071. 168. Ben-Amitai D, Davidson S, Schwartz M, et al. Sacral nevus flammeus simplex: the role of imaging. Pediatr Dermatol. 2000;17:469–471. 169. Nova H. Familial communicating hydrocephalus, posterior cerebellar agenesis, mega cisterna magna, and port-wine nevi. Report on five members of one family. J Neurosurg. 1979;51:862–865.

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V1

V2

VASCULAR MALFORMATIONS

V3

Figure 20.22  Anatomic drawing of trigeminal dermatomes. Note the blackened area – the so-called V1–V2 watershed area, which can be enervated by either V1 or V2. (Reprinted with permission from Enjolras O, Garzon MC. Vascular stains, malformations, and tumors. In: Eichenfield LF, Frieden IJ,   Esterly NB, eds. Textbook of neonatal dermatology. Philadelphia: WB Saunders; 2001:332).

Figure 20.21  Capillary malformation (port-wine stain) involving both V1 and V2 dermatomes (Courtesy Dr A. Lucky).

spontaneous resolution. These well-demarcated vascular stains grow in proportion to the growth of the child. They are usually unilateral and segmental, usually respecting the midline; occasionally there is a contralateral component in the same or adjacent dermatome. The stain may appear on any area of the body. In a review of 310 patients with PWS, 85% were unilateral, 15% were bilateral, and 68% had more than one dermatome involved. In this group, 8% of PWS involving the V1 dermatome were associated with ocular or CNS involvement, but this figure increased to 25% if there was bilateral V1 or complete involvement of all three trigeminal dermatomes (Figs 20.21, 20.22).170 PWS are usually pink or red during infancy. They often appear to lighten in the first 1–6 months of life, probably because of the marked drop in circulating blood hemoglobin concentration during this time period.171 This lightening should not be interpreted as an indication of spontaneous resolution which rarely, if ever, occurs. PWS often darken to a dull erythrocyanotic or purple hue with advancing age. Although most are initially macular, the surface may become irregular, thickened, and nodular during adulthood. Progressive ectasias manifested by thickening and nodularity of the PWS develop over time. This feature is frequent in facial PWS but is less commonly observed in those located on the trunk and limbs.172 Pyogenic

granulomas may arise within PWS, presenting as small vascular papules or nodules.3 A relatively common change is the development of dermatitis overlying a PWS, a finding which can also be seen in salmon patches. This can occur before or after laser therapy. Histopathologically, a PWS is composed of normal numbers of ectatic mature capillaries in the superficial dermis with no evidence of cellular proliferation. These vessels become more dilated over time and are found in the deep dermis and subcutaneous tissue when the clinical lesion is raised or nodular.29 Dermatoscopic evaluation of capillary malformations usually reveals horizontal telangiectasias representative of vessels in the superficial aspect of the dermis, while deeper plexus vessels are seen as pinpoint erythematous globules representing their perpendicular arrangement. Loosely arranged collagen fibers surround the ectatic vessels.173 Studies have demonstrated a decrease in the number of nerves surrounding the abnormal blood vessels. Progressive vascular dilatation is thought to be a result of impairment of neural control of the vascular elements.174 Other studies have documented impaired neural regulation of blood flow in PWS.175 Although almost all PWS are present at birth, rare instances of later onset lesions have been documented. These ‘acquired’ PWS sometimes develop after injury to the skin or in association with the use of oral contraceptives. Acquired telangiectatic nevus might be a more accurate term for these puzzling lesions.176–178 Differential diagnosis includes mastocytosis (the telangiectasia

170. Tallman B, Tan OT, Morelli JG, et al. Location of port-wine stains and likelihood of ophthalmic and or central nervous system complications. Pediatrics. 1991;87:323–327. 171. Cordoro KM, Speetzen LS, Koerper MA, et al. Physiologic changes in vascular birthmarks during early infancy: Mechanisms and clinical implications. J Am Acad Dermatol. 2009;60:669–675. 172. Klapman MH, Yao F. Thickening and nodules in port-wine stains. J Am Acad Dermatol. 2001;44:300–302. 173. Lever W, Schaumburg-Lever G. Histopathology of the Skin. 7th ed. Philadelphia: Lippincott, Williams and Wilkins; 1990.

174. Smoller B, Rosen S. Port wine stains. A disease of altered neural modulation of blood vessels? Arch Dermatol. 1986;122:177–179. 175. Gaylarde PM, Dodd HJ, Sarkany I. Port wine stains. Arch Dermatol. 1987;123:861. 176. Colver GB, Ryan TJ. Acquired port wine stains. Arch Dermatol. 1986;122:1415–1416. 177. Goldman L. Oral contraceptives and vascular anomalies. Lancet. 1970;ii:108–109. 178. Tsuji T, Sawabe M. A new type of telangiectasia following trauma. J Cutan Pathol. 1988;15:22.

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macularis eruptiva perstans type) and telangiectasias occurring in aluminum workers.179 PWS can occur as isolated cutaneous lesions or in association with other abnormalities. Although a midline PWS alone, without other associated hallmarks (e.g., fatty mass, dimple, tuft of hair), is very rarely associated with dysraphism,180 some physicians still recommend the evaluation of these areas with ultrasound (very early in infancy) or MR imaging. Neurogenic bladder and accompanying voiding dysfunction may be the initial symptom of tethered spinal cord and once established may be irreversible. Sturge–Weber syndrome (SWS), Klippel–Trenaunay (KT) and Proteus syndrome all feature PWS as a clinical manifestation. Rarely, lesions resembling PWS occur overlying AVMs and in rare disorders such as Cobb syndrome, capillary malformationarteriovenous malformation (CM-AVM syndrome), Bonnet– Dechaume–Blanc, or Wyburn–Mason syndromes. In some patients, the PWS-like area is the only indication of an underlying AVM. The genetic mutation RASA1 has been linked to the development of AVMs and associated syndromes such as CM-AVM and Parkes Weber syndrome (see below).181 The development of lasers that selectively ablate vascular lesions has greatly advanced our ability to treat PWS and other vascular anomalies, and the rationale for treatment, including psychosocial issues, has been well documented.182 PWS, especially when located on visible skin such as the face, can invoke teasing and stigmatization, causing significant emotional distress in affected children.183,184 Treatment in childhood can potentially prevent the superficial thickening and vascular nodules that develop over time in many PWS, although it is unlikely to affect deeper soft-tissue hypertrophy. The mainstay of treatment is the flashlamp-pumped pulsed dye laser (PDL), typically using wavelengths between 585 and 595 nm and a pulse duration between 0.45 and 1.5 ms, ideally with a cooling device to minimize thermal damage. PDLs have been used in children and adults for more than 10 years and have a low risk of scarring and high percentage of clinical response (Fig. 20.23). Although initial reports emphasized complete clearing,185 most patients achieve lightening but not complete clearance. Multiple treatments (typically ≥4–6) are needed to achieve maximal response, but the response itself is based on a number of factors including the size and location of the PWS. Lateral facial PWS have a much better response than those that are medial. Very large PWS, those located in a V2 distribution, or those involving the extremities also respond, but not as well as lesions in other sites (Fig. 20.24). Transient skin darkening is common but the risk of scarring is

179. Theriault G, Cordier S, Harvey R. Skin telangiectases in workers at an aluminum plant. N Engl J Med. 1980;303:1278–1281. 180. Tavafoghi V, Ghandehi A, Hambrick G, et al. Cutaneous signs of spinal dysraphism. Arch Dermatol. 1978;114:573–577. 181. Revencu N, Boon LM, Mulliken, et al. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29:959–965. 182. Strauss RP, Resnick SD. Pulsed dye laser therapy for port wine stains in children: psychosocial and ethical issues. J Pediatr. 1993;122: 504–510. 183. Lanigan SW, Cotterill JA. Psychological disabilities amongst patients with port wine stains. Br J Dermatol. 1989;121:209–215. 184. Troilus A, Wrangsjö B, Ljunggren B. Potential psychological benefits from early treatment of port-wine stains in children. Br J Dermatol. 1998;139: 59–65.

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A

B

Figure 20.23  Telangiectatic port-wine stain. (A) Before laser treatment. (B) Complete resolution after three laser treatments.

low. Some authors have reported that earlier treatment results in better clearance;186,187 others disagree.188 Re-darkening of PWS at 10 years post-treatment has been documented, and touch-up treatments may be needed even after good responses. Parents and patients must be counseled about these issues prior to beginning treatment.189 Laser treatments are typically performed every 1–3 months, allowing for maximal lightening of the lesion prior to subsequent treatment. The type of anesthesia necessary for treatment with PDL varies depending upon the age of child, location and the size of the PWS. Older children and those with small, welllocalized PWS can be treated without general anesthesia or sedation with the use of topical local anesthetics; however many younger patients, particularly those with larger PWS, require general anesthesia.

Sturge–Weber syndrome (SWS) (encephalotrigeminal angiomatosis) SWS is the triad of a facial PWS in a V1 distribution (Fig. 20.21), an ipsilateral leptomeningeal vascular malformation, and a

185. Tan OT, Sherwood K, Gilchrest BA. Treatment of children with port wine stains using the flashlamp-pulsed tunable dye laser. N Engl J Med. 1989;320:416–421. 186. Ashinoff R, Geronemus RG. Flashlamp-pumped pulsed dye laser for port wine stains in infancy: earlier versus later treatment. J Am Acad Dermatol. 1991;24:467–472. 187. Nguyen CM, Yohn JJ, Huff C, et al. Facial port-wine stains in childhood: prediction of rate of improvement as a function of the age of the patient, size and location of the port-wine stain, and the number of treatments with the pulsed dye (585 nm) laser. Br J Dermatol. 1998;138:821–825. 188. van der Horst CM, Koster PH, de Borgie CA, et al. Effect of the timing of treatment of port-wine stains with the flashlamp pumped pulsed dye laser. N Eng J Med. 1998;338:1028–1033. 189. Huikeshoven M, Koster PHL, de Borgie CAJM, et al. Redarkening of port-wine stains 10 years after pulsed-dye-laser treatment. N Engl J Med. 2007;356:1235.

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Figure 20.24  Port-wine stain V2 dermatome.

A

VASCULAR MALFORMATIONS

(A) Before laser treatment. (B) After eight laser treatments the lesion is considerably lighter but still persists.

B

choroidal vascular malformation of the eye, which can lead to ipsilateral glaucoma and buphthalmos. There is no clear evidence of a genetic predisposition, and the etiology remains unknown. The anatomic areas of involvement (skin, brain, eye) are all derivatives of the mesoectoderm. Theoretical causes of this disorder include an error of morphogenesis within the cephalic neural crest and lethal genes surviving by mosaicism.190,191 PWS in SWS follows the distribution of the first branch of the trigeminal nerve. Consequently, the PWS typically involves the forehead and upper eyelid. The distribution of V1 varies somewhat; it can involve the skin below the eye and the nose in some patients; however PWS that spare the upper face and eyelids are almost never associated with an intracranial vascular malformation (Fig. 20.22).190 Approximately 8–10% of patients with a PWS in the V1 distribution have SWS. Extensive and bilateral involvement including other trigeminal dermatomes may also occur, but the midline is respected in most cases. In infants with bilateral involvement of the V1 areas, there is often an association with other stains on the face and body, but only one side of the brain and eye is usually affected. Bilateral brain lesions, observed in about 15% of patients (including some patients with hemifacial PWS) carry a greater risk of neurologic impairment.191 There is no direct relationship between the size of the PWS and the severity of the brain lesion in affected patients.192 Patients may have partial forms of SWS, with only eye or only CNS involvement. Individuals with typical CNS or eye findings of SWS without a facial PWS have been reported.193 Common neurologic abnormalities include contralateral seizures, episodes

of contralateral hemiparesis or hemiplegia, headaches, and intellectual impairment. Seizures are usually of the focal motor or generalized tonic-clonic types. They usually have their onset before one year of age. Developmental delay in motor and cognitive skills is seen in about half of the affected children. Continued seizures can worsen CNS outcomes. Extensive brain lesions also contribute to poor intellectual development, behavioral abnormalities, and learning disabilities. Ocular abnormalities are common. Glaucoma develops in approximately half of the patients with V1 involvement and occurs independent of neurologic involvement. The precise cause of elevated intraocular pressure is unknown, but more than one mechanism is probably involved. Hyperemia of the ciliary body, anomalies of the anterior chamber angle structures, and abnormal arteriovenous communications in the episcleral vascular plexus may all play a role in the pathogenesis of glaucoma in SWS.194 Ophthalmologic examination at regular intervals (every 6–12 months) should be performed in all those affected, as glaucoma can develop early and should be tested for as soon as possible. Long-term follow-up is important because glaucoma can develop later in life. Early detection of increased intraocular pressure is important in order to prevent progressive disease. For 60% of patients with SWS and glaucoma, onset is at birth or in infancy, when the eye may stretch because of the increased intraocular pressure; these infants have an enlarged cornea, buphthalmos (bull eye – large eye), and myopia. For the other 40%, glaucoma begins in childhood or adulthood and there is no eye enlargement.195

190. Enjolras O, Riche MC, Merland JJ. Facial port wine stains and Sturge– Weber syndrome. Pediatrics. 1985;76:48–51. 191. Happle R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol. 1987;16: 899–906. 192. Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, et al. Sturge–Weber syndrome: study of 55 patients. Can J Neurol Sci. 2008;35: 301–307.

193. Martinez-Bermejo A, Tendero A, Lopez-Martin V, et al. Angiomatosis leptomeningea sin angioma facial. Debe considerarse como variante del syndrome de Sturge Weber? Rev Neurol. 2000;30:837–841. 194. Celebi S, Alagoz G, Aykan U. Ocular findings in Sturge–Weber syndrome. Eur J Ophthalmol. 2000;10:239–243. 195. Cheng KP. Ophthalmologic manifestations of Sturge–Weber syndrome. In: Bodensteiner JB, Roach ES, eds. Sturge–Weber syndrome. Mt Freedom: Sturge–Weber Foundation; 1999:17–26.

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Most affected children are initially neurologically normal, but neuroimaging studies should be performed to detect brain involvement. MR imaging with gadolinium enhancement is the most useful study for detection of SWS, because it provides clear identification of increased blood vessels as well as any accompanying cortical atrophy. MRI occasionally fails to detect small areas of vascular malformation in infants 1–2 cm difference in limb length. Those with significant differences in length should be referred for orthopedic evaluation. Non-invasive arterial/venous evaluation with ultrasonography/Doppler is preferred to conventional contrast angiography and contrast venography during childhood. MR imaging207 is the single best method for evaluation and delineation of the extent of the disorder. MR angiography and venography will demonstrate the anomalous vessels, located in the skin and subcutis, and indicate whether muscle involvement is present, although, in contrast to venous malformations, muscle involvement is very uncommon. MR lymphography, a new non-invasive tool, is useful for differentiating veins from lymphatics as enlarged axial and extra-axial lymphatic channels may be seen in children with KT syndrome.207 Pelvic, intestinal, and/or bladder vascular anomalies may be associated. Treatment of this condition is usually aimed at controlling symptoms and is, in general, conservative.208,209 Compression stockings are a mainstay of treatment, but accurate fitting for these stockings is not usually practical until the child is 2 or 3 years of age. Compressive wraps may be used in younger infants with significant venous congestion. Intermittent pneumatic compression devices can reduce limb size and control varicosities. This modality can be combined with use of elastic garments to provide continuous compression. Surgical correction of varicose veins is controversial; whereas some feel it is contraindicated, others feel it may be beneficial as long as the deep venous system is intact.205 Most patients do relatively well with compression alone. Debulking of soft tissue may be indicated to restore

function of the affected extremities; it carries a high risk of longterm complications (severe scarring, fibrosis, and pedal edema). Orthopedic management is mandatory in deciding whether epiphysiodesis will be necessary in early puberty, as a means of equalizing the limbs if discrepancy in length is significant. Other abnormalities have been described in association with KT syndrome, including the association with SWS, ocular anomalies, glaucoma, and retinal exudative vascular masses. Lymphatic obstruction, lymphatic involvement of the lungs,210 non-immune hydrops fetalis, severe menorrhagia,211 cerebral aneurysm, gastrointestinal hemorrhage,212 and pulmonary embolism213 have been reported. Many orthopedic abnormalities have been noted to occur in these patients, including polydactyly and syndactyly that may suggest possible Proteus syndrome. Patients frequently have a low-grade coagulopathy similar to that seen with venous malformations (see discussion below) and may benefit from low-dose aspirin or other anticoagulation regimes such as low-molecular weight heparin. Coagulation parameters, particularly D-dimers and fibrinogen but also PT and PTT, should be checked periodically in these patients. In KT patients, particularly those with larger ectatic leg veins, there is also a risk of enlarged pelvic veins and deep vein thrombosis resulting in pulmonary emboli. Placement of an inferior vena cava filter may decrease this risk or prevent recurrence of pulmonary emboli in selected cases.214 The differential diagnosis of KT syndrome includes extensive pure venous malformations of the extremities,215 the subset of patients with reticulate PWS and proportionate overgrowth, Parkes Weber, and Maffucci syndromes or other overgrowth syndromes such as Proteus. KT should also be differentiated from Servelle–Martorell syndrome, which is the association of capillary malformation and varicose veins with relative undergrowth rather than overgrowth of the affected limb.216

205. Gloviczki P, Stanson AW, Stickler GB, et al. Klippel–Trenaunay syndrome: the risks and benefits of vascular interventions. Surgery. 1991;110:469. 206. Aelvoet GE, Jorens PG, Roelen LM. Genetic aspects of the Klippel– Trenaunay syndrome. Br J Dermatol. 1992;126:603–607. 207. Laor T, Hoffer FA, Burrows PE, et al. MR lymphangiography in infants, children and adults. Am J Roentgenol. 1998;171:1111–1117. 208. Rogalski R, Hensinger R, Loder R. Vascular abnormalities of the extremities: clinical findings and management. J Pediatr Orthopaed. 1993;13:9–14. 209. Berry SA, Peterson C, Mize W, et al. Klippel–Trenaunay syndrome. Am J Med Genet. 1998;79:319–326. 210. Joshi M, Cole S, Knibbs D, et al. Pulmonary abnormalities in Klippel– Trenaunay syndrome. Chest. 1992;102:1274. 211. Markos AR. Klippel–Trenaunay syndrome – a rare cause of severe menorrhagia. Br J Obstet Gynaecol. 1987;94:1105. 212. Azizkhan RG. Life-threatening hematochezia from a rectosigmoid vascular malformation in Klippel–Trenaunay syndrome: long term palliation using an argon laser. J Pediatr Surg. 1991;26:1125.

213. Gianlupi A, Harper R, Dwyre D, et al. Recurrent pulmonary embolism associated with Klippel–Trenaunay–Weber syndrome. Chest. 1999;115: 1199–1201. 214. Gianlupi A, Harper RW, Dwyre DM, et al. Recurrent pulmonary embolism associated with Klippel–Trenaunay–Weber syndrome. Chest. 1999;115: 1199–1201. 215. Enjolras O, Ciabrini D, Mazoyer E, et al. Extensive pure venous malformations in the upper or lower limb, a review of 27 cases. J Am Acad Dermatol. 1997;36:219–225. 216. Mattassi R. Differential diagnosis in congenital vascular-bone syndromes. Semin Vasc Surg. 1993;6:233–244. 216a.  Wright DR, Frieden IJ, Orlow S, et al. The misnomer “macrocephaly-cutis marmorata telangiectatica congenita syndrome”: report of 12 new cases and support for revising the name to macrocephaly-capillary malformations. Arch Dermatol. 2009;145:287–293. 216b.  Toriello HV, Mulliken JB. Accurately renaming macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) as macrocephaly-capillary malformation (M-CM). Am J Med Genet A. 2007;143A:3009.

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Macrocephaly–cutis marmorata syndrome (macrocephaly-CM syndrome (M-CM, OMIM 602501) Macrocephaly-CM syndrome, previously known as macrocephaly-cutis marmorata telangiectatic congenita (M-CMTC), is a rare sporadic condition characterized by capillary malformation or persistent nevus simplex with macrocephaly, neonatal hypotonia, and developmental delay.216a, 216b

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Figure 20.26  (A,B) Phakomatosis pigmentovascularis type II (Both courtesy   Dr A. Torrelo).

VASCULAR MALFORMATIONS

A B

The cutaneous manifestation is typically a blotchy, ill-defined capillary malformation and should not be confused with CMTC as it lacks the fixed livedo pattern and cutaneous atrophy that are seen in typical CMTC. The capillary malformation is usually on the face, with the philtrum and glabella commonly involved. Other associated features include hydrocephalus, seizures, developmental delay, connective tissue defects (soft skin, joint hypermobility), toe syndactyly, frontal bossing, and, rarely, hemihypertrophy.

Phakomatosis pigmentovascularis Phakomatosis pigmentovascularis consists of an extensive PWS accompanied by either melanocytic or epidermal hamartomas. The melanocytic lesions may be persistent dermal melanocytosis (Fig. 20.26) or a speckled lentiginous nevus.217,218 The macules of dermal melanocytosis resemble Mongolian spots and are often present at sites other than the lumbosacral region. In most cases, these lesions are extensive. Four distinct types of phakomatosis pigmentovascularis, all characterized by a PWS and either a pigmented or an epidermal nevus, have been described. Type I has an associated epidermal nevus; type II has dermal melanocytosis (ectopic Mongolian spots) with or without nevus anemicus; type III has a speckled lentiginous nevus with or without nevus anemicus; and type IV has dermal melanocytosis and a speckled lentiginous nevus with or without nevus anemicus. Additional subtypes further classify the disorder as to the absence (type a) or presence (type b) of systemic manifestations. Happle has proposed that phakomatosis pigmentovascularis is caused by so-called ‘twin spotting.’219

217. Ruiz-Maldonado R, Tamayo L, Laterza AM, et al. Phakomatosis pigmentovascularis: a new syndrome? Report of 4 cases. Pediatr Dermatol. 1987;4:189–196.

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Telangiectasia Telangiectasias are dilated small vessels that may or may not blanch on diascopy. They appear on the skin and mucous membranes as small, red, linear, stellate or punctate markings. There are many causes of secondary telangiectasia, such as rosacea, actinic or radiologic damage; various connective tissue diseases; mastocytosis; poikiloderma; prolonged application of topical corticosteroids; and miscellaneous genodermatoses. Primary telangiectases include spider angioma, angioma ser­ piginosum, HHT, ataxia telangiectasia, generalized essential telangiectasia, hereditary benign telangiectasia, and unilateral nevoid telangiectasia.

Spider angioma (nevus araneus) Spider angioma is the most common of the telangiectases. In adults, spider angiomas frequently develop in large numbers during pregnancy and are also characteristically associated with liver disease. In childhood, they are commonly found in the absence of systemic disorders. Lesions are composed of small telangiectases radiating from a central point in fine hair-like branches. The central point is an arteriole from which the superficial blood vessels radiate peripherally. Blood flow from the arteriole is centrifugal, thus gradually increasing pressure over the central vessel will cause blanching of the lesion in a centripetal fashion. This phenomenon helps differentiate spider angioma from other telangiectases. In childhood, lesions appear most commonly on sun exposed areas including the face (malar areas), upper trunk, arms, and

218. Guiglia MC, Prendiville JS. Multiple granular cell tumors associated with giant speckled lentiginous nevus and nevus flammeus in a child. J Am Acad Dermatol. 1991;24:359–362. 219. Happle R. Allelic somatic mutations may explain vascular twin nevi. Hum Genet. 1991;86:321–322.

hands. They are never present at birth but may be detectable after 2 years of age, reaching a frequency of 30% of children by age 4, and 40% by age 8. The prevalence figures start to decline in the early teens to approximately 10–15% in the adult population.220 From these data, it is clear that >50% of spider nevi disappear by adult life. Therapy, when desired for cosmetic reasons, consists of gentle electrodesiccation of the central vessel or ablation of the lesion by PDL. Almost immediately after coagulating the central vessel, all the branches disappear. Therapy is cosmetic and can be delayed until puberty as many of the lesions disappear spontaneously.

The autosomal-dominant mucocutaneous and visceral vascular malformation disorder hereditary hemorrhagic telangiectasia (HHT) is heterogeneous in terms of age of onset and clinical

expression. It is defined by clinical characteristics, including autosomal dominance, mucocutaneous telangiectasias, epistaxis, and arteriovenous malformations. The skin lesions are rarely seen early, generally becoming evident during the third or fourth decade. The lesions develop primarily on the face, lips, nasal mucosa, tongue, palms, and palate, and can also be found in the nail beds, on the soles of the feet, and on the tympanic membrane. They are dark red and slightly elevated, with an ill-defined border and radiate from an eccentrically placed punctum. Recurrent epistaxis from telangiectases in the nasal septum and inferior turbinates is the presenting sign in over 50% of individuals and occurs in approximately 80% of patients at some time during the course of their disease.222,223 Gastrointestinal hemorrhage is the second most common complication, occurring in about 40% of affected individuals; unlike epistaxis, onset of this complication is rare before midlife. Bleeding may occur from lesions in the upper and lower bowel, but despite careful evaluation by endoscopy and radiologic studies, the bleeding site may remain undetermined. Bleeding is chronic and recurrent, and tends to be progressive as new telangiectases appear. About 15–30% of patients have pulmonary AVMs224 and this can be a relatively early manifestation of disease. Patients may be asymptomatic or may exhibit dyspnea, cyanosis, fingernail clubbing, and polycythemia; ischemic and septic neurologic complications may ensue as a result of these lesions.222,223,225 A small number of affected individuals have cerebral telangiectases, aneurysms, and AVMs of the brain and spinal cord, giving rise to focal and generalized neurologic deficits. Hepatic AVMs can cause liver enlargement and portal hypertension. HHT involves mainly capillaries but arteries, veins and arteriovenous fistulae, and the combinations of vessels may be affected in different patients. Cutaneous telangiectases are composed of a subepidermal tortuous mass of dilated capillaries and postcapillary venules with thinned walls comprising a single layer of endothelium. Improved understanding of molecular genetics has helped to explain the previously obscure heterogeneity of HHT. There are various phenotypes and genotypes. Identification of two genes endoglin (for HHT type 1) and ALK-1 (for HHT type 2), both of which can be affected by differing intragenic mutations, have brought new insights in the pathogenesis of HHT, as well as the hope of new treatments.226 Endoglin and ALK-1 proteins are specific endothelial receptors of the transforming growth factor (TGF)-β superfamily that are essential for vascular integrity.227 Many mutations have been identified in ENG and ACVRL1 genes and support the haploinsufficiency model for HHT.228 Genotype– phenotype correlations are not yet completely defined; however, pulmonary AVMs are more common in HHT1 than in HHT2, and hepatic AVMs are more common in HHT2, which tends to have a more benign course.225 Other genes may be involved, as

220. Wenzl JR, Burgert EO. The spider nevus in infancy and childhood. Pediatrics. 1964;33:227–232. 221. Stevenson JR, Lincoln CS. Angioma serpiginosum. Arch Dermatol. 1967;95:16–22. 222. Porteous MEM, Burn J, Proctor SJ. Hereditary hemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992;29:527. 223. Reilly PJ, Nostrant TT. Clinical manifestations of hereditary hemorrhagic telangiectasia. Am J Gastroenterol. 1984;79:363. 224. Cottin V, Blanchet AS, Cordier JF. Pulmonary manifestations of hereditary hemorrhagic telangiectasia. Rev Mal Respir. 2006;23:4S53–4S66.

225. McDonald JE, Miller FJ, Hallam SE, et al. Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. Am J Med Genet. 2000;93:320–327. 226. Azuma H. Genetic and molecular pathogenesis of hereditary hemorrhagic telangiectasia. J Med Invest. 2000;47:81–90. 227. Fernández LA, Sanz-Rodriguez F, Blanco FJ, et al. Hereditary hemorrhagic telangiectasia, a vascular dysplasia affecting the TGF-beta signaling pathway. Clin Med Res. 2006;4:66–78. 228. Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. J Med Genet. 2006;43:97–110.

Angioma serpiginosum Angioma serpiginosum is a distinctive, rare, acquired vascular malformation involving the capillaries of the dermis. The onset is usually in childhood, and 90% of the reported cases have been in females.221 The primary lesion consists of an asymptomatic vascular ectasia that appears clinically as a minute, partly compressible, red-to-purple punctum, which may require magnification for visualization. These small puncta appear in groups that fuse into patches and spread by forming new satellite puncta at the periphery. This can result in annular, linear, and serpiginous patterns. Angioma serpiginosum usually develops on the lower extremities and the buttocks, but occasionally lesions can be seen elsewhere. Although the lesions extend gradually, widespread cutaneous involvement is infrequent. The condition is progressive despite periods of relative stability. Although areas of fading and involution are evident, complete spontaneous resolution does not occur. Angioma serpiginosum can be confused with the pigmented purpuric eruption; it is not a capillaritis but rather a nevoid telangiectatic condition. There is no evidence of variegated pigmentation, scaling, atrophy, or lichenification in angioma serpiginosum. These lesions must be distinguished from other localized telangiectases. Histopathologically, the fundamental lesion is a dilatation of the capillaries of papillary and subpapillary regions of the dermis. The vessel walls may be slightly thickened. Other dermal structures are normal. An inflammatory infiltrate is not a significant feature, and no red cell diapedesis or hemosiderin pigment is present. Treatment with PDL may be helpful if desired.

Hereditary hemorrhagic telangiectasia (Osler– Weber–Rendu disease)

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demonstrated by a family with HHT and pulmonary AVMs229 where no genetic abnormality could be established. The vast majority of patients have a normal survival rate and die of unrelated causes, although for symptomatic patients, frequent treatment for hemorrhages and anemia is a lifelong necessity. Other treatments depend upon which organ systems are affected. Genetic counseling should be offered to all affected individuals, and if both partners are affected, they should be warned that the homozygous state might be lethal in childhood.

Generalized essential telangiectasia

VASCULAR MALFORMATIONS

This uncommon disorder might more appropriately be called essential progressive telangiectasia, because it does not become generalized until many years after its onset. The condition occurs more frequently in females and most commonly develops in late childhood or early adult life. It is not familial. It usually begins on the legs and slowly spreads to involve the thighs, lower abdomen, occasionally the arms, and, rarely, the face. The telangiectases are macular, retiform, and linear and may coalesce to form confluent sheets over large areas. Lesions are usually asymptomatic; however, occasionally, patients experience sensations of numbness, tingling, and burning in an involved limb.230 Essential telangiectasia must be differentiated from telangiectasia secondary to underlying disease as well as from HHT. For some patients, it represents a serious cosmetic problem, and pulsed dye laser therapy can be of benefit.

Hereditary benign telangiectasia Hereditary benign telangiectasia (OMIM 187260) has been described in several kindreds. Affected persons are noted to have widespread asymptomatic telangiectases unassociated with systemic disease.231,232 It is inherited as an autosomal dominant trait and maps to locus CMC1 for capillary malformation on chromosome 5q14.233 The telangiectases are not present at birth or during the first year of life but begin to appear between 2 and 12 years of age. Predominantly affected areas are the face, arms, and upper trunk, but lesions have been noted on the vermilion border of the lips and palate in some individuals. Typical lesions are macular, punctate or plaque-like, radiating, arborizing, or merely a diffuse blush; they often have a halo of pallor. Capillary microscopy reveals that the main feature is dilatation of the horizontal subpapillary venous plexus. This is accompanied by loss of the more superficial capillaries that normally stain with alkaline phosphatase and supply the papillae. The disorder is

229. Wallace GM, Shovlin CL. A hereditary hemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1. Thorax. 2000;5:685–690. 230. Abrahamian LM, Rothe MJ, Grant-Kels JM. Primary telangiectasia of childhood. Int J Dermatol. 1992;31:307. 231. Ryan TJ, Wells RS. Hereditary benign telangiectasia. St Johns Hosp Dermatol Soc Trans. 1971;57:148–156. 232. Gold MH, Eramo L, Prendiville JS. Hereditary benign telangiectasia. Pediatr Dermatol. 1989;6:194–197. 233. Brancati F, Valente EM, Tadini G, et al. Autosomal dominant hereditary benign telangiectasia maps to the CMC1 locus for capillary malformation on chromosome 5q14. J Med Genet. 2003;40:849–853. 234. Colver GB, Shrank AB, Ryan TJ. Unilateral dermatomal superficial telangiectasia. Clin Exp Dermatol. 1985;10:455.

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slowly progressive, but in old age it becomes less obvious because of the normal skin changes of aging. Hereditary benign telangiectasia must be differentiated from other primary telangiectases, the most important of which is HHT. Intervention is unnecessary except for cosmetic reasons; as with other benign telangiectasias, laser is a helpful treatment.

Unilateral nevoid telangiectasia Unilateral nevoid telangiectasia (unilateral dermatomal superficial telangiectasia) is a rare condition that occurs in both a congenital and an acquired form. The acquired type occurs mainly in females, either at puberty or during pregnancy, and is thought to be estrogen related; male alcoholics suffering from cirrhosis of the liver may also acquire the condition.234 Some authors have proposed that this entity represents a localized form of generalized essential telangiectasia.234 Congenital unilateral nevoid telangiectasia has been documented only rarely and affects males predominantly,235 with no evidence of endocrine abnormalities.235 Lesions occur unilaterally on the face, neck, chest, and arms (trigeminal, C3 and C4 or adjacent dermatomes) and rarely elsewhere. They present as macular telangiectatic mats, although elevated puncta and even pulsatile spider angiomas may be found in some cases. Lesions fade on pressure. Blanching or vasoconstriction surrounding individual lesions is common and represents ‘vascular steal.’ In the congenital type, the telangiectasias are permanent whereas in the acquired form they may resolve spontaneously in some patients. Lasers with selectivity for cutaneous vascular structures are the best treatment for areas causing disfigurement.

Cutis marmorata telangiectatica congenita (CMTC, van Lohuizen syndrome, congenital generalized phlebectasia) CMTC is a clinically distinctive cutaneous vascular malformation. The variable presence of cutaneous atrophy and coexistent livedo reticularis is frequent. The condition is said to be rare, although cases may be under-reported. The etiology is unclear, and there is no evidence of genetic involvement. It is usually stated that CMTC occurs predominantly in females, but in four large series, the male to female ratios were 7 : 6, 9 : 13, 5 : 5, and 5 : 3, respectively.236–239 CMTC is present at birth and mimics the physiologic cutis marmorata commonly seen in young infants, particularly when they are chilled or exposed to low environmental temperatures; it disappears on warming, but the pattern of CMTC is darker in

235. Wilkin JK, Smith JG Jr, Cullison DA, et al. Unilateral dermatomal superficial telangiectasia: 9 new cases and a review of unilateral dermatomal superficial telangiectasia. J Am Acad Dermatol. 1983;8: 468–477. 236. South DA, Jacobs AH. Cutis marmorata telangiectatica congenita (congenital generalized phlebectasia). J Pediatr. 1993;93:944–949. 237. Picascia DD, Esterly NB. Cutis marmorata telangiectatica congenita; report of 22 cases. J Am Acad Dermatol. 1989;20:1098–1104. 238. Kennedy C, Oranje AP, Keizer K, et al. Cutis marmorata telangiectatica congenita. Int J Dermatol. 1992;31:249–252. 239. Pehr K, Moroz B. Cutis marmorata telangiectatica congenita: long-term follow-up, review of the literature, and report of a case in conjunction with congenital hypothyroidism. Pediatr Dermatol. 1993;10:6–11.

Vascular birthmarks: tumors and malformations

B

Figure 20.27  Cutis marmorata telangiectatica congenita. (A) Note the fixed livedoid pattern, atrophy and in (B), frank ulceration.

Clinically, CMTC must be differentiated from physiologic cutis marmorata and from diffuse phlebectasia of Bockenheimer (see below). It may be difficult to distinguish CMTC from a reticulated PWS. Persistent livedo and telangiectases resembling CMTC have been described in neonates with Down syndrome, Cornelia de Lange syndrome, homocystinuria, neonatal lupus erythematosus, and other genetic, neurologic, and metabolic conditions. In the past, it was thought that CMTC was closely associated with ‘macrocephaly-cutis marmorata telangiectatica’ syndrome; however this syndrome is actually associated with a reticulate port-wine stain and/or a persistent nevus simplex (see above). The microscopic findings in CMTC are not specific, and diagnosis is best made on the basis of clinical criteria. The histologic appearance usually consists of an increased number of thinwalled dilated dermal capillaries, occasionally with venous lakes and large dilated veins in all layers of the dermis and subcutaneous tissue. Cutaneous atrophy, ulceration, and microthrombi may also be evident histopathologically. The management of CMTC involves careful examination for associated disorders. Occasionally, ulceration may be severe enough to require specific ulcer wound care regimens.

color and coarser in pattern (Fig. 20.27). Although it is always discernible at rest, it can be accentuated by cold exposure, vigorous movement, or crying. The reticulated livedo-like staining of the skin is accompanied by varying degrees of telangiectasia, phlebectasia, soft tissue atrophy and ulceration.236,240 The pattern of CMTC may be either generalized or localized, often with a segmental distribution and a sharp midline demarcation. The extremities are most commonly affected, followed by the torso, and only rarely the face, palms, soles, and mucous membranes. Most patients with CMTC experience improvement of their mottled vascular pattern over time, with the most dramatic change occurring in the first year and tapering thereafter. It has been theorized that this improvement may be a result of the normal skin maturation process with thickening of the epidermis and dermis; however persistence of the violaceous reticulated network is a common finding.241 Associated abnormalities are reported to occur in up to 50% of patients but this is overstated due to ascertainment bias and confusion with M-CM (see above).241 Reported associations include PWS, body asymmetry (both hemiatrophy and hemihypertrophy), dystrophic teeth, glaucoma, patent ductus arteriosus, pulmonary hypertension, mental retardation, SWS, macrocephaly, varicosities, hemangiomas, syndactyly, hypothyroidism, and delayed psychomotor development. CMTC is seen as an associated finding in a number of patients with the Adams– Oliver syndrome, which is characterized by distal transverse limb defects and aplasia cutis congenita.242 Decrease in the size of an affected limb is probably the most common finding associated with CMTC,243 especially those with involvement of the lower limb.244 A decrease in girth, rather than length, is obvious in some infants with a single affected limb.

ANGIOKERATOMAS

240. Gerritsen MJ, Steijlen PM, Brunner HG, et al. Cutis marmorata telangiectatica congenita. Br J Dermatol. 2000;142:366–369. 241. Enjolras O. Cutis marmorata telangiectatica congenita. Ann Dermatol Venereol. 2001;128:161–166. 242. Dyall-Smith D, Ramsden A, Laurie S. Adams Oliver syndrome: aplasia cutis congenita, terminal transverse limb defects and cutis marmorata telangiectatica congenita. Australas J Dermatol. 1994;35:19–22.

243. Devillers ACA, de Waard-van der Spek FB, Oranje AP. Cutis marmorata telangiectatica congenita. Clinical features in 35 cases. Arch Dermatol. 1999;135:34–38. 244. Ben Amitai A, Fichman S, Merlob P, et al. Cutis marmorata telangiectatica congenita: clinical findings in 85 patients. Pediatr Dermatol. 2000;17: 100–104.

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The term angiokeratoma is applied to a group of disorders characterized by ectasia of the superficial dermal vessels (capillaries) and compact hyperkeratosis of the overlying epidermis.153 All present as asymptomatic, firm, dark red-to-black papules, with varying degrees of secondary hyperkeratosis that increases with time. Classically, four types of angiokeratoma are described, all of which are probably related, but vary in size, depth, and location. They are solitary papular angiokeratoma, angiokeratoma circumscriptum, angiokeratoma of Mibelli, and angiokeratoma of the scrotum and vulva. Angiokeratoma corporis diffusum represents a distinctive fifth group which is often associated with Fabry’s or other metabolic diseases. Dermoscopy is helpful in confirming the diagnosis of angio­ keratoma. On dermoscopic examination, a solitary angio­ keratoma is characterized by a lacunar pattern of large, sharply demarcated, roundish or oval areas with a reddish, red-bluish or dark-red to black coloration. These lacunas are very distinctive and may be numerous, and together with whitish-yellow keratotic areas are diagnostic of angiokeratomas. The presence of a whitish veil due to the acanthotic epidermis with hypergranulosis and com­pact orthokeratosis is another typical dermatoscopic finding.

Papular angiokeratoma Papular angiokeratomas represent a response to trauma and can occur at any age and at any site, although the legs are the favored location. They can be solitary or multiple and consist of blue-black warty papules 2–10 mm in diameter. A single

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angiokeratoma may be mistaken for a viral wart, nevus, or malignant melanoma, but it can be differentiated on the basis of histopathologic examination or dermatoscopy. Microscopic features include grouped dilated papillary blood vessels, acanthosis and hyperkeratosis of the epidermis, and elongation of the rete ridges, which tend to enclose the underlying capillary spaces. Treatment of a solitary angiokeratoma for cosmetic reasons or because of undue anxiety can be accomplished by local excision, electrodesiccation, or by laser ablation.

Angiokeratoma circumscriptum

VASCULAR MALFORMATIONS

Angiokeratoma circumscriptum is a rare disorder typically appearing as a large, solitary, hyperkeratotic plaque on a lower extremity. Apart from its linear quality, it is clinically identical to so-called ‘verrucous hemangioma’ although in the latter, the abnormal vascular structures extend into the deep dermis and subcutaneous tissue. Some clinicians feel that these two entities are part of the same clinical spectrum and actually represent superficial manifestations of a predominantly lymphatic malformation (see below).245 The most common sites of involvement are the extremities. The condition may be present at birth or develop during infancy or childhood sometimes extending during adolescence. The aggregates of warty, keratotic, deep-red to blue-black papules and nodules are often distributed in a linear pattern suggesting somatic mosaicism. Angiokeratoma circumscriptum has also been confused with lymphangioma circumscriptum, both clinically and histologically. Thrombosis within a solitary angiokeratoma may cause changes in size and color simulating melanoma.246 Small lesions can be removed by electrodesiccation and curettage, cryosurgery or laser ablation; for larger lesions, laser and/or surgical excision can be considered.

Angiokeratoma of Mibelli Angiokeratoma of Mibelli is a rare condition that occurs primarily in female children and adolescents. It has been seen in siblings and in children with an affected parent, suggesting a dominant mode of inheritance with variable penetrance.247 The frequent association of lesions with acrocyanosis, chilblains, and frostbite suggests that cold sensitivity is the precipitating factor. The lesions are most often seen on the dorsal and lateral aspects of the toes and fingers, and the knees and elbows. Less frequently, they arise on the knuckles, malleoli, palms, soles, and ears. Early lesions are minute bright-red macules that fade somewhat on diascopic pressure. The lesions slowly increase in size and become elevated, warty, and darker in color, attaining a diameter of 5–10 mm. They are asymptomatic but bleed easily. There is no spontaneous involution, although this may occur following trauma.

245. Tennant LB, Mulliken JB, et al. Verrucous hemangioma revisited. Pediatr Dermatol. 2006;23:208–215. 246. Goldman L, Gibson SH, Richfield DF. Thrombotic angiokeratoma circumscriptum simulating melanoma. Arch Dermatol. 1981;117:138. 247. Smith RBW, Prior IAM, Park RG. Angiokeratoma of Mibelli: a family with nodular lesions of the legs. Aust J Dermatol. 1968;9:329. 248. Ramsay B, Dahl MCG, Malcolm AJ, et al. Acral pseudolymphomatous angiokeratoma of children. Arch Dermatol. 1990;126:1524.

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Microscopically, there are ectatic vessels in the papillary dermis. The epidermis is hyperkeratotic and often acanthotic, with elongated rete ridges that enclose the vascular lacunae. There may be predominantly lymphocytic cellular infiltrates. Clinically, the lesions resemble acral pseudo lymphomatous angiokeratoma of children (APACHE) but this is usually unilateral, unassociated with cold exposure, and has histologic features of a pseudolymphoma, rather than true angiokeratoma.248,249 Treatment of angiokeratoma of Mibelli consists of cryosurgery, electrodesiccation, or laser ablation.

Angiokeratoma of the scrotum and vulva (Fordyce) Angiokeratomas of the scrotum and vulva are relatively common and are primarily a phenomenon of aging. The lesions usually appear in middle to later adult life and arise as multiple, small, bright-red vascular papules that subsequently become keratotic. They are distributed along the superficial veins of the scrotum and rarely over the penis, inguinal area, and upper thighs in men and on the labia majora in women. With increasing age, they may become numerous. On occasion, these angiokeratomas become bothersome and may itch or bleed when traumatized. The diagnosis of angiokeratoma corporis diffusum must be considered in any patient with these lesions, particularly if onset is early in life. Symptomatic lesions can be removed with cryotherapy, electrodesiccation, or laser ablation.

Angiokeratoma corporis diffusum In the past, angiokeratoma corporis diffusum has been used synonymously with Fabry syndrome, but, it is now used as a descriptive term because the characteristic clinical findings can be seen in patients with several metabolic diseases as well as in some metabolically normal individuals.250

Anderson–Fabry disease (Fabry disease; angiokeratoma corporis diffusum) Fabry disease is a rare X-linked recessive lysosomal storage disorder caused by an error in glycosphingolipid metabolism. The incidence is estimated at approximately 1 in 117 000 worldwide.251 The defect in α-galactosidase A results in intracellular accumulation of globotriaosylceramide (ceramide trihexoside) and galactosylceramide, which is responsible for the multi­ systemic involvement. Various mutations have been described in the gene for α-galactosidase A. The disorder exhibits complete penetrance but variable clinical expressivity in hemizygous males. Heterozygous females generally have α-galactosidase A activity and plasma globotriaosylceramide levels intermediate to that of hemizygous males and normal individuals. Among

249. Hara M, Matsunaga J, Tagami H. Acral pseudolymphomatous angiokeratoma of children (APACHE): a case report and immunohistological study. Br J Dermatol. 1991;124:387. 250. Gasparini G, Sarchi G, Cavicchini S, et al. Angiokeratoma corporis diffusum in a patient with normal enzyme activities and Turner’s syndrome. Clin Exp Dermatol. 1992;17:56. 251. Zarate YA. Fabry’s disease. Lancet. 2008;372:1427–1435.

Vascular birthmarks: tumors and malformations

affected male.

female carriers, 15% have similar clinical findings in one or more organs, and approximately 70% show evidence of the distinctive whorl-like corneal dystrophy.252 Progression of clinical findings and symptoms in Fabry’s disease can be divided into three distinct age periods. The earliest symptoms occur during childhood in the first decade of life (Fig. 20.28). Pain and dysesthesia in the hands and feet is the most common presenting symptom and usually persists into adulthood. Bouts of severe, often excruciating, pain occur in association with fever of unknown origin. The pain, caused by vasomotor disturbances, usually occurs subsequent to changes in temperature, but it also may be spontaneous or elicited by exertion or emotional stress. Gastrointestinal complaints also start in childhood, with nausea, and recurrent abdominal pain. Frequent absences and difficulty in school are common, with poor attention, behavior problems and chronic pain issues. In the mid-teen years (between the ages 14–16), the cutaneous finding of angiokeratomas can be observed in about 40%251 of male adolescents with Fabry’s. Angiokeratomas tend to increase in number with age, clustering around the umbilical area, and in the swimming trunk distribution. The angiokeratomas can often bleed and cause significant cosmetic concern; they are also a valuable clue to the diagnosis of Fabry’s disease. A decrease in sweating is often noted by the time puberty begins. Sweating may be entirely absent by the third decade, with the exception of the face where sweating may be normal or increased. Other dermatologic findings in Fabry’s that begin in childhood include lymphedema and telangiectasias. These findings

252. Burda CD, Winder PR. Angiokeratoma corporis diffusum universale in female subjects. Am J Med. 1967;42:293. 253. Ashton-Prolla P, Tong B, Shabbeer J, et al. Fabry disease: twenty-two novel mutations in the alpha-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes. J Invest Med. 2000;48:227–235.

often precede cardiac and renal dysfunction.251 The onset of renal involvement during early adult life is indicated by abnormal findings on urinalysis or renal biopsy. Renal failure, the most common cause of death usually ensues due to lipid accumulation in the kidney. Hypertension, angina pectoris, and congestive heart failure are also frequent findings. Myocardial infarction may occur as early as 29 years and cerebrovascular disease can also present in early adult life. Death usually occurs by age 50 due to renal failure, cardiac or cerebrovascular disease. In women, cardiac and CNS involvement may occur. Valvular disease, arrhythmia (bradycardia) and ischemia are the most common cardiac manifestations while strokes and transient ischemic events are common cerebrovascular complications. Involvement of the ocular tissues occurs early in the disease. The conjunctiva, cornea, lens, and retina can all be affected. Distinctive corneal opacities (corneal verticillata) are characteristic of Fabry’s disease and consist of one or more lines that radiate outward from a point near the center of the cornea.251 The opacities are usually present during childhood and are found in all affected males as well as almost all female carriers: they are diagnostic of the disease. A pathognomonic posterior cortical cataract with narrow wavy spokes also develops in the lens of about 50% of the hemizygotes but not in the heterozygous females. Ectasia and tortuosity of the conjunctival and retinal vessels are another early finding. The diagnosis of Fabry disease is often delayed due to the non-specific nature of the initial signs and symptoms. Fabry’s should be suspected in any individual with the characteristic clinical findings, a positive family history, and a marked decrease in activity of α-galactosidase A in white blood cells or cultured fibroblasts. Early in the course of the disease, casts, red cells, fat-laden epithelial cells (mulberry cells), and lipid inclusions with characteristic birefringent ‘Maltese crosses’ appear in the urinary sediment. Biopsy of the skin or kidney is confirmatory if intracellular birefringent lipoid deposits can be demonstrated. Skin biopsy specimens contain deposits of glycosphingolipid in the walls of the blood vessels, which stain positively with Sudan black and periodic acid–Schiff reagent. Analysis of genomic DNA, isolated from patients and related family members, allows the accurate detection of heterozygous carriers, so that effective genetic counseling can be provided.253 Prenatal and pre-implantation diagnosis is possible. Treatment of Fabry disease has traditionally been supportive, but enzyme replacement therapy with recombinant human α-galactosidase has been available for several years (FDA approved in the USA in 2003). It has been effective in clinical studies, although damage prior to initiation of treatment is usually irreversible. Aggressive treatment with Agalsidase Alfa (α-galactosidase) with adjunctive angiotensin converting enzyme (ACE) inhibitors was shown to slow the decline in renal function in 165 patients with Fabry disease.254 There are several different preparations of α- or β-galactosidase available showing decreased cardiac mass, decreased frequency of pain crises, and

VASCULAR MALFORMATIONS

Figure 20.28  Fabry disease with multiple angiokeratomas in a mother of an

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254. Feriozzi S, Schwarting A, Sunder-Plassmann G, et al. Agalsidase alfa slows the decline in renal function in patients with Fabry disease. Am J Nephrol. 2008;29:353–361.

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clearance of storage in the skin and kidneys. There is also some evidence of improved sweating, decreased GI symptoms and improvement in hearing and sensation.255–257 Currently the evidence is not yet available to clearly show long-term benefit. Protection from extremes of temperature is advised. Phenytoin and carbamazepine have been found to provide relief from the severe pain crises of Fabry syndrome, although carbamazepine may exacerbate autonomic dysfunction in some patients. Hemodialysis is indicated for chronic renal failure; renal transplantation has restored renal function and provided a source of functional enzyme in some individuals.

Fucosidosis VASCULAR MALFORMATIONS

Disseminated angiokeratomas are seen in patients with fucosidosis,258 an autosomal-recessive lysosomal storage disorder, caused by deficient α1-fucosidase activity in all tissues. This rare disorder is manifest by accumulation of fucose-containing glycolipids and glycoproteins in the skin and other organs; various mutations of the gene FUCA1 lead to nearly absent enzyme function.259 Phenotypically, there is a spectrum of severity of the disease. Patients dying at an early age usually lack the angio­ keratomas that develop later in the course of the disease. Common clinical manifestations include progressive mental and motor deterioration, coarse facies, growth retardation, recurrent infections, dysostosis multiplex, visceromegaly, and seizures. Angiokeratoma corporis diffusum is seen in >50% of patients. The skin lesions appear in the groin and on the genitalia, rarely as early as 6 months of age but more often later in life, and gradually spread over the trunk and limbs. Mats of telangiectases develop on the palms and soles and occasionally on the trunk. The gingivae may also be the site of vascular ectasia, and there is dilatation and tortuosity of the conjunctival vessels in almost all affected individuals. Sweating abnormalities, both hypo- and hyperhidrosis, have been recorded in a number of patients. Clinical differences260 distinguish fucosidosis from other metabolic disorders characterized by angiokeratomas. The diagnosis is firmly established by biochemical assay of fucosidase enzyme activity in fibroblasts or peripheral leukocytes. The gene FUCA has been localized to chromosome 1. Fucosidase assays of amniocytes and direct detection of the mutation by DNA analysis permits prenatal diagnosis.

Miscellaneous disorders with angiokeratomas Several rare metabolic disorders are associated with angiokeratomas. These include β-galactosidase deficiency (GM1 gangliosidosis), sialidosis with combined deficiency of β-galactosidase and neuraminidase, aspartyl glycosaminuria, mannosidosis, partial combined deficiency of fucosidase and α-galactosidase, and α-N-acetylgalactosaminidase deficiency.

255. Sakuraba H, Murata-Ohsawa M, Kawashima I, et al. Comparison of the effects of agalsidase alfa and agalsidase beta on cultured human Fabry fibroblasts and Fabry mice. J Hum Genet. 2006;51:180–188. 256. Schiffmann R, Kopp JB, Austin HA 3rd, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285:2743–2749. 257. Ramaswami U, Wendt S, Pintos-Morell G, et al., Enzyme replacement therapy with agalsidase alfa in children with Fabry disease. Acta Paediatr. 2007;96:122–127.

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Figure 20.29  Venous malformation of the lip and oral mucosa, resulting in an open bite.

VENOUS MALFORMATIONS Venous malformations (VMs) are structural anomalies of the venous vasculature which are often, but not always, evident at birth. They may occur either as localized or extensive lesions (Fig. 20.29) crossing several anatomic planes, as part of complex syndromes or without associated abnormalities. Most VMs occur sporadically, but about 1% of VMs are familial. They are composed of anomalous dilated veins with irregularly thickened walls, which often have focal regions lacking smooth muscle cells.29,153,163 They are associated with slit-like or open lumens. Interconnected channels dissect through normal tissues. Thromboses may give rise to calcifications, which become more evident over time and progress to form phleboliths. The clinical expression, sequelae, and management of VM differ, depending on the age of the patient, the severity of the disease, and the anatomic location. VM gives a blue or purple hue to the involved skin and mucous membranes. They are soft and compressible, sometimes resembling a ‘bag of worms’ (Fig. 20.30). They swell and enlarge when dependent and with exertion or activities (such as Valsalva maneuvers or crying) that increase venous pressure. Skin temperature is normal or minimally warm but neither a thrill nor a bruit is present. Pain is variable but fairly common. Slow enlargement with deformation of anatomic structures is commonly observed over time. Radiologic imaging is helpful in delineating the extent of involvement and in differentiating VM from other vascular anomalies and soft tissue tumors. MR imaging is the best radiological modality: it gives a bright hyperintense signal on T2-weighed sequences, because of slow flow, and this clearly indicates the extent of the lesions throughout the involved tissues.41 Rarely a CT scan may be necessary to look for associated bony defects. Doppler ultrasound is a useful study for limb VM, as it is a rapid and easy

258. Willems PJ, Seo HC, Coucke P, et al. Spectrum of mutations in fucosidosis. Eur J Med Genet. 1999;7:60–67. 259. Fleming C, Rennie A, Fallowfield M, et al. Cutaneous manifestations of fucosidosis. Br J Dermatol. 1997;136:594–597. 260. Kodama K, Kobayashi R, Abe A, et al. A new case of N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Ménière’s syndrome and without mental retardation. Br J Dermatol. 2001;144:363–368.

Vascular birthmarks: tumors and malformations

musculature.

method of portraying the vascularization and low-flow velocity.261 Arteriography and venography are usually not necessary. Based on MR characteristics, four distinct morphologic subtypes have been identified which may predict response to treatments such as sclerotherapy. In type I lesions, malformations are isolated with no draining vessels. Type II drain into normal veins, type III into abnormal or dysplastic veins and type IV represent more generalized venous dysplasia. In general, sac like or type I malformations usually respond the best to scelerotherapy.262 VMs of the head and neck create a blue discoloration of the skin and mouth, distortion of facial features, and pain when swelling occurs in dependent positions or with straining. Involvement of the cheek and tongue can cause dental malocclusion, cross-bite and/or open-bite deformity through a mass effect on the developing mandible/maxilla during childhood (Fig. 20.29). Deep mucous membrane lesions, involving the palate, pharyngeal and laryngeal areas, can cause snoring, progressive sleep apnea and respiratory difficulties. Orbital involvement, in communication with cheek and infratemporal venous

261. Trop I, Dubois J, Guibaud L, et al. Soft-tissue venous malformations in pediatric and young adult patients: diagnosis with Doppler. US Radiology. 1999;212:841–845. 262. Puig S, Aref H, Chigot V, et al. Classification of venous malformations in children and implications for sclerotherapy. Pediatr Radiol. 2003;33:99–103. 263. Enjolras O, Deffrennes D, Borsik M, et al. Les ‘tumeurs vasculaires’ et les règles de prise en charge chirurgicale. Ann Chir Plast Esthet. 1998;4:455–490. 264. Berenguer B, Burrows PE, Zurakowski D, et al. Sclerotherapy of craniofacial venous malformations. Plast Reconstr Surg. 1999;104:1–15. 265. Yakes WF. Extremity venous malformations. Semin Intervent Radiol. 1994;11:322–329.

malformations through the sphenomaxillary fissure, can cause enophthalmos when standing, and exophthalmos when supine; dark-blue veins may be visible on the inner surface of the conjunctiva or sclera. Usually there is no visual impairment. Management of cephalic venous malformations combines percutaneous sclerotherapy, staged excisions, and/or intervention with laser modalities such as the Nd:YAG. A multistep approach, through multiple procedures over years, will give the best results. In many patients, ‘cure’ is impossible; treatment aims at improving appearance, maintaining facial symmetry and muscle dynamics, and restoring lip competence. Soft tissue venous lesions and bone deformities can be treated in parallel.263,264 VM of the limb can be well localized or diffuse. Deeper venous malformations often involve the musculature and in some cases, the synovium of the joints may also be affected.215,265 In rare cases, the muscle is affected without overlying skin involvement. Genitalia are commonly affected in association with a lower extremity VM. Limb length discrepancy is uncommon and generally mild. If there is synovial involvement, the symptoms often manifest before 10 years of age and include pain, swelling, and functional impairment, owing to effusion or hemarthrosis. Permanent joint damage and severe muscle pain may follow. Extensive or bulky VMs are often associated with a localized intravascular coagulopathy (LIC). It is present in 58% of patients affected with VMs;266 they may cause pain, thromboses, and phlebolith formation and may result in severe bleeding during surgical procedures. Low fibrinogen and elevated D-dimers are the hallmarks of this disorder. LIC is often mislabeled in the literature as Kasabach–Merritt phenomenon (KMP) (see above and Table 20.4), however the two conditions are easily differentiated based on the characteristics of the vascular lesion and the hematologic parameters.215 In VM associated LIC, the platelet count may be slightly decreased, but not to the degree seen in KMP. LIC is most often associated with large and intramuscular VMs of the extremities.267 Treatment with aspirin and/or lowmolecular-weight heparin is indicated in severe disease.266 Conservative management with compression is always recommended, and for localized lesions percutaneous sclerotherapy or Nd:YAG laser ablation may be beneficial.265 Excision is considered in some patients with symptomatic lesions.268 Staged excisions are usually necessary and, in contrast to AVMs, this does not trigger the growth of the residual venous malformation. Knee joint venous malformation embedded in the synovial membrane that causes repeated episodes of hemarthrosis is an indication for resection to prevent joint degeneration, similar to that observed in hemophiliacs. For episodes of bleeding, vasopressin can be a helpful adjunctive therapy.269

VASCULAR MALFORMATIONS

Figure 20.30  Venous malformation of the leg involving the skin and

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266. Mazoyer E, Enjolras O, Bisdorff A, et al. Coagulation disorders in patients with venous malformation of the limbs and trunk: a case series of 118 patients. Arch Dermatol. 2008;144:861–867. 267. Dompmartin A, Acher A, Thibon P, et al. Association of localized intravascular coagulopathy with venous malformations. Arch Dermatol. 2008;144:873–877. 268. Upton J, Coombs CJ, Mulliken JB, et al. Vascular malformations of the upper limb: a review of 270 patients. J Hand Surg (US). 1999;24:1019–1035. 269. Huang JT, Koerper MA, Frieden IJ, et al. Treatment of vaginal bleeding from a pelvic vascular malformation with desmopressin. J Pediatr Hematol Oncol. 2006;28:845–846.

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Venous malformation cutaneous and mucosal syndrome (VMCM, OMIM 600195) In recent years, the genetic basis of familial cases of VMs has been elucidated. In most familial cases, affected individuals present with multifocal lesions in random distribution throughout the body. They are usually only found within the skin and subcutaneous tissue and rarely involve the muscles or deeper structures. Visceral involvement in VMCM is extremely rare. The genetic basis for this syndrome was recently elucidated by Vikkula et  al.163 The single gain of function gene mutation lies within the endothelial cell-specific receptor tyrosine kinase, Tie2/TEK on 9pQ21 and is autosomal dominant. Familial VMCM comprises approximately 1% of all venous malformations.

A

VASCULAR MALFORMATIONS

Blue rubber bleb nevus syndrome (Bean syndrome) Blue rubber bleb nevus syndrome (BRBNS) is an autosomal dominant condition characterized by multiple, circumscribed VMs in the skin and mucosa. Clinically, they present as blue hued, soft, compressible nodules, identical to classic VM described above. The gastrointestinal tract is very commonly involved and gastrointestinal bleeding is a major finding. There is some controversy in the literature as to whether BRBNS represents a variable form of VMCM with GI involvement, but in BRBNS, the underlying genetic basis has not yet been firmly elucidated. The VMs in BRBNS present in the same manner as those seen in VMCM (see above); with multifocal, soft, bluehued compressible nodules on cutaneous and mucosal sites. Most VMs are present at birth, and like classic VMs, tend to gradually expand or dilate over time. They become symptomatic in the second decade. VM-LIC is commonly associated.

C

Figure 20.31  Glomuvenous malformation. (A) Family history was positive in this case. (B,C) Note the purple color, cobblestoned appearance and segmental distribution.

GVMs are a relatively uncommon subtype of venous malformation in which the malformed veins have an associated increase in glomus cells. GVMs account for approximately 5% of VMs but differ from VMs in several respects.270 Although solitary GVMs can occur sporadically in adults, most GVMs are usually familial, multifocal, large or segmental lesions, that are caused by a genetic defect. They present as pink, purple or blue papules and nodules which may develop an overlying thickening, but usually have a smooth surface. They are superficial within the dermis and often have localized tenderness. The size of VMs vary from a few millimeters to large segmental areas of involvement, and are most often located on the trunk and extremities. GVMs unlike other VMs involve skin and subcutis only, rarely involve the mucosa, and virtually never involve muscle, bone, or viscera. GVMs are familial in 70% of cases. They are caused by loss of function mutations in the glomulin gene on chromosome 1p21–

22.271 Familial GVMs can be differentiated from VMs by their clinical characteristics described above (Fig. 20.31). They are firm and difficult to compress, whereas most VMs are soft, compressible and blue-hued. GVMs are mainly located on the extremities and involve only skin and subcutis, whereas VMs commonly affect muscles and joints. GVMs are painful on compression, whereas VMs are reportedly painful on awakening, after activity, or with hormonal changes. Elastic compression garments tend to worsen pain in GVM patients in contrast to VMs where compression provides major benefit. Solitary, sporadic glomus tumors usually occur on the upper extremities, particularly in the nail beds, although occasionally they are found on the lower extremities, head, neck, or genitalia. These extremely tender, purple nodules vary in size. In addition to marked tenderness, there may be paroxysms of pain, which occur either spontaneously or are evoked by trauma. On histopathologic examination, inherited glomuvenous malformations have venous-like channels surrounded by poorly differentiated smooth muscle-like cuboidal shaped glomus cells that stain positively for smooth muscle α-actin and vimentin.270,271

270. Boon LM, Mulliken JB, Enjolras O, et al. Glomuvenous malformation (glomangioma) and venous malformation: distinct clinicopathologic and genetic entities. Arch Dermatol. 2004;140:971–976.

271. Brouillard P, Boon LM, Mulliken JB, et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations (‘glomangiomas’). Am J Hum Genet. 2002;70:866–874.

Glomuvenous malformations (GVM) (glomangioma, OMIM 138000)

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B

Figure 20.32  (A,B) Maffucci syndrome with radiographic evidence of bony involvement.

Bockenheimer syndrome (diffuse phlebectasia) Bockenheimer syndrome was first described by Bockenheimer in 1907. In his eponymous syndrome, Bockenheimer described a patient with an extensive VM involving the upper extremity and limited to the skin and subcutaneous tissue. Many clinicians believe that Bockenheimer syndrome and extensive VM can and should be used synonymously.272 Like all VMs, these lesions present at birth and are progressive.272 Treatment is identical to other VMs and includes supportive care, such as compression garments, sclerotherapy or resection and possibly anticoagulation therapy.

Maffucci syndrome Maffucci syndrome is a rare congenital disorder with no recognized genetic basis. It is characterized by dyschondroplasia of one or more limbs, multiple enchondromas, and VMs, which are not true VMS; they are often large and located in the subcutaneous tissues. Maffucci syndrome is grouped with other syndromes in which multiple enchondromas are the prominent feature (the enchondromatoses, of which there are six types). The lesions appear early in life, often in infancy. There is no racial or sex predilection. The VMS are blue or purple, soft, compressible, and occasionally tender. Phleboliths can also be observed (Fig. 20.32). Pathologic specimens exhibit anomalous venous channels and features of a vascular tumor, the spindle

272. Kubiena HF, Liang MG, Mulliken JB. Genuine diffuse phlebectasia of Bockenheimer: dissection of an eponym. Pediatr Dermatol. 2006;23:294–297. 273. Hisaoka M, Aoki T, Kouho H, et al. Maffucci’s syndrome associated with spindle cell hemangioendothelioma. Skeletal Radiol. 1997;26:191–194. 274. Nakamura K, Matsushita T, Haga N, et al. Swelling of the dorsum of the hand and/or foot can be a first sign of Maffucci syndrome. Arch Orthop Trauma Surg. 1999;119:470–473.

cell hemangioendothelioma.153,273 Maffucci syndrome may present with swelling. In these cases histologic specimens have typical features of spindle cell hemangioendothelioma in addition to anomalous lymphatic channels.274 Although the vascular lesions may develop anywhere on the body surface, the hands and feet are involved most frequently. Localized forms involving a single extremity are observed. The site of the vascular malformations does not necessarily correlate with the appearance of skeletal lesions, and lesions in bones may appear before the skin lesions.275 Skeletal changes consist of multiple enchondromas, exostoses, and recurrent fractures. Bone lesions are usually bilateral but asymmetric (Fig. 20.32B). Radiographic findings include oval defects in association with expansion and thinning of the cortex of involved bones. Limb deformity and leg lengthening, as well as scoliosis, occur in approximately one-third of patients. The diagnosis of Maffucci syndrome is usually based on clinical findings. The differential diagnosis of the skeletal changes includes Ollier and Gorham syndromes. The skin changes often resemble multiple VMs clinically. The most serious complications of Maffucci syndrome, aside from multiple fractures in childhood, are the neurologic deficits, resulting from encroachment of cranial enchondromas on the cerebral cortex, and the development of malignant tumors. Chondrosarcomas are the most common malignancy and occur in 15% of patients. Other malignancies, such as angiosarcomas, fibrosarcomas, lymphangiosarcomas, and intracranial tumors,276 have also been reported. Treatment involves surgical extirpation of skeletal and vascular lesions where possible. Diagnostic biopsy is mandatory to exclude malignancy in any bony or soft tissue tumor that enlarges rapidly or becomes painful. Radiation is of no therapeutic value.

VASCULAR MALFORMATIONS

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ARTERIOVENOUS MALFORMATIONS (AVMS) AVMs are fast-flow vascular malformations with direct arterio­ venous shunts and no intervening capillary bed. They are rare, and can occur anywhere in the body, both in the skin and subcutaneous tissue and internally, and are among the most dangerous of the vascular anomalies. There is no gender predominance. AVMs are noted at birth in 30–40% of patients. Progression during childhood occurs in the majority of patients. Known trigger factors include puberty, pregnancy, trauma, and iatrogenic causes such as subtotal surgical resection, proximal artery ligation, or arterial embolization that is too proximal. AVMs can be classified according to the ISSVA–Schobinger staging2 into four clinical stages: stage 1, dormancy; stage 2, expansion; stage 3, destruction; and stage 4, destruction plus congestive cardiac failure. In stage 1, AVMs mimic a PWS or an involuting hemangioma, or they create a small pulsatile mass under normal skin (Fig. 20.33). In stage 2, the expansion creates plaques or masses, which are red and warm, with local tenderness, pulsations,

275. Enjolras O, Wassef M, Merland JJ. Syndrome de Maffucci; une fausse malformation veineuse? Un cas avec hémangioendothéliome à cellules fusiformes. Ann Dermatol Venereol. 1998;125:512–515. 276. Balcer LJ, Galetta SL, Cornblath WT, et al. Neuro-ophthalmologic manifestations of Maffucci’s syndrome and Ollier’s disease. J Neuroophthalmol. 1999;19:62–66.

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even years after a technically and clinically effective embolization.279 In some distal extremity AVMs with local complications, one may stabilize the disease by covering the region with a vascularized, anastomosed cutaneous and muscular flap transfer, after wide excision or localized amputation.280 Similar flap transfer is used for severe facial AVMs in adolescents and adults, and this may also cure the lesion or stabilize the progress of a residual AVM; nevertheless, the results are cosmetically poor.263 A multidisciplinary approach to the management of AVMs is recommended. Therapies that are known to cause worsening of AVMs include arterial ligation, partial excision, proximal or incomplete embolization, PDL for the red staining of the skin overlying the arteriovenous nidus, and cryosurgery. These should be avoided. VASCULAR MALFORMATIONS

Figure 20.33  Scalp arteriovenous malformation mimicking a port-wine stain.

bruits, and enlarged tortuous veins. In stage 3, skin necrosis, ulcers, bleeding and hemorrhage become evident and lytic bone lesions may develop. Stage 4 is rare, occurring in approximately 2.5% of AVMs and consists of increasing congestive cardiac failure from increased arterial pressure.277,278 When a diagnosis of AVM is considered, investigations are necessary. Ultrasound/Doppler studies can help confirm the high-flow nature of the condition and will provide measurements of the comparative output between arteries on the affected and unaffected sides of the body. This helps in serial re-evaluation. If the output is markedly increased on the affected side, cardiac evaluation and follow-up become mandatory. MR imaging and arteriography plus conventional arteriography are all helpful in characterizing the angio-architecture and extent of the AVM. Effects on the bone are best evaluated with CT scan, which can identify complications such as draining veins penetrating the skull and draining into an intracranial sinus.

Management Treatment is difficult and no one treatment can be guaranteed to provide total cure. Embolization alone may initially appear to be successful, but good long-term results are rare, particularly for lesions on the extremities or face.277 Combining embolization and resection of the AVM nidus and overlying skin may provide good results for small AVMs,278 but because determining the extent of an AVM is difficult, many authors suggest deferring treatment of quiescent AVMs (particularly stage 1), since trauma can activate growth and recruitment of new vessels. For larger lesions (stage 2 and 3), embolization and excision are performed, but covering the surgical wound is difficult, and the therapeutic outcome is uncertain. In patients with pain, ulcers, and hemorrhage, particularly those with extensive AVMs in limbs, distal amputation may be required,

277. Enjolras O, Logeart I, Gelbert F, et al. Malformations artérioveineuses. Etude de 200 cas. Ann Dermatol Venereol. 2000;127:17–22. 278. Kohout MP, Hansen M, Pribaz JJ, et al. Arteriovenous malformations of the head and neck: natural history and management. Plast Reconstr Surg. 1998;102:643–654.

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Parkes Weber syndrome Parkes Weber syndrome is a sporadic condition that presents at birth or early childhood with a high flow vascular anomaly affecting an extremity, and progressive overgrowth of the affected limb. The presence of arteriovenous fistulae distinguishes Parkes Weber from KT syndrome.29 Other features include warmth and tenderness overlying the malformation, dilated veins with a thrill on palpation, lengthening of the affected limb, and hypertrophy in girth owing to both lipomatosis and lymphatic hyperplasia. Patients with Parkes Weber syndrome may develop high-output congestive heart failure secondary to the arteriovenous fistulae. The prognosis is poorer than with KT syndrome, because of progressive increase of pain and worsening functional outcome. Treatment of Parkes Weber syndrome should be conservative. Compression stockings are recommended. Surgical orthopedic management may be necessary when leg length discrepancy is disabling. Epiphysiodesis may be considered, to achieve symmetric lower extremities, but if there are arteriovenous fistulae in the area of the knee where they are commonly located, worsening of the fast-flow malformation may occur. Embolization is usually unsatisfactory because of multiple arteriovenous shunts along the limb. Surgical resection of the shunts usually fails, as new vessels are recruited and complicate the anomalous vascular network. Overaggressive surgical management can precipitate local complications, including pigmentary changes in the skin, pseudo-Kaposi sarcoma skin alterations, pain, ulcers, hemorrhage, and ischemic distal changes in the toes or digits necessitating amputation. These patients are evaluated initially with Doppler studies, MR and conventional arteriography. Isotopic lymphography should be performed if lymphatic involvement is suspected. The genetic basis of multifocal capillary and arteriovenous malformations in the autosomal dominant CM-AVM syndrome has been elucidated (see below). Some of the patients with CM-AVM and associated RASA1 mutations have also been noted to have concomitant Parkes Weber syndrome with AVM of an extremity, or intracranial AVMs, including the vein of

279. White RI, Pollack J, Persing J, et al. Long-term outcome of embolotherapy and surgery for high-flow extremity vascular malformations. J Vasc Interv Radiol. 2000;11:1285–1295. 280. Toh S, Tsubo K, Arai H, et al. Vascularized free-flaps for reconstruction after resection of congenital arteriovenous malformations of the hand. J Reconstr Microsurg. 2000;16:511–517.

Vascular birthmarks: tumors and malformations

Cobb syndrome Cutaneomeningospinal angiomatosis (Cobb syndrome) consists of a capillary stain or a fast-flow skin mass on the posterior thorax in association with a contiguous or nearly contiguous fast-flow vascular malformation of the spinal cord.282 A vertebral body is sometimes involved. The location of the spinal cord lesion corresponds within a segment or two of the involved dermatome of the skin lesion. The syndrome is much rarer than isolated intraspinal AVMs.283 The neurologic problems can occur suddenly or gradually, with onset most often during adolescence or young adulthood. Affected patients experience pain, altered sensation, and motor deficits, such as loss of sphincter control, which are the result of cord compression by the AVM. One-third of patients develop a spinal subarachnoid hemorrhage. The neurologic problems vary with the level of spinal cord involvement and are thought to result from physical cord compression and/or anoxia. The spinal AVM is intramedullary in most patients, meningeal, or perimedullary. The patient becomes symptomatic as the spinal AVM increases in size. The diagnosis of Cobb syndrome is suggested by the presence of a posterior thoracic vascular stain in association with a neurologic deficit. The vascular lesion either mimics a PWS or AVM with a thrill and bruit. In the latter, the skin may have color changes or appear normal. It is accompanied by neurologic evidence of a vascular abnormality of the spinal cord. MR imaging and angiography,284 and spinal angiography will demonstrate the vascular fast flow lesion and pinpoint its precise location. Patients are generally not considered at risk for Cobb syndrome if the cutaneous vascular malformation is venous, capillary– lymphatic–venous, or purely capillary, although on rare occasions, quiescent AVMs may appear as a macular ‘pseudo-port-wine stain.’ Endovascular embolization of spinal AVM has greatly improved the neurologic prognosis of Cobb syndrome although results may be temporary. If there is a symptomatic vertebral vascular lesion, it can be treated by means of intralesional injections of ethanol or glue under CT guidance. Intramedullary lesions can be resected in some patients when embolization is impossible or too dangerous.285

Capillary malformation–arteriovenous malformation syndrome (CM-AVM, OMIM 608354) CM-AVM is a recently described autosomal dominant condition caused by activating mutations in the RASA1 gene. RASA1 is an

281. Revencu N, Boon LM, Mulliken JB, et al. Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008;29:959–965. 282. de Vera C, Peiro R, Gort A, et al. Cobb syndrome. Rev Neurol. 1996;24:720. 283. Aminoff MJ, Logue V. Clinical features of spinal vascular malformations. Brain. 1974;97:197–210. 284. Binkert CA, Kollias SS, Valavanis A. Spinal cord vascular disease: characterization with fast three-dimensional contrast-enhanced MR angiography. Am J Neuroradiol. 1999;20:1785–1793. 285. Huffmann BC, Spetzger U, Reinges M, et al. Treatment strategies and results in spinal vascular malformations. Neurol Med Chir (Tokyo). 1998;38:231–237.

inhibitor of the Ras-Map kinase pathway.286 The disorder is characterized by small, multifocal capillary malformations in association with underlying arteriovenous malformations/arteriovenous fistulas and sometimes Parkes Weber syndrome. There is a wide clinical heterogeneity in terms of size and number of capillary malformations and the different fast flow lesions associated. Affected individuals exhibit atypical CMs, usually presenting as multifocal, small, pink-to-red-brown, round-to-oval lesions, which may be associated with high flow or bruit on Doppler examination. Usually multiple family members are affected.287

Bonnet–Dechaume–Blanc and Wyburn–Mason syndromes Bonnet–Dechaume–Blanc syndrome is a rare, cerebrofacial, arteriovenous syndrome characterized by a vascular stain on the face, which is usually a quiescent AVM.288 It is associated with retinal and brain AVMs. Lesions worsen progressively or become evident during childhood. The cutaneous lesion is either hemifacial, involving the eyelids and cheek, or located in the central portion of the face (nose, forehead and upper lip). The most common presenting sign is reduced visual acuity. Symptoms worsen gradually over many years, particularly when incomplete resection is performed. The intracranial lesions occur predominantly around the thalamus and mesencephalon and become clinically apparent after hemorrhage; vascular accidents occur in childhood or early adult life. Wyburn–Mason syndrome is similar, combining a facial cutaneous AVM, midbrain AVM and unilateral congenital anomalies of the retinal vessels. Treatment of these unusual syndromic neuro-ophthalmologic and cutaneous AVMs is daunting; it is rarely possible to excise the whole facial lesion, using either free-flap transfer or cutaneous expansion to cover the large wound created. Arterial embolization is a palliative therapy that is usually unable to change a frequently bad prognosis.

VASCULAR MALFORMATIONS

Galen aneurysmal malformation.281 It is still not clear if sporadic AVM or isolated Parkes Weber syndrome is due to mutations in RASA1.

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LYMPHATIC MALFORMATIONS Lymphatic malformations (LMs) are disorders of the lymphatic system and circulation of lymph fluid. In the past, numerous descriptions and names were assigned to LMs such as ‘cystic hygroma’ and ‘lymphangioma’. It is more precise to divide LMs into their two morphologic and histologic subtypes: microcystic and macrocystic, depending on the size and organization of the lymphatic channels. Combined micro- and macrocystic LMs are common, particularly in the head and neck areas (Fig. 20.34). In a review of 186 patients, LMs involved the head and neck in 48%, the trunk and extremities in 42%, and were visceral in 10%.289 Common complications of LMs include disfigurement, infection, and bleeding (superficial vesicles become hemorrhagic

286. Denayer E, de Ravel T, Legius E. Clinical and molecular aspects of RAS related disorders. J Med Genet. 2008;45:695–703. 287. Eerola I, Boon LM, Mulliken JB, et al. Capillary malformationarteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003;73:1240–1249. 288. Enjolras O. Color Atlas of vascular tumors and malformations. Cambridge, MA: Cambridge University Press; 2007. 289. Alqahtani A, Nguyen LT, Flageole H, et al. 25 years’ experience with lymphangiomas in children. J Pediatr Surg. 1999;34:1164–1168.

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VASCULAR MALFORMATIONS

Figure 20.34  Lymphatic malformation of the cheek.

or there is a sudden hemorrhage in a large cyst). Recurrent inflammation with swelling can be particularly dangerous in locations such as the orbital area where it can cause proptosis and may impair vision and in the mouth and perioral area where it can cause deformity of the maxilla and mandible resulting in crossbite, openbite, and speech impairment. The diagnosis is often clinical but is best confirmed with MR imaging, which often demonstrates fluid levels to suggest cystic components and shows the extent of the malformation. The stagnant lymphatic lesions show a bright hypersignal on T2-weighed sequences.

Macrocystic lymphatic malformations Macrocystic LMs (cystic hygroma) most often occur in the neck, axilla, groin, or chest wall. They are usually large, single or multiloculated and are typically noticed at birth or by 2 years of age. Rare documented cases of sudden development in an adolescent or an adult have been described.290 Large congenital forms are documented by ultrasound as early as the 4th month of pregnancy; in some of these fetuses, a chromosomal abnormality is present (Down or Turner syndrome). In all cases, there is an increase of amniotic fluid α-fetoprotein levels.291 Macrocystic LMs persist unchanged, if not treated, or they slowly expand; there are instances of spontaneous regression, usually after infection. In more extensive LMs, both macro- and micro-cystic elements may be present and those involving the neck may extend

290. Rahbar R, Rowley H, Perez-Atayde AR, et al. Delayed presentation of lymphatic malformation of the cervicofacial region: role of trauma. Ann Otol Rhinol Laryngol. 2002;111:828–831. 291. Musone R, Bonafiglia R, Menditto A, et al. Fetuses with cystic hygroma. A retrospective study. Panminerva Med. 2000;42:39–43. 292. Ogita S, Tsuto T, Deguchi, et al. OK-432 therapy for unresectable lymphangiomas in children. J Pediatr Surg. 1991;26:263–270. 293. Nehra D, Jacobson L, Barnes P, et al. Doxycycline sclerotherapy as primary treatment of head and neck lymphatic malformations in children J Pediatr Surg. 2008;43:451–460.

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into the mediastinum or involve the tongue and floor of the mouth. Infection and hemorrhage into the lesion or close to it may lead to rapid enlargement, with resultant respiratory compromise, dysphagia, infection, and death. Radiologic assessment of LMs with MRI and contrast is essential for proper management of all patients and careful airway evaluation of patients with neck lesions is imperative as acute or chronic airway obstruction can be a dangerous complication. Recommendations for the management of macrocystic LMs have varied from early total excision to waiting for spontaneous regression for several years. As resection often has considerable morbidity, percutaneous sclerotherapy has gained favor as an excellent method of treatment. Various sclerosants, including doxycycline, alcohol, OK-432,292 Ethibloc, and bleomycin, have been reported to be effective but comparative studies are lacking.293 Shrinkage of the lesions after single or multiple procedures is the result of the intense inflammatory reaction and subsequent fibrosis. A good response is seen in >50% of patients with macrocystic LMs and the technique is now considered a first-line effective treatment. Sclerotherapy is much more effective in macrocystic than in microcystic LMs.

Microcystic lymphatic malformations Microcystic LMs are more common than macrocystic LMs. The lesions are sometimes present at birth or appear in childhood. They may develop anywhere on the body surface, but the most common sites are the axillary folds, shoulders, neck, proximal limbs, perineum, tongue, and floor of the mouth, where they may encroach on parapharyngeal spaces and the larynx, and create bony overgrowth.294,295 Sometimes diagnosed in utero, large LMs of the neck, mouth and airway often require emergent and permanent tracheostomy shortly after delivery. The lesions consist of grouped small papules and translucent thin-walled vesicles resembling frog spawn, occasionally with superimposed thickening. Some of the vesicles may contain varying amounts of blood, giving them a pink-red appearance; coagulation of blood will produce a purple-to-black color.296 Microcystic LMs range in size from small (1 cm) plaques of vesicles to exceedingly large lesions covering extensive areas. A deeper component is almost always present and may be detectable as diffuse swelling or thickening and a bluish hue of the underlying tissues. Massive LMs deeply invading the dermis, subcutis, and underlying muscles, may involve an entire limb and appear as spongy subcutaneous masses without overlying color change or as multiple dark red vesicles, often with a thickened or even verrucous surface (sometimes labeled angiokeratomas).296 Very often, clusters of vesicles develop in the vicinity of the scar from a previously excised LM. Leakage of lymphatic fluid may occur.

294. Padwa BL, Hayward PG, Ferraro NF, et al. Cervicofacial lymphatic malformation: clinical course, surgical intervention, and pathogenesis of skeletal hypertrophy. Plast Reconstr Surg. 1995;95:951–960. 295. Hartl DM, Roger C, Denoyelle F, et al. Extensive lymphangioma presenting with upper airway obstruction. Arch Otolaryngol Head Neck Surg. 2000;126:1378–1382. 296. Davies D, Rogers M. Morphology of lymphatic malformations, a pictorial review. Australas J Dermatol. 2000;41:1–7.

Vascular birthmarks: tumors and malformations

Lymphedema Lymphedema is divided into primary and secondary forms. Secondary lymphedema (acquired lymphedema) is caused by lymphatic obstruction following surgery, recurrent lymphangitis or cellulitis, an extralymphatic process (such as compression by neoplastic invasion of lymphatics or obesity), and by fibrosis resulting from radiation therapy or scar formation. Secondary lymphedema is rare in childhood. Patients with primary lymphedema are usually subdivided into clinical groups according to the age of onset. In congenital lymphedema, the swelling is firm and is characterized by pitting on pressure. In lymphedema praecox, females are primarily affected, and the swelling appears spontaneously, generally between the ages of 9 and 25 years. It is common to see patients with one extremity involved for years and later have the other one become affected. Using isotopic lymphography in patients with one limb involved, it is evident that the lymphatic network of these patients is bilaterally impaired; but the clinical manifestations may occur at different periods of life. About 20% of primary lymphedema is familial. When the lymphedema occurs distally and is present at birth, it is referred to as Milroy disease. Meige disease describes later onset. In these autosomal dominant disorders, the edema is almost always confined to the legs and feet. It is at first pitting and disappears completely with elevation. Subsequently, with the development

297. Orvidas LJ, Kasperbauer JL. Pediatric lymphangiomas of the head and neck. Ann Otol Laryngol. 2000;109:411–421. 298. Hennekam RC, Geerdink RA, Hamel BC, et al. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet. 1989;34:593–600.

of fibrosis, the swelling becomes harder. The epidermis may become thickened and warty (so-called pseudoverrucous hyperplasia) over time, and fissures and secondary infection often occur. Changes of elephantiasis, similar to that caused by parasitic infection in the tropics, occur in severe cases. Another familial form of lymphedema is Hennekam disease, combining limb lymphedema, facial anomalies (flat face, flat nasal bridge, tooth and ear anomalies), intestinal lymphangiectasia with protein-losing enteropathy, mental retardation, and cerebral anomalies. Most reported patients are born from consanguineous parents.298,299 Several other syndromes have been described that combine congenital primary lymphedema with various associated anomalies. Many are genetic with a varied inheritance pattern. Lymphedema has been associated with Turner and Noonan syndromes. Opitz has proposed that the presence of generalized congenital lymphedema is associated with certain facial dysmorphisms as well as minor abnormalities of the ears, hair patterns, nails, and palmar prints.300 Lymphedema-distichiasis syndrome (LD, OMIM 153400) is an autosomal dominant disorder caused by mutations in the FOXC2-gene. LD is characterized by late childhood or pubertal onset lymphedema of the limbs and distichiasis (double row of eyelashes).300,301 Treatment of advanced lymphedema is very unsatisfactory, but early treatment can often prevent further deterioration. This includes external pressure by elastic stockings or bandages, active muscle exercises, and centripetal massage (so-called manual lymphatic drainage). Systemic antibiotics may be necessary for the recurrent inflammatory episodes and infections. Sequential pneumatic compression devices have been efficacious in many instances in preventing progression of the lymphedema. Newer devices such as Flexitouch (Tactile Systems Technology Inc., Minneapolis, MN), which more closely approximate the technique of manual lymphatic drainage, may be particularly helpful. Operations to restore the damaged or absent lymphatics are generally unsatisfactory, with only transient improvement. Surgery, to remove the grossly thickened tissues, and liposuction are sometimes performed. Lymphaticovenous shunts have given some improvement in visceral forms with massive effusions.

VASCULAR MALFORMATIONS

Recurrent cellulitis is common and can cause worsening lymphedema, sometimes necessitating hospitalization with intravenous antibiotics. Prophylactic antibiotics are sometimes needed to prevent recurrent cellulitis. As with macrocystic LMs, microcystic lesions also require MR imaging with gadolinium contrast to delineate the extent of the disease. The treatment of microcystic and combined micromacrocystic LMs depends on the size and location of the lesion, but with more extensive lesions can be exceedingly difficult. Treatment is often supportive, with use of compression garments if the extremities are involved. Surgical removal (either complete or partial) can be helpful in some cases, but decisions are best made using a multidisciplinary approach. If therapy is indicated, deep and extensive surgery is necessary. When possible, this should be performed after tissue expansion of adjacent normal skin to take a larger area and avoid recurrences. A number of patients with extensive lesions of the head and neck undergo multiple resections with a high rate of recurrence, persistent disease, and poor cosmetic and functional results.295,297 Patients with jaw involvement and overgrowth need orthodontic and orthognathic procedures after completion of skeletal growth, but overgrowth may recur and is difficult to repair. Carbon dioxide, diode and Nd:YAG lasers have been used successfully to obliterate the vesicular component in some LMs while PDL usually gives only a temporary improvement after multiple procedures.

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COMBINED MALFORMATIONS Vascular malformations can be found in a number of different combinations, depending on what vessel differentiation is present within the lesion. Combinations of any of the four vessel types: capillary, venous, lymphatic and arterial can occur within a combined malformation. Complex combined vascular malformations can be syndromic in their clinical presentation and are often associated with hemihypertrophy of soft tissue, muscle and sometimes bone. For example, the combined capillary-lymphvenous-malformation (CLVM) is most commonly associated with Klippel–Trenaunay syndrome (see above).

299. Huppke P, Christen HJ, Sattler B, et al. Two brothers with Hennekam syndrome and cerebral abnormalities. Clin Dysmorphol. 2000;9:21–24. 300. Opitz J. On congenital lymphedema. Am J Med Genet. 1986;24:127–129. 301. Vreeburg M, Heitink MV, Damstra RJ, et al. Lymphedema-distichiasis syndrome: a distinct type of primary lymphedema caused by mutations in the FOXC2 gene. Int J Dermatol. 2008;47:S52.

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VERRUCOUS HEMANGIOMA 153

Verrucous ‘hemangioma’ is a misnomer for a vascular malformation with hyperkeratosis and involvement of capillaries, veins, and, in many cases, lymphatics. Distinctive hyperkeratotic, cutaneous capillary–venous malformations resembling angio­ keratomas have been described in a small group of patients with cerebral capillary malformations (also known as familial cerebral cavernomas). These patients may present with headaches and life-threatening cerebral hemorrhages.302 In some families, the skin lesion represents a hallmark for risk of brain involvement.303 The mutated gene, CCM1, is located on 7q21–22 and encodes the protein KRIT-1.

VASCULAR MALFORMATIONS

GORHAM SYNDROME (GORHAM–STOUT SYNDROME) Gorham syndrome (Gorham’s massive osteolysis, disappearing bone disease, phantom bone disease) is an extremely rare sporadic disorder. It is characterized by local proliferation of small vascular or lymphatic channels, resulting in progressive destruction and resorption of bone and partial or complete replacement of bone by fibrous tissue.304,305 The translucent ‘phantom’ bones develop in any part of the skeleton. Bone loss may stabilize after a year of progression but the destruction often creates local complications. When the spine is affected, neurologic deficits may develop and thoracic involvement can cause chylothorax. Areas of osteolysis are probably the result of intense osteoclastic activity.306 Multiple pathologic poorly healing fractures can occur and require orthopedic care. Because of increased osteoclastic activity, it has been suggested that bisphosphonates and calcitonin be given to these patients.307 Implants of bone in the osteolytic areas are usually absorbed in a few months; therefore,

302. Labauge P, Enjolras O, Bonerandi JJ, et al. An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic capillaro-venous cutaneous vascular malformation in 4 families. Ann Neurol. 1999;45:250–254. 303. Eerola I, Plate KH, Spiegel R, et al. KRIT 1 is mutated in hyperkeratotic cutaneous capillaro-venous malformation associated with cerebral capillary malformation. Hum Mol Genet. 2000;9:1351–1355. 304. Bruch-Gerharz C, Gerharz H, Stege J, et al. Cutaneous lymphatic malformations in disappearing bone (Gorham-Stout) disease: a novel clue to the pathogenesis of a rare syndrome. J Am Acad Dermatol. 2007;56: S21–S25. 305. Yalniz E, Alicioglu B, Benlier E, et al. Gorham-Stout disease of the humerus. JBR-BTR. 2008;91:14–17. 306. Moller G, Priemel M, Amling M, et al. A report of six cases with histopathological findings. J Bone Joint Surg Br. 1999;81:501–506.

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artificial devices like titanium implants should be utilized to stabilize the lesions or to replace the bone after curettage of the vascular lesion.308 Amputation may rarely be necessary.

BANNAYAN–RILEY–RUVALCABA SYNDROME Bannayan–Riley–Ruvalcaba syndrome (BRRS) is caused by mutations in the PTEN tumor suppressor gene. It is characterized by macrocephaly, cutaneous lipomas, penile lentigines, and vascular anomalies. Other associated clinical features include developmental delay, intestinal polyps, macrodactyly, pseudopapilledema and Hashimoto thyroiditis. BRRS is allelic to Cowden’s syndrome and is associated with an increased risk of malignancy.309,310 Mutations in PTEN have also been seen in patients with features of Proteus syndrome. Some authors suggest that these three disorders be classified together as part of a spectrum: the PTEN hamartoma-tumor syndrome.311 The vascular anomalies associated with the PTEN mutation are distinct; the majority of lesions are multifocal, intramuscular combinations of fast-flow channels and ectopic fat.312 In 54% of patients with the PTEN mutation, there is an associated vascular anomaly, which is deep, multifocal and fast flow.312 Intracranial developmental venous anomalies are a common finding in this subset of patients. Individuals presenting with similar, deep, high-flow vascular malformations and macrocephaly should be screened for PTEN mutations; and affected patients require screening for PTEN associated malignancies. Acknowledgments The authors would like to thank Nancy Esterly and Odile Enjolras for their work on earlier editions of this chapter.

307. Lehmann G, Pfeil A, Böttcher J, et al. Benefit of a 17-year long-term bisphosphonate therapy in a patient with Gorham-Stout syndrome. Arch Orthop Trauma Surg. 2009;129:967–972. 308. Sato K, Sugiura H, Yamamura S, et al. Gorham massive osteolysis. Arch Orthop Trauma Surg. 1997;116:510–513. 309. Tok Celebi J, Chen FF, Zhang H, et al. Identification of PTEN mutations in five families with Bannayan–Zonana syndrome. Exp Dermatol. 1999;8:134–139. 310. Lowichik A, White FV, Timmons CF, et al. Bannayan–Riley–Ruvalcaba syndrome: spectrum of intestinal pathology including juvenile polyps. Pediatr Dev Pathol. 2000;3:155–161. 311. Orloff MS, Eng C. Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome. Oncogene. 2008;27:5387–5397. 312. Tan WH, Baris HN, Burrows PE, et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet. 2007;44:594–602.

Walter H. C. Burgdorf, Pedram Gerami and Albert C. Yan

INTRODUCTION The spectrum of tumors in the skin of children is vast. Lesions include congenital malformations, hamartomas, epithelial and mesenchymal neoplasms, cutaneous infiltrates by hematopoietic cells and all these may present with papules, plaques, or nodules. While most are harmless, life-threatening soft tissue sarcomas, leukemias, and lymphomas must be promptly recognized. Many other childhood tumors are discussed elsewhere in this text.

CLINICAL APPROACH The unexpected finding of a new growth in an infant or child often elicits great anxiety for parents and family and usually results in an urgent visit to either the pediatrician or dermatologist. Five clinical danger signs taken together suggest the possibility of a malignant tumor.1

• • • • •

Onset at birth or in the neonatal period A history of rapid and progressive growth A firm mass >3 cm in diameter Skin ulceration Fixation to deep tissues or location below the fascia.

Before attempting to apply these criteria, one should exclude common benign processes such as an infantile hemangioma, since these lesions often fulfill several of the criteria. If an exact clinical diagnosis is not obvious and one or more of these signs is present, a biopsy should be undertaken. If none is present, the lesion can usually be observed, depending on the clinical judgment of the physician. In many instances, a tumor will be removed for cosmetic purposes. Using this approach, only a small number (≈3/1000) of malignant tumors will be missed on the first assessment.

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Dermatologists take congenital tumors somewhat for granted, since both melanocytic nevi and infantile hemangiomas are frequently present at birth or soon afterwards. Estimates of the prevalence of either a vascular or a melanocytic tumor during this congenital period range from 5% to 15%. Included among the malignant tumors that may present at birth are leukemia, neuroblastoma and sarcomas (usually rhabdomyosarcoma), as well as Langerhans cell disease. The classification of congenital tumors is confusing because there are overlaps among the following: 1. Hamartoma – a benign overgrowth or disarray of tissues at their usual anatomic site. Many hamartomas are present at birth or in early infancy, but this is not a prerequisite. Hamartoma has been used to describe so many unrelated processes that it has lost specificity 2. Nevus – often used as a synonym for a hamartoma, such as a connective tissue nevus. Nevus is also employed to describe benign melanocytic lesions, such as compound nevus or Spitz nevus. When used without qualification, the term nevus generally implies a melanocytic process 3. Choristoma or heterotopia – an overgrowth or disarray of tissues at the wrong site 4. Teratoma – a germ cell neoplasm involving two or more of the primitive germ layers: ectoderm, mesoderm, and endoderm 5. Malformation – a morphological defect resulting from aberrant developmental process. All the overlaps between the above terms cause more confusion than clarity. Thus, we have avoided such classification.

MOSAICISM

Congenital lesions are those present at birth or appearing within the first 30 days of life. They are even more distressing to the parents as they are noticed at a time when emotions are already high. Counseling done at this time should always be repeated later, to be sure the desired information has been conveyed.

As first espoused by Happle and discussed in Chapter 7, mosaicism2 is responsible for a wide range of lesions that are sometimes interpreted as tumors. The underlying principle is that if a mutation occurs early in embryonic life, cutaneous lesions may become segmental as that mutation is transmitted to descendant cells along Blaschko lines, such as in an epidermal nevus. If the same mutations occur in later life, solitary tumors deve­ lop. A simple example is that of epidermolytic hyperkeratosis – a

1.

2.

CONGENITAL TUMORS

Knight PJ, Reiner CB. Superficial lumps in children: what, when, and why? Pediatrics. 1983;72(2):147–153.

INTRODUCTION

Benign and malignant tumors

Itin PH, Buechner SA. Segmental forms of autosomal dominant skin disorders: the puzzle of mosaicism. Am J Med Genet. 1999;85(4):351–354.

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distinctive histologic pattern caused by specific keratin mutations that may produce a widespread ichthyosis if a germline mutation, an epidermal nevus if an early somatic mutation, and focal acanthomas if a late sporadic mutation. Happle refined his concepts regarding the segmental lesions, dividing them into two types:

• Type 1 segmental lesions arise from a post-zygotic new mutation as outlined above.

and hemangiomas (three tumors not covered in this chapter) make up about 75% of all lesions.1 Only 1–2% of lesions are malignant, which is reassuring. In some childhood tumors, the microscopic appearance correlates poorly with the clinical course. Some bland tumors with little atypia (e.g., desmoid tumors) can behave aggressively, while on the other hand, some microscopically worrisome tumors have a good prognosis (Spitz nevi).

• Type 2 lesions result from a loss of heterozygosity in a patient

INTRODUCTION

who already has a germ-line mutation. For example, a patient with multiple leiomyomas may have a segment of skin with many more leiomyomas than the background of the rest of the body. In another instance, someone with neurofibromatosis 1 may have an area following Blaschko lines where there are an extremely high number of neurofibromas and café-aulait macules.

The terms tumor and neoplasm are used interchangeably in this chapter, connoting a palpable swelling of tissue. Benign tumors usually show a lesser degree of histologic atypia and lack the properties of invasion and metastasis. Several studies exist on the prevalence of skin tumors in childhood. One older analysis of 775 superficial lumps of childhood gives an indication of the prevalence of various tumors. Pilomatricomas, epidermoid cysts,

Soft tissue tumors are rare in childhood, but because of the paucity of epidermal tumors, they assume a more prominent role. While the majority of these tumors are benign, some are malignant. Sarcomas are malignant soft tissue tumors with mesenchymal differentiation. They account for about 7% of pediatric cancers; their incidence is about 8/million. Rhabdomyosarcomas and undifferentiated sarcomas account for over half of this group, while fibrosarcomas, synovial sarcomas, and malignant peripheral nerve sheath tumors make up most of the rest. There are striking differences between infants and older children.4 The vast majority of tumors in infancy are benign, usually vascular or fibroblastic-myofibroblastic in nature. In older children, the risk of a sarcoma is greater. Most sarcomas present as poorly defined, often large masses, in the deep soft tissues of extremities, retroperitoneum, or head and neck. Sarcomas of the extremities are often fixed to underlying fascia and muscle. True subcutaneous sarcomas are uncommon. Deep incisional biopsy is usually needed for a correct diagnosis. Small or superficial biopsies may be misleading, while needle biopsies of possible sarcomas are not desirable because biopsy tract seeding may complicate therapy and even lead to disease recurrence. The biopsy site should always be planned so that it falls into the area of later excision. The mainstay of diagnosis is expert light microscopic evaluation coupled with immunohistochemical stains. The latter usually enable the pathologist to identify the tissue of origin or direction of differentiation of the sarcoma, although poorly differentiated tumors may often lack expected markers (Table 21.1). This is a simplified table and ignores the complex determinations needed to study hematological tumors. A wide range of relatively specific chromosomal abnormalities has been recognized in both benign and malignant soft tissue tumors; the diagnosis of sarcoma is rarely made without cytogenetic analysis.5 The mainstay of treatment of all sarcomas is meticulous surgical excision with particular attention paid to spread along fascial lines followed by exact histologic control of margins. Sarcomas truly limited to soft tissue are usually resectable; problems arise when the tumor involves skeletal, neurovascular, or internal organ structures. In adult sarcomas, radiation therapy and chemo­therapy are employed both for prophylaxis after an apparently successful excision and to control recurrences and metastases. The exact indications vary widely from tumor to tumor and center to center. In childhood sarcomas, there are more

3.

5.

The clinical relevance of this phenomenon is that even after identifying an apparent segmental mutation, one must examine the entire patient carefully to exclude this Type 2 phenomenon, for such patients are capable of transmitting their disease to their offspring in 50% of cases.

SOLITARY VERSUS MULTIPLE Another good general rule of childhood tumors is that while a solitary lesion, be it epithelial or adnexal, is likely to be sporadic, just as in adults, multiple cutaneous tumors should suggest the possibility of autosomal-dominant inheritance and an underlying syndrome. Often the cutaneous changes may be a marker for underlying systemic changes or even for potential tumors, which may be expected to appear later in life, as discussed later under cancer-associated genodermatoses.3

PAINFUL TUMORS While any tumor can be painful if it is traumatized, necrotic or impinges upon a nerve, some tumors are often painful. They can be best recalled using the mnemonic BENGAL:

• • • • • •

Blue rubber bleb nevus Eccrine tumors Neural tumors Glomus tumor Angiolipoma Leiomyoma.

BENIGN VERSUS MALIGNANT

4.

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SOFT TISSUE TUMORS

Burgdorf WH, Koester G. Multiple cutaneous tumors: what do they mean? J Cutan Pathol. 1992;19(6):449–457. Coffin CM, Dehner LP. Soft tissue tumors in first year of life: a report of 190 cases. Pediatr Pathol. 1990;10(4):509–526.

Singer S, Demetri GD, Baldini EH, et al. Management of soft-tissue sarcomas: an overview and update. Lancet Oncol. 2000;1:75–85.

Benign and malignant tumors

21

ANTIGEN

NORMAL STRUCTURES IDENTIFIED

MOST COMMON TUMORS WHICH EXPRESS ANTIGEN

Actin

Smooth muscle cells, pericytes, myofibroblasts, myoepithelial cells

Leiomyoma, leiomyosarcoma, some dermatomyofibromas

CD1a

Langerhans cells

Langerhans cell disease

CD34

Stem cells, dermal dendritic cells, endothelial cells, others

Dermatofibrosarcoma protuberans

CD68

Macrophages

Xanthogranuloma family

Desmin

Myogenous cells

All muscular tumors

Factor VIII

Endothelial cells

Vascular tumors

Factor XIII

Dermal dendrocytes

Dermatofibromas, fibrous papule

Keratins

Keratinocytes

Epidermal tumors

Neurofilaments

Neurons, nerve fibers

Neural tumors

S100

Melanocytes, Langerhans cells, neural cells

Malignant melanoma, Langerhans cell disease

Ulex europaeus I

Endothelial cells

Vascular tumors

Vimentin

Endothelial cells, fibroblasts, many others

All mesenchymal tumors

Figure 21.1  Nevus lipomatosus superficialis.

other developmental abnormalities. Histopathologically, there is mature fat in the superficial dermis. A skin tag with extensive fatty change can be identical, as can a biopsy from focal dermal hypoplasia (Goltz syndrome) (Ch. 7), but the latter can be readily excluded clinically. Smaller lesions can be excised if desired; larger lesions are a surgical challenge, but fortunately are almost never on exposed sites.6–8

Skin tag

Nevus lipomatosus superficialis, also known as nevus lipomatosus of Hoffmann–Zurhelle, presents at birth or in childhood as a rectangular or linear plaque composed of coalescing soft, polypoid, skin-colored, slightly yellow or red papules (Fig. 21.1). Sometimes the epidermis is thinned or there is outpouching. There may be associated hypertrichosis. These nevi most often occur in the pelvic or lumbosacral region. They may be large and cosmetically disfiguring, but are usually not associated with

Skin tags, acrochordons, or soft fibromas are soft, fleshy, polypoid, and pedunculated lesions commonly found in the axillae and on the neck in adults. Occasionally, obese adolescents also acquire skin tags in these areas. More commonly, childhood skin tags are larger, solitary and often congenital. They occur most commonly over the trunk, lumbosacral, groin, axillary and perineal areas. Larger pedunculated lesions have been described as pedunculated lipofibromas.9 Multiple skin tags may be seen in tuberous sclerosis or the mucopolysaccharidoses; periorificial skin tags are a feature of focal dermal hypoplasia. Histologic examination reveals a polypoid tumor with an epidermis that may range from atrophic to acanthotic, and a dermis that lacks appendages and is composed of loose connective tissue, fat, and telangiectatic vessels. Oculocerebrocutaneous syndrome (Delleman syndrome) presents with periorbital or facial skin tags, orbital cysts, cerebral malformations, and focal cutaneous hypoplasia.10 Young patients with nevoid basal cell carcinoma syndrome may have what appear to be multiple skin tags on the neck, but the lesions are histologically tiny basal cell carcinomas. Moving skin tags suggest a striated muscle hamartoma. Congenital ‘skin tags’ in the preauricular area usually turn out to be accessory tragi or branchial cleft remnants. Smaller lesions can

6.

8.

chemotherapy-sensitive tumors and thus, this approach plays a far greater role.

TUMORS AND TUMOR-LIKE LESIONS OF SUBCUTANEOUS FAT BENIGN TUMORS Nevus lipomatosus superficialis

7.

Cardot-Leccia N, Italiano A, Monteil MC, et al. Naevus lipomatosus superficialis: a case report with a 2p24 deletion. Br J Dermatol. 2007; 156(2):380–381. Wilson-Jones E, Marks R, Pongsehirun D. Naevus superficialis lipomatosus. A clinicopathological report of twenty cases. Br J Dermatol. 1975;93(2):121–133.

TUMORS AND TUMOR-LIKE LESIONS OF SUBCUTANEOUS FAT

Table 21.1  Common immunohistochemical stains

Lane JE, Clark E, Marzec T. Nevus lipomatosus cutaneus superficialis. Pediatr Dermatol. 2003;20(4):313–314. 9. Ozturkcan S, Terzioglu A, Akyol M, et al. Pedunculated lipofibroma. J Dermatol. 2000;27(4):288–290. 10. Cambiaghi S, Levet PS, Guala G, et al. Delleman syndrome: report of a case with a mild phenotype. Eur J Dermatol. 2000;10(8):623–626.

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be removed by scissors or shave excision; larger ones can be excised. Lesions anterior to the tragus should be excised with caution or in consultation with a head and neck surgeon because deeper sinus tracts may be present complicating the surgery. In addition, patients should be screened for hearing problems.

Generalized folded skin with underlying nevus lipomatosus

TUMORS AND TUMOR-LIKE LESIONS OF SUBCUTANEOUS FAT

Symmetric ringed creases associated with thickened subcutaneous tissue in a newborn have been referred to as the ‘Michelin tire baby syndrome’. This is a very rare condition with fewer than 20 case reports. The folds may be caused by an underlying fatty nevus, smooth muscle hamartoma, constriction bands, or fibrosis. Chromosomal abnormalities, familial occurrence, cleft palate, and other developmental abnormalities have been reported. Michelin tire baby syndrome is not a single syndrome, but a clinical finding seen in unrelated disorders.11,12

Lipomas

Hibernoma A hibernoma is a tumor of brown fat, a tissue normally found only in children (and hibernating mammals); surprisingly it occurs most often in young adults, usually in the thigh or shoulder girdle. In a large series, only nine of 170 were found in children.17 The lesions are typically slowly growing soft masses that can be quite large.

Solitary lipoma

Lipomatoses

Ordinary lipomas are uncommon in children but are encountered so frequently in adults that they are the most common mesenchymal neoplasm. The wide histological spectrum of lipomas seen in adults is of little significance in children. Lipomas are most often found on the trunk and proximal portions of the extremities. On palpation, they tend to be multilobular, slightly compressible, subcutaneous masses with smooth margins. Several variants are of clinical interest in young adults. The subgaleal or frontalis-associated lipoma is a firm forehead nodule, often misdiagnosed as an osteoma. It presents a surgical challenge to the unwary because of its deep location. The mobile encapsulated lipoma is typically on the forearm and is freely mobile, much like a subcutaneous marble. Angiolipomas tend to be painful. Sclerotic lipomas are more common in young adults and can be mistaken for the sclerotic fibromas of Cowden syndrome.13 Lipomas can be easily excised, but they can usually be identified clinically with certainty, and the patient can be reassured.

There are a number of rare syndromes in which multiple or diffuse lipomas may be identified:

Lumbosacral lipoma A lumbosacral lipoma is a rare congenital developmental anomaly with mature fat forming a lobular mass in the lumbosacral region. Superficially, there is often a dimple, pit or sinus; in addition, hypertrichosis, skin tags, nevus lipomatosus, hemangioma or even a human tail may be seen. There is almost

11. Kharfi M, Zaraa I, Chaouechi S, et al. Michelin tire syndrome: a report of two siblings. Pediatr Dermatol. 2005;22(3):245–249. 12. Sardana K, Mendiratta V, Kakar N, et al. Spontaneously improving Michelin tire baby syndrome. Pediatr Dermatol. 2003;20(2):150–152. 13. Laskin WB, Fetsch JF, Michal M, et al. Sclerotic (fibroma-like) lipoma: a distinctive lipoma variant with a predilection for the distal extremities. Am J Dermatopathol. 2006;28(4):308–316. 14. Donovan DJ, Pedersen RC. Human tail with noncontiguous intraspinal lipoma and spinal cord tethering: case report and embryologic discussion. Pediatr Neurosurg. 2005;41(1):35–40. 15. Samura K, Morioka T, Hashiguchi K, et al. Coexistence of a human tail and congenital dermal sinus associated with lumbosacral lipoma. Childs Nerv Syst. 2009;25(1):137–141. 16. Xenos C, Sgouros S, Walsh R, et al. Spinal lipomas in children. Pediatr Neurosurg. 2000;32(6):295–307.

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invariably a laminar defect in the underlying spine and sometimes a tethered or split cord. Mature fat may extend through this defect as an intradural or extradural lipoma. When this occurs, then one usually speaks of a lipomyelomeningocele. Slow progressive enlargement with compression or tethering of the spinal cord and neurological defects may result. Recognition of the neurologic features may be delayed until early childhood or later. Lumbosacral skin lesions should prompt imaging studies and neurologic evaluation. Early surgical intervention is generally the treatment of choice, although there is not always reversal of neurologic symptoms.14–16

Encephalocraniocutaneous lipomatosis The syndrome is best viewed as a variant of Proteus syndrome. It is also known as Fishman syndrome, or Haberland syndrome and may clinically overlap with oculocerebrocutaneous syndrome.18 Patients present at birth with a unilateral fatty nevus of the scalp associated with alopecia, as well as facial skin tags, usually periocular. The scalp lesion has been described as nevus psiloliparus, differing from nevus lipomatosus because of the presence of numerous arrector pili muscles.19 In addition, the patients may have ipsilateral ocular choristomas and intracranial lipomas that lead to both epilepsy and mental retardation.20

Infiltrating lipomatosis Infiltrating, diffuse, or congenital lipomatosis usually presents in the first 2 years of life as a soft, poorly circumscribed, enlarging mass. Facial lesions are common and present management difficulties. Histologically, mature fat without hypercellularity or pleomorphism is present in increased quantities in the subcutis and extending into muscle. Recurrence often follows surgical resection. There may be bone hypertrophy leading to macro­ dactyly or hemihypertrophy.21

17. Furlong MA, Fanburg-Smith JC, Miettinen M. The morphologic spectrum of hibernoma: a clinicopathologic study of 170 cases. Am J Surg Pathol. 2001;25(6):809–814. 18. Rubegni P, Risulo M, Sbano P, et al. Encephalocraniocutaneous lipomatosis (Haberland syndrome) with bilateral cutaneous and visceral involvement. Clin Exp Dermatol. 2003;28(4):387–390. 19. Happle R, Kuster W. Nevus psiloliparus: a distinct fatty tissue nevus. Dermatology. 1998;197(1):6–10. 20. Sofiatti A, Cirto AG, Arnone M, et al. Encephalocraniocutaneous lipomatosis: clinical spectrum of systemic involvement. Pediatr Dermatol. 2006;23(1):27–30. 21. Gorken C, Alper M, Bilkay U, et al. Congenital infiltrating lipomatosis of the face. J Craniofac Surg. 1999;10(4):365–368.

Benign and malignant tumors

A fibrolipomatous hamartoma of nerve consists of a proliferation of mature fat and fibrous tissue surrounding peripheral nerves of an extremity. Some 80% of cases involve the median nerve and thus the hand. Some patients present with macrodactyly. The tumor is palpable as a sausage-shaped mass and there is no muscle infiltration.22

Lipofibromatosis This rare neoplasm combines features of a fibrous proliferation with a lipoma. Most lesions involve the extremities and may be present at birth. Typically, there is mature fat tissue with fibro­ blastic proliferation involving the fat septa and adjacent muscle fascia. Nerves are frequently entrapped. The tumors often persist or recur following surgery, but do not metastasize.23

Multiple familial lipomas Also known as familial lipomatosis, this condition is inherited in an autosomal-dominant pattern (OMIM 151900). Mutations in the high-mobility group AT-hook 2 gene at 12q14.3 are responsible. This can be viewed as an adipocyte gene, as it also often mutated in myxoid liposarcoma. Patients develop multiple otherwise ordinary lipomas, most often in adult life, frequently with a rapid onset. There are undoubtedly other genes responsible for multiple lipomas; for example, some pedigrees show multiple angiolipomas. A number of other genodermatoses (Ch. 7) may also feature multiple lipomas. They include Gardner syndrome, Proteus syndrome and Cowden syndrome, as well as the other PTEN-related disorders.

Lipoblastoma and lipoblastomatosis Lipoblastoma and lipoblastomatosis occur most frequently in children Antimongoloid slant of eyes >> Ptosis >> Double row of eyelashes (distiachis) >> High-arched (ogival) palate >> W-shaped low-set posterior hairline >> Puffy hands and feet >> Wide carrying angle of arms >> Hyperconvex, hypoplastic nails >> Hypoplasia of fourth and fifth metacarpals and metatarsals >> Keloids >> Multiple nevocellular nevi >> Shield-shaped chest >> Short stature >> Delayed puberty with primary amenorrhea

A buccal smear is not a reliable test in the neonatal period. In infancy, up to 1 year of age, and again at puberty, there is a characteristic highly elevated level of follicle-stimulating hormone (FSH), reflecting the absence of gonadal development.

Pathophysiology and histogenesis The absence or malfunction of an X chromosome has innumerable profound effects on normal development. For example, the Short Stature Homeobox-containing gene (SHOX) has been found to be the determinant of short stature in TS and other conditions.60 From a cutaneous perspective, there is a failure of normal lymphatic development and, thus, the resulting webbed neck or pterygium colli in infancy and postpubertal lymphedema.48–50

Differential diagnosis The most difficult differential diagnosis is between gonadal dysgenesis and Noonan syndrome, which has been attributed to autosomal dominant mutations in RAS/MAPK genes.61 Many of the clinical features in Noonan syndrome, including facial shape, nails, nevi, and lymphedema, are identical to those seen in gonadal dysgenesis, although short stature and infertility

58. Zvulunov A, Wyatt DT, Laud PW, et al. Influence of genetic and environmental factors on melanocytic naevi: a lesson from Turner’s syndrome. Br J Dermatol. 1998;138:993–997. 59. Gibbs P, Brady B, Gonzalez R, et al. Nevi and melanoma: Lessons from Turner’s syndrome. Dermatology. 2001;202:1–3. 60. Marchini A, Rappold G, Schneider KU. SHOX at a glance: from gene to protein. Arch Physiol Biochem. 2007;113:116–123. 61. Jorge AA, Malaquias AC, Arnhold IJ, et al. Noonan syndrome and related disorders: a review of clinical features and mutations in genes of the RAS/ MAPK pathway. Horm Res. 2009;71:185–193.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

22

are not constant features. Interestingly, cardiac disease in Noonan syndrome tends to be pulmonic stenosis rather than the coarctation of the aorta seen in gonadal dysgenesis. In the newborn period, infants with Down syndrome and congenital hypothyroidism may appear somewhat similar to those with gonadal dysgenesis. Slow growth rate may raise the question of growth hormone deficiency or pituitary dysfunction in later childhood. All short girls with primary amenorrhea should be suspected of having gonadal dysgenesis.

Estrogen replacement therapy at an appropriate age during adolescence is essential for normal maturation of secondary sexual characteristics.62 Treatment of short stature with recombinant growth hormone has become standard therapy.63 There is a high incidence of Hashimoto’s thyroiditis associated with gonadal dysgenesis. Because these patients are already short, growth failure may not be picked up as readily. Periodic examination of the thyroid gland and blood studies of thyroid hormone, TSH, and/or thyroid antibodies may be indicated.

Figure 22.7  Diffuse hyperpigmentation, which persisted into autumn months, in a 11-year-old boy with Addison’s disease.

Pediatric aspects

Presenting history

Girls with gonadal dysgenesis need counseling about their absent secondary sexual characteristics, hormone replacement therapy, and infertility. Although they are not mentally retarded, these children are often socially immature. Some psychologists believe there are specific visuomotor learning disabilities unique to gonadal dysgenesis.

Insidious onset of weakness, lethargy, and apathy, which may be interpreted as psychiatric or emotional disturbance, is the earliest sign of primary adrenocortical insufficiency. Patients often deny feeling ill and may not note how poorly they are feeling until after therapy has been initiated. Abdominal pain is common in children with Addison’s disease. Vomiting, diarrhea, salt craving, headache, sweating, and behavior changes occur later. Eventually, most patients note gradually increasing hyperpigmentation or failure to lose a summer suntan. They often do not seek medical attention unless they present in acute hypocortisolemia crisis.

ADRENAL DISORDERS The adrenal cortex produces three major classes of hormones: glucocorticoids, mineralocorticoids, and androgens. Excesses or deficiencies of glucocorticoids and androgens may have profound cutaneous manifestations. Adrenal steroid hormone biosynthesis is under the control of pituitary ACTH, which in turn is controlled by hypothalamic corticotropin-releasing hormone (CRH). Primary adrenocortical insufficiency, adrenocortical excess, and adrenal androgen excess are discussed separately.

ADRENOCORTICAL INSUFFICIENCY Adrenocortical insufficiency, also known as hypoadrenalism or Addison’s disease, is rare but does occur in children and adolescents.64,65 It is often undiagnosed for long periods of time.

Epidemiology Primary Addison’s disease is seen in Western countries at a rate of approximately 120/million.64 Both sexes are affected equally. Addison’s disease may appear at any age.

62. Hjerrild BE, Mortensen KH, Gravholt CH. Turner syndrome and clinical treatment. Br Med Bull. 2008;86:77–93. 63. Baxter L, Bryant J, Cave CB, et al. Recombinant growth hormone for children and adolescents with Turner Syndrome. Cochrane Database Syst Rev. 2007;24(1): CD003887.

ADRENAL DISORDERS

Therapy and prognosis

Physical examination The skin of the patient with primary adrenal insufficiency shows diffuse brown hyperpigmentation as the hallmark of this disease (Fig. 22.7). There is prominent darkening of the areolae, scrotum, labia, pre-existent nevi, palmar and plantar creases, and scars. Pigmentation of the linea alba (changing it to a linea nigra) may appear on the lower abdomen. There is also a strong association of vitiligo with Addison’s disease. In post-pubertal patients, public and axillary hair becomes sparse. Some patients will also complain of loss of scalp hair. Hyperpigmented, longitudinal streaks may appear on the nails (Fig. 22.8). Blue-black pigment deposits can be seen in the gums, along the tooth margins, and on the hard palate. Associated findings include a wan and weak appearance and a narrow cardiac silhouette on chest radiography. Blood pressure tends to be quite low.

64. Ten S, New M, Maclaren N. Clinical review 130: Addison’s disease 2001. J Clin Endocrinol Metab. 2001;86:2909–2922. 65. Nieman LK, Chanco Turner ML. Addison’s disease. Clin Dermatol. 2006;24: 276–280.

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BOX 22.2 CAUSES OF HYPOADRENALISM

Adrenal dysgenesis/hypoplasia

>> Mutations in nuclear hormone receptor genes >> Congenital adrenal hypoplasia >> Familial glucocorticoid deficiency (unresponsiveness to ACTH) Adrenal destruction

ADRENAL DISORDERS

Figure 22.8  Pigmented linear streaks appeared on the nails of this young woman with primary idiopathic adrenal failure. She sought medical attention for her darkening complexion.

Laboratory findings Low or absent cortisol can be diagnosed by plasma samples or by 24-h collections of urine for 17-hydroxysteroids or urinaryfree cortisol. The best diagnostic test for primary adrenal insufficiency is the failure of adrenal cortisol levels to rise in response to IM or IV ACTH stimulation. If available, direct radioimmunoassay (RIA) of ACTH will reveal high levels. Metabolic abnormalities include low sodium and high potassium with hypoglycemia. Secondary pituitary hypothalamic ACTH insufficiency can be diagnosed by failure of the adrenal to produce 11-deoxycortisol (compound S) during a metyrapone test. Such patients retain normal mineralocorticoid function and do not have pigmentary abnormalities.

Pathophysiology and histogenesis The causes of adrenocorticoid hypofunction are summarized in Box 22.2.64 In those disorders in which there is primary destruction or unresponsiveness of the adrenal gland, there will be consequent high levels of ACTH producing cutaneous hyperpigmentation. It remains unclear whether this hyperpigmentation is secondary to an effect of the elevated levels of ACTH or to simultaneous overproduction of melanocyte-stimulating hormone (MSH). It is also possible that there is elevation of another peptide derived from pre-pro-opiomelanocortin, the large precursor hormone for many of the neuroactive peptides, including ACTH and MSH.

Differential diagnosis In childhood, presenting complaints may most closely mimic inflammatory bowel disease. Likewise, emotional and/or psychiatric disorders may be suspected in the patient with Addison’s disease until adrenal crisis occurs. The diffuse and progressive hyperpigmentation, however, should distinguish Addison’s disease.

66. Lucky AW. Principles of the use of glucocorticosteroids in the growing child. Pediatr Dermatol. 1984;1:226–235.

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>> Autoimmune Addison’s disease (APS-1 and APS-2) >> Adrenal leukodystrophy (males) >> Infections (TB, histoplasmosis, coccidioidomycosis) >> Adrenal hemorrhage – Meningococcus (Waterhouse–Friderichsen) – Neonatal sepsis (Pseudomonas) Impaired steroidogenesis

>> Cholesterol biosynthesis – Abetalipoproteinemia – Smith–Lemli–Opitz syndrome >> Steroid biosynthesis – Congenital adrenal hyperplasias – Mitochondrial disorders >> Drugs Modified from Ten et al. 2001.64

BOX 22.3 STRESS DOSES OF GLUCOCORTICOIDS

Moderate stress or illness

>> Double or triple oral maintenance >> Prednisone 10–15 mg/m2 per day >> Hydrocortisone 50–75 mg/m2 per day If unable to take oral medication

>> Hydrocortisone 75 mg/m2 IM and cortisone acetate 75 mg/m2 IM at least every other day

Severe stress or shock

>> Hydrocortisone 50 mg/m2 IM or IV STAT and then every 6 h (From Lucky AW. Principles of the use of glucocosteroids in the growing child. Pediatr Dermatol. 1984;1:226–235.)

Therapy With replacement of physiologic levels of glucocorticosteroids, there is rapid reversal of all symptoms, including hyperpigmentation. Prognosis is excellent if appropriate therapy is maintained and increased to cover periods of stress, such as surgery or major illness (Box 22.3).66,67 Patients diagnosed with adrenal insufficiency with positive anti-adrenal antibodies should be followed prospectively for the detection and treatment of other manifestations of polyglandular immune syndromes.

67. Axelrod L. Glucocorticoid therapy. Medicine (Balt). 1976;55:39–65.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

ADRENOCORTICAL EXCESS

Table 22.2  Skin manifestations of Cushing disease in children and adolescentsa SKIN MANIFESTATION

(%)

Striae

77.7

Acne

58.3

Hirsutism

63.7b

Acanthosis nigricans

27.7

Ecchymoses

27.7

Hyperpigmentation

16.6

Fungal infections

11.1

a

From Stratakis C, Mastorakos G, Mitsiades NS, et al. Skin manifestations of Cushing disease in children and adolescents before and after the resolution of hypercortisolemia. Pediatr Dermatol. 1998;15:253–258, based on 36 patients with pituitary Cushing Syndrome. bOf 22 girls.

ADRENAL DISORDERS

The term Cushing disease is applied to endogenous overproduction of adrenocortical glucocorticoids, specifically cortisol, in reaction to stimulation from pituitary and/or hypothalamic hormones. Cushing syndrome, however, is a phenotypic copy due to the effects of excessive glucocorticosteroids from causes other than pituitary hypothalamic overstimulation. Cushing syndrome is most commonly produced from the iatrogenic overuse of steroids, usually systemic but rarely also topical. All causes of Cushing syndrome except exogenous steroid hormone administration may manifest signs of combined glucocorticoid and androgen excess.68 By contrast, congenital adrenal hyperplasia (CAH) is a disorder of underproduction of glucocorticoids due to specific enzymatic defects in the biosynthesis of cortisol and resulting overproduction of androgens. (CAH is described separately under Disorders of androgen excess, below.)

22

Presenting history The most consistent finding in the prepubertal child with Cushing syndrome is growth failure with markedly delayed skeletal osseous maturation (bone age). Linear bone growth is exquisitely sensitive to glucocorticosteroids. In addition, there may be weight gain with a redistribution of normal fat to the trunk. Children may also present with insomnia, emotional lability, and headaches associated with hypertension. There may be menstrual irregularities in the postmenarchal female. New onset or exacerbation of acne and/or hirsutism may also be presenting complaints.

Physical examination The most common skin conditions noted in 36 children with Cushing syndrome in one study are listed in Table 22.2.69 Except for striae (Fig. 22.9), all findings resolved within one year of therapy. Striae are due to glucocorticoid stimulation and represent both epidermal thinning and dermal atrophy and appear to occur in areas of skin tension. Large subcutaneous vessels can be seen under a wrinkled, atrophic, transparent epithelial covering. Rupture of striae with slow healing may be a severe cutaneous complication of Cushing syndrome. Hyperpigmentation of striae is associated with generalized hyperpigmentation (such as that seen in Addison’s disease) and is due to overproduction of ACTH and/or MSH. Excessive glucocorticoids also cause redistribution of subcutaneous fat to produce roundness of the cheeks (moon facies), accumulation in the upper back (buffalo hump), and deposits in the buttocks and abdomen, with striking sparing of the extremities. In some cases of Cushing syndrome, there may be secondary plethora, telangiectasia, and flushing of the face. Because of androgen excess, there may be typical acne vulgaris. Acne in childhood may be the presenting sign of an adrenal tumor. However, glucocorticoids alone produce distinct perifollicular pustules on the back, upper arms, chest, and face that are all in the same stages of development. This is called ‘steroid acne’ and is more of a folliculitis. Initially, comedones

68. Shibli-Rahhal A, Van Beek M, Schlechte JA. Cushing’s syndrome. Clin Dermatol. 2006;24:260–265.

Figure 22.9  Striking number and distribution of deep, red striae in a young woman with Cushing syndrome.

are not present. With a prolonged course, these primary follicular pustules may develop abnormal keratinization and secondary comedones, a pathophysiology quite different from that seen in acne vulgaris. Acanthosis nigricans can also be a feature of Cushing syndrome and will be discussed later in this chapter. Glucocorticoids promote fine, long, downy hair, especially on the sides of the face (Fig. 22.10), but androgens cause true hirsutism in secondary sex locations such as upper lip, chin, mid chest and abdomen, and around the areolae. Secondary cutaneous features associated with glucocorticoid excess are primarily due to superinfection with organisms whose normal colonization becomes pathologic in the milieu of excessive glucocorticoids. Tinea versicolor (due to superficial

69. Stratakis C, Mastorakos G, Mitsiades NS, et al. Skin manifestations of Cushing disease in children and adolescents before and after the resolution of hypercortisolemia. Pediatr Dermatol. 1998;15:253–258.

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tion. ACTH overproduction includes disorders of the pituitary and/or hypothalamus as well as rare cases of ectopic ACTH production from neural crest tumors arising in pancreas, thymus, or ovary. These rare tumors have been described primarily in adults. Primary pigmented nodular adrenocortical disease (PPNAD) (now reported in McCune–Albright syndrome,70 in Carney complex or as an isolated condition) has been associated with several gene defects.71 Benign adenomas,72 and malignant carcinomas72,73 as well as exogenous excess of systemic, topical, inhaled or intralesional glucocorticosteroids used therapeutically74 will all result in suppressed ACTH. In all of the disorders except exogenous treatment, there may be concurrent adrenal androgen hyperproduction.

ADRENAL DISORDERS

Differential diagnosis Figure 22.10  Fine downy hair on the cheeks of a young woman with Cushing syndrome. She also had new onset of acne, oral and nail candidiasis, and redistribution of body fat.

colonization of Pityrosporum ovale) may appear prepubertally and may be refractory to standard therapy. Candidiasis can occur on the oral mucosa (thrush), vaginal mucosa (vaginitis), nail plate and bed (onychomycosis) and surrounding tissues (paronychia), interdigital webs (blastomycetica interdigitalis erosio), the corners of the mouth (perlèche), and intertriginous folds such as neck, axillae, under the breast and in the groin (intertrigo). Bacterial infections, especially with Staphylococcus aureus, can cause diffuse folliculitis, furunculosis, and large carbuncles and abscesses in glucocorticoid excess. Other features of adrenocortical excess include hypertension, glucose intolerance or frank diabetes mellitus, altered mental status, emotional lability, and menstrual disturbances.

Laboratory findings The most reliable diagnostic tools to diagnose glucocorticoid excess are serum ACTH levels, a 24-h urine level of free cortisol, and plasma cortisol levels showing absence of normal diurnal variation. Normally, plasma cortisol is highest in the early morning and reaches a low level after noon. Failure to reach the low afternoon levels is suggestive of Cushing syndrome. Dexa­ methasone suppression tests and diagnostic imaging studies such as ultrasound, computed tomography (CT) and magnetic resonance imaging are essential to differentiate pituitary ACTH excess from primary adrenal tumors.

Pathophysiology Glucocorticoid excess can be a result of excessive stimulation of the adrenal gland from ACTH or of primary adrenal hypersecre-

70. Kirk JMW, Brain CE, Carson DJ, et al. Cushing’s syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome. J Pediatr. 1999;134:789–792. 71. Horvath A, Stratakis C. Primary pigmented nodular adrenocortical disease and Cushing’s syndrome. Arq Bras Endocrinol Metabol. 2007;51:1238–1244. 72. Ciftci AO, Senocak ME, Tanyel FC, et al. Adrenocortical tumors in children. J Pediatr Surg. 2001;36:549–554. 73. Liou LS, Kay R. Adrenocortical carcinoma in children. Review and recent innovations. Urol Clin North Am. 2000;27:403–421.

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The usual diagnostic dilemma is to distinguish between Cushing syndrome and exogenous obesity. In addition, patients with polycystic ovary syndrome, who tend to be obese with irregular menses as well as acne and hirsutism, may be thought to have Cushing syndrome. Children presenting with precocious puberty or pseudoprecocious puberty (i.e., partial precocious development without true puberty) should be evaluated for adrenal tumors. Differential diagnosis also includes diabetes mellitus and obesity with multiple secondary infections.

Therapy and prognosis Cushing syndrome can be treated by transsphenoidal hypophysectomy along with radiation and chemotherapy of pituitary adenomas.69,75 In hypercortisolism secondary to adrenal nodular hyperplasia and adrenal tumors surgery is indicated.72,73,76 Malignant adrenal tumors have a very poor prognosis72,73,76 despite surgical excision and chemotherapy. Cushing’s disease can be iatrogenic. The various potencies of systemic glucocorticoids are illustrated in Table 22.3.66 Although there are studies of average plasma and tissue half-life and hypothalamic pituitary suppression, each individual has a different metabolic clearance rate and thus treatment must be individualized. In general, therapy with the shortest acting, least potent steroid for the shortest period of time that will give therapeutic benefit is most highly recommended. Guidelines for what duration of treatment will require careful tapering rather than immediate discontinuation of steroids are not established. Certainly, therapy beyond two to three weeks has been shown to have prolonged suppressive effects on the hypothalamic pituitaryadrenal axis. In fact, suppression is achieved with doses as low as 30 mg prednisone for 5 days or 20 mg prednisone for 7 days in adults.66 Response to a 30-min IM or IV bolus of ACTH or cosyntropin (Cortrosyn) may provide useful information about adrenal recovery in patients treated for long periods of time.

74. Güven A, Gülümser O, Ozgen T. Cushing’s syndrome and adrenocortical insufficiency caused by topical steroids: misuse or abuse? J Pediatr Endocrinol Metab. 2007;20:1173–1182. 75. Savage MO, Chan LF, Grossman AB, et al. Work-up and management of paediatric Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes. 2008;15:346–351. 76. Patalano A, Brancato V, Mantero F. Adrenocortical cancer treatment. Horm Res. 2009;71:S99–S104.

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Table 22.3  Potencies of glucocorticoids COMPOUND

PLASMA HALFLIFE (min)

TISSUE DURATION (h)

HPA SUPPRESSION (h)

GLUCOCORTICOID POTENCY

DOSE EQUIVALENTS (mg)

MINERALOCORTICOID ACTIVITY

Cortisol (hydrocortisone)

60–115

4–8

24–36

1

20

+

Cortisone acetate

30–90

6 (PO, IV) 72 (IM)

24–36

0.8

25

+

Prednisone Dexamethasone

60 110–300+

6–8

24–36

4

8–12

48

25–40

5 0.5–0.75

+ −

Doses can be tapered gradually to a physiologic level and then switched to an alternate-day regimen, which allows for more recovery of the pituitary-adrenal axis. Alternately, some physicians prefer gradually reducing an alternate-day dose until 1 day’s dosage is eliminated and then reducing the other alternate dosage. The recurrence of primary disease or appearance of withdrawal symptoms is a guideline for this kind of taper. For intercurrent illnesses or major stress, such as surgery or trauma, guidelines are available for replacement (Box 22.3).64 Excessive use of intralesional and even topical steroids, especially highpotency steroids, can lead to iatrogenic Cushing disease with growth retardation and many of the major side-effects, including extraordinary local atrophy.74 For this reason, children on longterm topical steroids should, if possible, be treated with the smallest amount of low-potency steroids needed for therapeutic effect.

DISORDERS OF ANDROGEN EXCESS Excessive amounts of circulating androgens can contribute to cutaneous disorders including acne, hirsutism, and alopecia. Since manifestations of androgen excess are quite variable from individual to individual, a high index of suspicion is required for diagnosis of an underlying hyperandrogenic disorder. The causes of androgen excess are varied: these include tumors as well as functional overproduction of androgens from the ovary and/or adrenal gland (Box 22.4) and exogenous use of anabolic steroids by athletes. Insulin resistance is a key factor in many patients with polycystic ovary syndrome (PCOS).

Epidemiology Onset of androgen excess may occur at any age and can affect both sexes. Depending on the disorder, there may be a genetic predisposition.

77. Rosenfield RL, Lucky AW. Acne, hirsutism, and alopecia in adolescent females. Endocrin Metab Clin North Am. 1993;22:507–532. 78. Essah PA, Wickham EP 3rd, Nunley JR, et al. Dermatology of androgenrelated disorders. Clin Dermatol. 2006;24:289–298. 79. Practice Committee of the American Society for Reproductive Medicine. The evaluation and treatment of androgen excess. Fertil Steril. 2004;82:S173–S180.

DISORDERS OF ANDROGEN EXCESS

(From Lucky AW. Principles of the use of glucocosteroids in the growing child. Pediatr Dermatol. 1984;1:226–235.)

BOX 22.4 CAUSES OF ANDROGEN EXCESS

Ovarian or testicular

>> Benign or malignant tumors >> Polycystic ovarian disease Adrenal

>> Benign or malignant tumors >> Congenital adrenal hyperplasia >> Functional adrenal androgen overproduction (premature or exaggerated adrenarche)

Clinical features Prepubertal children with androgen excess may present with precocious sexual development as a primary complaint. Such development would be sex-appropriate in males and inappropriate in females. Besides rapid linear growth and development of axillary and pubic hair, there is increased maturation of genitalia in boys and clitoromegaly in girls. Acne vulgaris and hirsutism may be early signs of an androgen abnormality. One of the earliest signs of androgen excess is the appearance of adult-type underarm odor. Postpubertally, diagnosis may be more difficult because acne is so common, but hirsutism, alopecia of the scalp, amenorrhea, irregular menses, and infertility are more reliable indicators of androgen excess.

Physical examination The main clinical features of androgen excess, acne, hirsutism and androgenetic alopecia,77–79 have been covered in Chapters 13 and 11. Acne may be the first sign of androgen excess and, in normal puberty, is associated with rising levels of DHEAS.80,81 In older adolescents and adults, acne is also

80. Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in early adolescent boys. Correlations with pubertal maturation and age. Arch Dermatol. 1991;127:210–216. 81. Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in premenarchal girls. An early sign of puberty associated with rising levels of dehydroepiandrosterone. Arch Dermatol. 1994;130:308–314.

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Figure 22.11  Typical thinning hair on the crown of the scalp in a 13-year-old girl. Onset was early, just prior to menarche. Her mother had had a similar pattern of female pattern hair loss (androgenic alopecia).

associated with higher levels of free testosterone.82 Hirsutism is defined as excessive terminal hair in androgen-dependent locations. Although normal amounts of terminal hair have been established for women over age 18,83 there are different standards for adolescent girls: smaller amounts of upper lip hair are abnormal in girls ages 10–19 than in adult women.84 Androgenetic alopecia in females is usually confined to the crown of the scalp (Fig. 22.11); in males there is bi-frontal as well as vertex thinning.

Laboratory findings Accelerated growth with upward crossing of percentiles is indicative of androgen excess. Advancement of the bone age (derived from standards of radiographs of the bones of the left hand and wrist85) is also indicative. Elevated plasma free testosterone (T) and dehydroepiandrosterone (DHEAS) are two common findings in androgen excess. Testosterone circulates bound to a carrier protein, testosterone estrogen-binding globulin (TEBG), also known as sex hormone-binding globulin (SHBG). A small fraction of T is also bound to albumin. The small, free fraction of T is biologically active. Assays of total T measure both T and TEBG; thus changes in TEBG may misleadingly affect the total T value without biologic significance. For example, estrogen increases TEBG production and elevates total T, but in fact the increased availability of binding sites actually lowers biologically active free T. By contrast, androgens depress TEBG; thus, total T values appear relatively lower in precisely those patients who

82. Lucky AW, Biro FM, Simbartl LA, et al. Predictors of severity of acne vulgaris in young adolescent girls: Results of a five-year longitudinal study. J Pediatr. 1997;130:30–39. 83. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab. 1961;21:1440–1447. 84. Lucky AW, Biro FM, Daniels SR, et al. The prevalence of upper lip hair in black and white girls during puberty: A new standard. J Pediatr. 2001;138: 134–136.

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have functionally high free T. Free T is a much more reliable measurement than total T. One problem with measurements of T is that there are fluctuations in circulating levels over minutes, hours, and days. The ideal way to overcome this problem is by multiple sampling, such as three consecutive hourly samples. But this plan has economic limitations. The origin of T is appro­ ximately equal from the ovary and the adrenal gland and thus measurement of T or free T cannot distinguish ovarian from adrenal sources. DHEA and its sulfate, DHEAS, have been found to be elevated in about one-half of female acne patients.77–79 These hormones are >95% adrenal in origin and serve as markers for adrenal overproduction of androgen. Other hormones may be elevated in special circumstances. Delta4-androstenedione (A) is produced by both the ovary and the adrenal gland and provides about one-half the plasma T via peripheral conversion. It is very rapidly metabolized and thus is an unreliable marker for elevated androgens. 17-α-hydroxyprogesterone (17-Prog) is a specific marker for 21-hydroxylase deficiency, and 11-deoxycortisol (compound S) is a specific marker for 11-β-hydroxylase deficiency, the two most common forms of congenital adrenal hyperplasia. In milder forms of this disease, baseline levels of these hormones may not be elevated, and diagnostic stimulation with ACTH is necessary to diagnose such enzymatic defects definitively.86–88 Baseline levels of 17-Prog should be measured in the follicular phase of the menstrual cycle because in the luteal phase there is a large ovarian contribution of 17-Prog. The gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) demonstrate a ratio of LH/FSH elevated above 3 : 1 in a majority of patients with polycystic ovarian (PCO) disease. ACTH stimulation and dexamethasone suppression tests may define specific enzymatic defects and diagnose non-suppressible adrenal tumors. From a practical point of view, plasma free T, DHEAS, LH, and FSH seem to be reasonable tests to screen patients in whom hyperandrogenemia is suspected.

Pathophysiology There are three sources of androgenic steroid hormones: the gonads (ovary or testes), the adrenal gland, and a variety of peripheral organs including the skin, which can convert less potent precursors to highly potent androgens. Interactions between these are abundant and often frustrate our attempts to neatly categorize the cause of androgen excess.

The ovary Ovarian tumors may be virilizing and can be benign or malignant. Usually, there is rapid onset of symptoms and the timing is not necessarily associated with puberty. Testosterone is often very high (i.e., >200 ng/dL). Ovarian tumors can be diagnosed

85. Greulich WW, Pyle, SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford: Stanford University Press; 1959. 86. Demirci C, Witchel SF. Congenital adrenal hyperplasia. Dermatol Ther. 2008;21:340–353. 87. Lin-Su K, Nimkarn S, New MI. Congenital adrenal hyperplasia in adolescents: diagnosis and management. Ann N Y Acad Sci. 2008;135: 95–98. 88. Speiser PW. Nonclassic adrenal hyperplasia. Rev Endocrinol Metab Disord. 2009;10:77–82.

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22

Figure 22.12  Simplified diagram of adrenal

ACTH

a 17-PREG

c 17-PROG

b

d CPD S

CORTISOL

steroid biosynthesis. Any interruption in the production of cortisol will lead to excessive ACTH production and consequent androgen excess. 17-Preg, 17-hydroxypregnenolone; 17-Prog, 17α-hydroxyprogesterone; CPD S, 11-deoxycortisol; DHEA, dehydroepiandrosterone; A, Δ4− androstenedione; T, testosterone; DHT, dihydrotestosterone.

b a A

T

DHT

(a) 3β-Hydroxysteroid dehydrogenase (b) C17-20-Lyase (c) 21-Hydroxylase (d) 11β-Hydroxylase

by pelvic examination, ultrasound, magnetic resonance imaging (MRI) scan, laparoscopy, or laparotomy. Polycystic ovary syndrome (PCOS)89,90 is the most common ovarian abnormality encountered in association with hyperandrogenemia and will be discussed in detail below. The ovary is relatively quiescent in childhood until puberty when the production of LH and FSH increases. This phenomenon begins as early as age 7 or 8 years, with night time spikes of LH that may be detected with 24-h urinary assays. LH stimulates the thecal cells of the ovarian follicle to produce T and, most abundantly, A, which are converted by the enzyme aromatase to the estrogens, estrone (E1) or estradiol (E2), respectively. These androgens are the primary product of the ovary. Androstenedione can be converted to T inside or outside the ovary, and ovarian production accounts for approximately 50% of circulating testosterone. Aromatase is present in granulosa cells and its action is catalyzed by FSH. As granulosa cells multiply in a dominant, growing follicle cyclically each month before ovulation, that follicle produces a surge of estrogen that helps induce ovulation. After ovulation, the granulosa cells transform to luteal cells and primarily produce progesterone (Prog) and 17-Prog. If instead of a cyclic production of estrogen there is tonic, continuous output, especially of E1, a paradoxical positive feedback of LH occurs.91 Thus, if there is overproduction of A, it can be converted to E1, which will stimulate high levels of LH, perpetuate further increase in androgen, and further disrupt normal cyclic ovulation. The result of elevated androgens from any source, including the adrenal gland, may be to raise the ratio of LH/FSH by the tonic production of estrogen and the process becomes self-perpetuating. Thus, follicles that might have become dominant and ovulated become the androgen-producing cysts of polycystic ovaries instead. More recent theories postulate a role for prenatal androgen excess in PCOS.92

In summary, the ovary produces about 50% of the circulating T, much of which is derived from A. E1 and E2 are derived from A and T, respectively, in a cyclic manner during normal ovulation, but when follicular maturation is interrupted, there may be androgen-producing cysts associated with increased ratio of LH/FSH. The rationale for treatment of PCOS is primarily to interrupt tonic LH stimulation, and this is most easily accomplished with estrogen-containing oral contraceptives.

89. Rosenfield RL. What every physician should know about polycystic ovary syndrome. Dermatol Ther. 2008;21:354–361. 90. O’Brien RF, Emans SJ. Polycystic ovary syndrome in adolescents. J Pediatr Adolesc Gynecol. 2008;21:119–128. 91. Yen SSC. The polycystic ovary syndrome. Clin Endocrinol. 1980;12:177–208. 92. Franks S. Polycystic ovary syndrome in adolescents. Int J Obes (Lond). 2008;32:1035–1041.

93. De Peretti E, Forest MG. Pattern of plasma dehydroepiandrosterone sulfate levels in humans from birth to adulthood: evidence for testicular production. J Clin Endocrinol Metab. 1978;47:572–577. 94. Winter JSD, Hughes IA, Reyes FI, et al. Pituitary-gonadal relations in infancy. 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age. J Clin Endocrinol Metab. 1976;42:679–686.

DISORDERS OF ANDROGEN EXCESS

DHEA

The adrenal gland Adrenal tumors, including adenomas and carcinomas as well as pituitary-hypothalamic ACTH-producing tumors (Cushing syndrome), can all be rare causes of virilization in children and adults. Usually, onset is abrupt and signs of androgen excess severe. Diagnosis is made by imaging techniques or exploratory surgery. More common adrenal abnormalities causing hyper­ androgenemia are biochemical disorders: congenital adrenal hyperplasia and functional overproduction of androgens in response to ACTH. The primary secretory product of the adrenal is cortisol (Fig. 22.12). In order to produce cortisol from the basic precursor cholesterol, a series of enzymatic steps produce intermediates that have androgenic potential. ACTH stimulates the adrenal and responds only to cortisol (or very similar compounds such as prednisone or dexamethasone) for negative feedback control. Similar to the ovary, the androgen-predominant cells of the inner zona reticularis of the adrenal cortex are quiescent in childhood from about ages 1–7 but are quite active in the perinatal months and pubertal years.93,94 The inner fetal adrenal zone of the newborn adrenal gland (which is analogous to the zona reticularis, both histologically and biochemically) disappears in the first year of life and a well-defined zona reticularis first

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appears in late childhood between the ages of 5 and 8.95 The presence of these zones is associated with a biochemical synthetic pathway that favors the production of androgens and androgen precursors, notably DHEA and its sulfate DHEAS.

Premature adrenarche

DISORDERS OF ANDROGEN EXCESS

The process of adrenal maturation is termed adrenarche, and it appears to be independent of gonadal development. The specific changes noted in adrenarche are a relatively decreased efficiency of the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) and increased efficiency of C17–20 lyase, resulting in elevated levels of 17-α-hydroxypregnenolone (17-Preg), DHEA, and A.96,97 Premature adrenarche (PA) is the early (before age 8) reappearance of adrenal androgens (adrenarche) and stimulates growth of public and axillary hair (pubarche). It is much more common in girls. Although considered ‘benign’ for many years, there is growing evidence that PA may be the first sign of hormonal imbalance: many of these girls will go on to develop insulin resistance, NIDDM, and/or PCOS.98–100 Girls with PA and acanthosis nigricans or elevated insulin/glucose ratios may be particularly at risk.101 Some girls with premature adrenarche actually have late-onset congenital adrenal hyperplasia.102,103 The mature adrenal gland contributes approximately one-half of the circulating plasma T, primarily via conversion of A to T. The adrenal is also the source of >95% of the circulating DHEA and DHEAS, which can serve as markers of adrenal androgen production. DHEAS is present in 1000-fold higher quantities than DHEA. Although DHEA itself is not a strong androgen, it can be metabolized peripherally in tissues, including skin, to more potent androgens and thus has androgenic potential.

Figure 22.13  Ambiguous genitalia (intersex) in a female 46XX infant with congenital adrenal hyperplasia due to severe 21-hydroxylase deficiency. Note hyperpigmentation of the fused labia, clitoral hypertrophy, and a phallic urethra.

Congenital adrenal hyperplasia If there is a deficient or inefficient enzyme in any step along the pathway to cortisol biosynthesis, which results in lowered cortisol, there will be a compensatory increase in ACTH via negative feedback control. The resulting accumulation of androgens or androgenic precursors will produce clinical signs of androgen excess. In the classical form of congenital adrenal hyperplasia (CAH) where the enzyme block has been severe in utero, infants are born with ambiguous genitalia and shock from lack of cortisol. The primary skin manifestation seen is hyperpigmentation of the genitalia (Fig. 22.13). It can be confused with the normal hyperpigmentation seen in dark-skinned neonates (Fig. 22.14). However, of interest to dermatologists are the milder enzymatic defects, which may not manifest with signs of androgen excess until puberty. Among the young women who present with acne

95. Dhom G. The prepubertal and pubertal growth of the adrenal (adrenarche). Beitr Path Bd. 1973;150:357–377. 96. Rich BH, Rosenfield RL, Lucky AW, et al. Adrenarche: changing adrenal response to adrenocorticotropin. J Clin Endocrinol Metab. 1981;52: 1129–1136. 97. Dickerman Z, Grant DR, Faiman C, et al. Intraadrenal steroid concentrations in man: zonal differences and developmental changes. J Clin Endocrinol Metab. 1984;59:1031–1036. 98. Ibáñez L, Dimartino-Nardi J, Potau N, et al. Premature adrenarche-normal variant or forerunner of adult disease? Endocr Rev. 2000;21:671–696. 99. Ibanez L, Potau N, Marcos MV, et al. Adrenal hyperandrogenism in adolescent girls with a history of low birthweight and precocious pubarche. Clin Endocrinol. 2000;53:523–527. 100. DiMartino-Nardi J. Pre- and postpubertal findings in premature adrenarche. J Pediatr Endocrinol Metab. 2000;13:1265–1269.

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Figure 22.14  Normal black newborn girl with hyperpigmentation of the labia.

and/or hirsutism, ACTH stimulation tests can detect some specific enzyme defects (i.e., mild- or late-onset CAH).104,105 The most common form of CAH is 21-hydroxylase deficiency.86–88 It is an autosomal-recessive disorder and the heterozygote carrier state occurs as frequently as 1 in 35 to 1 in 50 individuals. Elevated 17α-OH-Prog response to ACTH is a marker for this disorder. 11-β-Hydroxylase deficiency (with high 11-deoxycortisol or Cpd S response to ACTH) and 3β-HSD (with high 17-Preg and DHEA response to ACTH) are other forms of CAH found in young adult women.

101. Vuguin P, Saenger P, DiMartino-Nardi J. Fasting glucose insulin ratio: A useful measure of insulin resistance in girls with premature adrenarche. J Clin Endocrinol Metab. 2001;86:4618–4621. 102. Siegel SF, Finegold DN, Urban MD, et al. Premature pubarche: etiological heterogeneity. J Clin Endocrinol Metab. 1992;74:239–247. 103. Hawkins LA, Chasalow PI, Blethen SL. The role of adrenocorticotropin testing in evaluating girls with premature adrenarche and hirsutism/ oligomenorrhea. J Clin Endocrinol Metab. 1992;74:248–253. 104. Siegel SF, Finegold DN, et al. ACTH stimulation tests and plasma dehydroepiandrosterone sulfate levels in women with hirsutism. N Engl J Med. 1990;323:849–854. 105. Eldar-Geva T, Hurwitz A, Vecsei P, et al. Secondary biosynthetic defects in women with late-onset congenital adrenal hyperplasia. N Engl J Med. 1990;323:855–863.

Not all adrenal overproduction of androgen neatly fits into specific enzymatic defects. There also exist functional abnormalities of adrenal response to ACTH that have been called exaggerated adrenarche, or functional adrenal hyperandrogenism. The existence of such a functional state might help explain how stress, via ACTH, could cause flares of androgen-dependent acne.

Primary treatment of acne is discussed at length in Chapter 13. Hormonal therapy should be reserved for specific patients not responsive to conventional therapy or who have a welldocumented ovarian or adrenal disorder. Most patients with acne do not have androgen excess. By contrast, significant hirsutism and androgenetic alopecia are very likely due to androgen excess. Non-hormonal therapy for hirsutism includes bleaching, plucking, waxing, shaving, chemical depilatories, topical eflornithine, electrolysis, and laser therapy. Topical minoxidil is the only non-hormonal therapy for androgenetic alopecia to be shown clinically superior to placebo, despite many claims that some over-the-counter products stimulate hair growth (see Ch. 11). Hormonal therapy for acne, hirsutism, and androgenetic alopecia includes oral contraceptives, low-dose steroids, and anti­ androgens. Estrogen-containing oral contraceptives have been shown to be effective for acne.108,109 Estrogen-containing oral contraceptives act by elevating TEBG and thus decreasing available free T as well as by interfering with the normal gonadotro-

pin feedback mechanism and essentially eliminating ovarian hormone production. Some oral contraceptives which have less androgenic progestins or a progestin which is also an antiandrogen, such as drospirenone, are theoretically more effective, but most combined oral contraceptive pills do improve acne. Gonadotropin releasing hormone (GnRH) analogs, alone or in combination with estrogens,110,111 may be useful in some situations. Progestogen-only contraceptives, given orally, intramuscularly, or via implantation, are not useful for acne and actually exacerbate it because of the androgenic activity of some progestins.112 Low-dose corticosteroids act by suppressing adrenal production of androgens via ACTH suppression.113 Doses such as 2.5– 5 mg prednisone or 0.25–0.5 mg dexamethasone, given at night to suppress the late night diurnal surge of ACTH, may be effective. However, patients need to be carefully monitored for adreno­cortical suppression, especially with dexamethasone, which could be life-threatening. Antiandrogens are drugs which interfere with the effect of androgens on the end organ, either as competitive inhibitors of the androgen receptor or as blockers of 5-α-reductase.114 Spironolactone, a competitive inhibitor of the androgen receptor, is the most widely used antiandrogen in the USA, although blockage of androgen excess is an off-label use of this medication.115–117 It is given as 50–200 mg/day in two doses with meals. Polymenorrhea, increased urination, breast tenderness, and fatigue are the most common side-effects. Hyperkalemia is rare, especially at the lower doses. Spironolactone seems to be especially useful in older adolescents and women with acne flares related to the menstrual cycle. It is not used in males. Cyproterone acetate, another inhibitor of the androgen receptor,111 combined with ethinyl estradiol, is successfully used in many countries for hyperandrogenemia but is not available in the USA. Flutamide, a non-steroidal competitive inhibitor of the androgen receptor,118 has also been recommended for hirsutism, even in adolescents, but with its potential for hepatotoxicity, it is less popular. Finasteride inhibits the Type 2, 5-α reductase found in hair follicles and thus is useful in hirsutism and androgenetic alopecia.119 However, the Type 1 enzyme predominates in sebaceous glands so finasteride is not useful in acne. Extreme caution needs to be exercised when using antiandrogens in reproductive-aged women to avoid potential teratogenicity affecting the development of male genitalia.

106. Thiboutot D, Jabara S, McAllister JM, et al. Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1). J Invest Dermatol. 2003;120:905–914. 107. Chen W, Thiboutot D, Zouboulis CC. Cutaneous androgen metabolism: basic research and clinical perspectives. J Invest Dermatol. 2002;119: 992–1007. 108. Lucky AW, Henderson TA, Olson WH, et al. Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris. J Am Acad Dermatol. 1997;37:746–754. 109. Thiboutot D, Archer DF, Lemay A, et al. A randomized, controlled trial of a low dose contraceptive containing 20 µg of ethinyl estradiol and 100 µg of levonorgestrel for acne treatment. Fertil Steril. 2001;76:461–468. 110. Vegetti W, Testa G, Maggiono P, et al. An open randomized comparative study of an oral contraceptive containing ethinyl estradiol and cyproterone acetate with and without the GnRH analogue goserelin in the long-term treatment of hirsutism. Gynecol Obstet Invest. 1996;41:260–268. 111. Carmina E, Lobo RA. Gonadotrophin-releasing hormone agonist therapy for hirsutism is as effective as high dose cyproterone acetate but results in a longer remission. Hum Reprod. 1997;12:663–666. 112. Darney PD. The androgenicity of progestins. Am J Med. 1998;98:104S–110S.

113. Carmina E, Lobo RA. The addition of dexamethasone to antiandrogen therapy for hirsutism prolongs the duration of remission. Fertil Steril. 1998;69:1075–1079. 114. Schmidt JB. Other antiandrogens. Dermatology. 1998;196:153–157. 115. Cumming DC, Yang JC, Rebar RW, et al. Treatment of hirsutism with spironolactone. JAMA. 1982;247:1295–1298. 116. Moghetti P, Castello R, Zamberlan N, et al. Spironolactone, but not flutamide, administration prevents bone loss in hyperandrogenic women treated with gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab. 1999;84:1250–1254. 117. Sprtizer PM, Lisboa KO, Mattiello S, et al. Spironolactone as a single agent for long-term therapy of hirsute patients. Clin Endocrinol. 2000;52:587–594. 118. Ibanez L, Potau N, Marcos MV, et al. Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia and hyperinsulinism in nonobese, adolescent girls: Effect of flutamide. J Clin Endocrinol Metab. 2000;85:3251–3255. 119. Moghetti P, Tosi F, Tosti A, et al. Comparison of spironolactone, flutamide and finasteride efficacy in the treatment of hirsutism: A randomized, double blind, placebo-controlled trial. J Clin Endocrinol Metab. 2000;85:89–94.

Peripheral metabolism of androgens Many tissues, including skin, hair, and sebaceous glands, have androgen receptors and enzymes to further metabolize steroid hormones.106 Androgens are taken up into the cytoplasm, attach to cytosol receptors, and are translocated to nuclear receptors where their effect is mediated via RNA synthesis. Testosterone is converted to the more potent dihydrotestosterone (DHT) by 5-α-reductase in the skin as well as other tissues. Skin has the ability to metabolize less potent androgenic precursors such as DHEA into potent androgens such as T and DHT. Inactive steroid end products such as 5-α-androstanediol glucuronide, a reduced metabolite of DHT, may serve as a marker for cutaneous androgen metabolism.107

Therapy and prognosis

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DISORDERS OF ANDROGEN EXCESS

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DISORDERS OF INSULIN RESISTANCE INTRODUCTION The concept of insulin resistance has unified a group of seemingly unrelated disorders, many of which are familiar to dermatologists. Insulin resistance is the inability of insulin to exert its metabolic effects.120,121 It can result from a variety of mechanisms including primary and secondary disorders of the insulin receptor, post-receptor defects, antibodies to the insulin receptor, and other abnormalities of gluconeogenesis. Obesity is one of the primary causes of insulin resistance. No matter what the cause, the end result is hyperinsulinemia. High circulating levels of insulin are important in the pathogenesis of a variety of disorders, which will be discussed below. DISORDERS OF INSULIN RESISTANCE

ACANTHOSIS NIGRICANS The association of acanthosis nigricans (AN) with tumors, endocrine disorders, and obesity has been noted in the literature for decades. The correlation of insulin resistance with AN has been recognized with the landmark work of Kahn et al. in 1976,122 The old classification of ‘malignant’ and ‘benign’ AN should now be discarded in favor of a more etiologic classification. There are diverse causes of insulin resistance and AN123 (Box 22.5). Because AN is common, occurring in 0.5% of adolescents of European ancestry, 6% of Hispanics, 13% of African-Americans, and up to 40% of native Americans,124 dermatologists need to be aware of the associated findings.

BOX 22.5 DISORDERS ASSOCIATED WITH ACANTHOSIS NIGRICANS

>> Obesity >> Insulin-resistance syndromes – Leprechaunism (Donohue syndrome) – Rabson–Mendenhall syndrome – Congenital and acquired generalized and partial lipodystrophies

>> Polycystic ovary syndrome (PCOS) >> Endocrine disorders – Hyperandrogenic states – Acromegaly, gigantism – Cushing disease, pituitary basophilism – Hypogonadal syndromes with insulin resistance – Addison’s disease – Hypothyroidism >> Hormone production by malignant neoplasms >> Iatrogenic – Glucocorticoid therapy – Diethylstilbestrol, oral contraceptives >> Syndromes – Prader–Willi syndrome – Alstrom and other familial hypogonadal syndromes – Crouzon syndrome – Ataxia telangiectasia

Physical examination Acanthosis nigricans refers to a complex of skin findings usually localized to flexural areas of the body such as the neck, axilla, groin, and under the breasts (Figs 22.15, 22.16). There is hyperpigmented, velvety, rugated hypertrophy of the overlying skin. Parents complain that their children’s skin is dirty and cannot be scrubbed clean. Often there are associated papillomatous overgrowths, which appear to be skin tags. In addition to these changes in the flexural areas, one also finds firm, verrucous, hyperpigmented plaques with pebbly surfaces located over bony prominences such as elbows, knees, and knuckles (Fig. 22.17). The buccal mucosa can also develop a pebbly surface.

Laboratory findings Laboratory findings vary with the etiology of the AN in each individual. Hyperinsulinemia seems to be present in most, if not all, cases.

Pathophysiology and histogenesis The term acanthosis nigricans is really a misnomer, as skin biopsy exhibits neither acanthosis nor hyperpigmentation. The

120. Longo N, Wang Y, Smith SA, et al. Genotype-phenotype correlation in inherited severe insulin resistance. Hum Mol Genet. 2002;11:1465–1475. 121. Nakae J, Accili D. The mechanism of insulin action. J Pediatr Endocrinol Metab. 1999;12:721–731. 122. Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans. N Engl J Med. 1976;294:739–745.

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Figure 22.15  Acanthosis nigricans of the neck in an obese adolescent boy with Down syndrome and hypothyroidism.

123. Sinha S, Schwartz RA. Juvenile acanthosis nigricans. J Am Acad Dermatol. 2007;57:502–508. 124. Stuart CA, Gilkison CR, Smith MM, et al. Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus. Clin Pediatr. 1998;37:73–80.

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DISORDERS OF INSULIN RESISTANCE

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

Figure 22.18  An adolescent girl with confluent and reticulate papillomatosis Figure 22.16  Acanthosis nigricans of the axilla in the same patient shown in

of Gougerot and Carteaud (CARP) on her back. This responded to therapy with minocycline.

Figure 22.15.

the neck, and is easily removed with alcohol, but not with soap and water. CARP is histologically identical to AN but occurs on the trunk in a reticulate pattern. Oddly, it responds to the tetracycline class of antibiotics.125

Therapy and prognosis The therapeutic options for AN itself are dismal, as it does not respond well to keratolytics or bleaching agents. Therapy of the underlying disorder, presumably thus lowering levels of circulating insulin or other peptides that are stimulating the skin, may be helpful.

Pediatric aspects of the disease Figure 22.17  Hyperpigmentation and skin thickening over the knuckles of a patient with acanthosis nigricans.

primary abnormality is papillomatosis of the epidermis with orthokeratotic scale and no apparent abnormality of pigmentation. It is believed that high levels of circulating insulin directly stimulate epidermal growth, but a specific mechanism of action has not been elucidated.123 Obesity is the most common cause of AN.

Differential diagnosis The primary conditions simulating AN are retained keratin and confluent and reticulate papillomatosis of Gougerot and Carteaud (CARP) (Fig. 22.18). Retained keratin can be found in areas such as the supraclavicular notch, behind the ears, and on

125. Fuller LC, Hay RJ. Confluent and reticulate papillomatosis of Gougerot and Carteaud clearing with minocycline. Clin Exp Dermatol. 1994;19:343–345. 126. Roth SI, Schedewie HK, Herzberg VK, et al. Cutaneous manifestations of leprechaunism. Arch Dermatol. 1981;117:531–535.

When AN is found in routine cutaneous examination, physicians should be aware of the variety of underlying associated problems and initiate appropriate diagnostic measures, especially if obesity is not present.

INSULIN RESISTANCE SYNDROMES Leprechaunism Patients with leprechaunism, or Donahue’s disease,126,127 have intrauterine growth retardation, absent subcutaneous fat, acanthosis nigricans, hyperpigmentation, and hypertrichosis. They also have distinctive features of wrinkled skin and thick lips with gingival hypertrophy, low set ears, and upturned nostrils leading to a so-called ‘elfin’ facies (Fig. 22.19). There is rugation of periorificial skin. In addition, patients have visceromegaly and large genitalia, and some reportedly show a yellow discoloration of the palms and soles with hyperkeratotic nodules of unknown

127. Taylor SI, Hedo JA, Underhill LH, et al. Extreme insulin resistance in association with abnormally high binding affinity of insulin receptors from a patient with leprechaunism: evidence for a defect intrinsic to the receptor. J Clin Endocrinol Metab. 1982;55:1108–1113.

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A DISORDERS OF INSULIN RESISTANCE

A

B

Figure 22.19  An infant with (A) leprechaunism showing lipoatrophy of the buttocks and (B) a typical ‘elfin’ facies (Courtesy Dr Nancy Esterly).

etiology. Café-au-lait spots, coarse curly scalp hair, and low frontal hairline are associated. Some cases have been reported with dysplastic, small, hyperconvex, thin nails. There is poor glucose homeostasis and insulin resistance. Because many of these children die early and suddenly in infancy, not all have had acanthosis nigricans reported, as this is a later manifestation. It is inherited as an autosomal recessive trait with a variety of mutations in the insulin receptor gene on chromosome 19.120

Rabson–Mendenhall syndrome Children with this rare syndrome have severe disorders of glucose metabolism with both hypo- and eventually hyperglycemia at different stages of life. They have acanthosis nigricans, unusual coarse facies, premature or dysplastic teeth, and gingival hyperplasia (Fig. 22.20). They may exhibit pineal hypertrophy and sexual precocity. Rabson–Mendenhall patients tend to survive longer than patients with leprechaunism. It is also

128. Thiel CT, Knebel B, Knerr I, et al. Two novel mutations in the insulin binding subunit of the insulin receptor gene without insulin binding impairment in a patient with Rabson–Mendenhall syndrome. Mol Genet Metab. 2008;94:356–362.

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B

Figure 22.20  A 3-year-old boy with Rabson–Mendenhall syndrome with coarse facial features and a ‘cupid’s bow’ mouth (A) also had hypertrichosis, low-set, large ears and acanthosis nigricans (B).

inherited as an autosomal recessive trait with mutations in the insulin receptor gene.120 It has been suggested that leprechaunism and Rabson– Mendenhall syndromes be considered on a spectrum of severity based on how completely the mutations affect insulin binding to the insulin receptor.120,128

The lipodystrophies The current classification and genetic mutations associated with the lipodystrophies are summarized in Table 22.4.129

129. Monajemi H, Stroes E, Hegele RA, et al. Inherited lipodystrophies and the metabolic syndrome. Clin Endocrinol (Oxf). 2007;67:479–484.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

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Table 22.4  Inherited lipodystrophies TYPE

COMMON NAME

GENE MUTATION

CHROMOSOME

Inherited generalized lipodystrophies   Congenital generalized lipodystrophies (Berardinelli–Seip)   Generalized with dysmorphic features

CGL1 CGL2 Mandibulo-acral dysplasia B (MADB) Progerias

AGPAT2 (BSCL1) Seipin (BSCL2) ZMPSTE24 LMNA (lamin A/C)

9q34 11q13

Kobberling (FPLD1) Dunnigan (FPLD2) Dunnigan (FPLD3)

LMNA (lamin A/C) PPARγ

1q21–22 3p25

Mandibuloacral dysplasia A (MADA) Protein kinase mutation

LMNA (lamin A/C) AKT2

1q21–22 14q32–33

Inherited partial lipodystrophies   Familial partial lipodystrophy

1q21–22

DISORDERS OF INSULIN RESISTANCE

Other partial lipodystrophies

Adapted from Monajemi H, Stroes E, Hegele RA et al. Inherited lipodystrophies and the metabolic syndrome. Clin Endocrinol (Oxf). 2007;67:479–484.

Rarer forms of generalized lipodystrophy are mandibulo-acral dysplasia (MAD) and the progeria syndromes.129 The acquired Seip–Lawrence type has similar but milder features. These patients have associated xanthomas and autoimmune disorders.129,130

Familial partial lipodystrophies (FPLD) The FLPD1 type (Kobberling) affects the limbs, sparing the face and trunk. Patients exhibit acanthosis nigricans, xanthomas, and a high metabolic rate Most patients are female. No gene defect has been located. The FLPD2 (Dunnigan) type is characterized by excess fat on the face and neck with lipoatrophy on the limbs. Most patients are female. Mutations have been found in Lamin A (LMNA), the same gene which is abnormal in Hutchinson– Guilford progeria. The FLPD3 type (also Dunnigan) has milder lipodystrophy but severe insulin resistance and has been found to have mutations in the gene encoding PPARγ.129,130

HIV-associated lipodystrophy Figure 22.21  The hand of a 7-year-old girl with congenital, generalized lipoatrophy.

Generalized lipodystrophies

Children with HIV-AIDS treated with anti-retroviral therapy (HAART) may develop lipohypertrophy, lipoatrophy, hyperlipidemia and insulin resistance.131 This is discussed in detail in Chapter 28.

Polycystic ovary syndrome (PCOS)

The autosomal-dominant condition, Berardinelli–Seip congenital lipodystrophy (BSCL) is characterized by generalized lipo­ dystrophy (Fig. 22.21), acanthosis nigricans, hyperhidrosis, thick hair, fatty liver disease, and muscular hypertrophy. The patients have a high anabolic rate, precocious growth and development, and, unfortunately, cardiomyopathy that can lead to early death. Mutations in two genes have been identified: BSCL1 which encodes for AGPAT2 and BSCL2 which encodes for seipin.

PCOS may be the most common endocrinopathy in women, affecting 4–12% of reproductive-aged females. It was originally described as Stein–Leventhal syndrome, and it shares features of HAIR-AN syndrome, syndrome X, and the metabolic syndrome. A definitive definition of PCOS has been elusive despite con­ sensus conferences in 1990 (NIH-NICHD), 2003 (Rotterdam), and 2009 (Androgen Excess Society). but clinical and/or laboratory evidence of hyperandrogenism, ovarian dysfunction and exclusion of other androgen excess or related disorders appears

130. Garg A, Agarwal AK. Lipodystrophies: Disorders of adipose tissue biology. Biochim Biophys Acta. 2009;791:507–513.

131. Krause JC, Toye MP, Stechenberg BW, et al. HIV-associated lipodystrophy in children. Pediatr Endocrinol Rev. 2005;3:45–51.

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to broadly define PCOS.132,133 Early diagnoses are being made in pubertal and even prepubertal girls.134 There is some evidence that PCOS may be genetic.89,90,134 Dermatologists and pediatricians are likely to see these patients because of cutaneous manifestations such as acne, hirsutism, and androgenetic alopecia: 75–80% of females with hirsutism, 20–40% with acne and 10% with androgenetic alopecia will have PCOS.132 However, irregular or absent menstrual periods, obesity, ovarian cysts, and infertility can be presenting complaints. The physical examination of these patients is similar to that described above for women with androgen excess. Not all patients are obese. Acanthosis nigricans, especially in the thin patient, may be a clue to underlying insulin resistance. The android body habitus with a high waist:hip ratio is also characteristic.

BOX 22.6 MEDICAL CONSEQUENCES OF PCOS WITH INSULIN RESISTANCE

DISORDERS OF INSULIN RESISTANCE

>> Hyperandrogenism – Acne – Hirsutism – Androgenetic alopecia >> Non-insulin dependent diabetes mellitus >> Obesity >> Cardiovascular disease – Coronary artery disease – Dyslipidemia – Hypercoagulability – Hypertension

Laboratory findings Laboratory findings are similar to those found in other hyperandrogenic disorders with elevations in DHEAS, free testosterone, and a ratio of LH:FSH of. 3 : 1. However, many patients with PCOS will have normal laboratory studies, perhaps because a single blood test only reflects one moment in time and is not an indication of integrated hormone levels. Ovarian ultrasound is not always necessary because not all patients have ovarian cysts, and conversely not all patients with ovarian cysts have PCOS. Because of the risks for more serious metabolic disorders in PCOS other studies which should be obtained in patients suspected of having PCOS include fasting blood glucose and insulin levels which may reveal elevated insulin levels and/or NIDDM, and a fasting lipid profile, which may show hypertriglyceridemia with elevated VLDL and LDL cholesterol and low HDL cholesterol.

Pathophysiology The pathophysiology of PCOS is complex and no doubt multifactorial. PCOS appears to be related to insulin resistance in many but not all cases. There is evidence for a genetic component. Current hypotheses propose that intrauterine small size135 and prenatal exposure to high androgens may predispose to later PCOS.136 Four categories of potential medical consequences of PCOS with insulin resistance are important (Box 22.6): 1. Hyperandrogenism:89,90 the primary origin of elevated androgen in PCOS is the ovary and insulin stimulation of ovarian cells promotes steroidogenesis as has been demonstrated in vitro.137 This propensity may be genetic

132. Azziz R, Carmina E, Dewailly D, et al. Task Force on the Phenotype of the Polycystic Ovary Syndrome of the Androgen Excess and PCOS Society. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil Steril. 2009;91:456–488. 133. Dunaif A. Drug insight: insulin-sensitizing drugs in the treatment of polycystic ovary syndrome – a reappraisal. Nat Clin Pract Endocrinol Metab. 2008;4:272–283. 134. Rosenfield RL. Identifying children at risk for polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92:787–796. 135. de Zegher F, Ibáñez L. Prenatal growth restraint followed by catch-up of weight: a hyperinsulinemic pathway to polycystic ovary syndrome. Fertil Steril. 2006;86:S4–S5.

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and intrinsic to ovarian cells from women with PCOS. The adrenal gland also responds to hyperinsulinemia with high output of DHEA. 2. Obesity:89,106 insulin resistance is directly related to obesity of any cause. In turn, it is difficult for women with PCOS to lose weight. Therapy with insulin-lowering agents may reverse this. 3. Early onset NIDDM:89,90,138 women with PCOS are more likely to develop NIDDM and the earliest signs are elevated fasting plasma insulin levels or slight elevations of fasting glucose. Oral glucose tolerance tests may be helpful in borderline cases. 4. Early cardiovascular disease:139 patients with PCOS have a variety of risks including early macrovascular coronary artery disease, such as angina and myocardial infarction, stroke, dyslipidemias, hypercoagulability, hypertension and early death.

Therapy and prognosis Therapy for PCOS needs to be individualized for the specific concerns of each particular patient (i.e., acne, hirsutism, alopecia, infertility etc.). Weight reduction and exercise are lifestyle changes that can lower insulin resistance and reduce risks. The standard therapy for acne, hirsutism, and androgenetic alopecia is noted above. However, the recent availability of drugs for NIDDM that lower insulin levels may enhance the der­ matologists’ therapeutic armamentarium. Metformin, a biguanide that improves insulin resistance probably via enhanced

136. Nisenblat V, Norman RJ. Androgens and polycystic ovary syndrome. Curr Opin Endocrinol Diabetes Obes. 2009;16:224–231. 137. Franks S, Gilling-Smith C, Watson H, et al. Insulin action in the normal and polycystic ovary. Endocrinol Metab Clin North Am. 1999;28:361–378. 138. Legro RS, Kunselman AR, Dodson WC, et al. Prevalence and predictors of risk for Type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;85:165–169. 139. Giallauria F, Orio F, Palomba S, et al. Cardiovascular risk in women with polycystic ovary syndrome. J Cardiovasc Med (Hagerstown). 2008;9: 987–992.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

Pediatric aspects of the disease134 PCOS may present in prepubertal girls with acanthosis nigricans, premature adrenarche, or very early acne. Recognition of these high-risk factors, especially in light of a positive family history of PCOS, should allow early diagnosis, but the classic hallmarks of PCOS may not be apparent for several years. Careful follow-up of girls suspected to have PCOS, with repeat monitoring of the clinical course and laboratory studies, may lead to early diagnosis and prevent some of the severe medical consequences of PCOS.

DIABETES MELLITUS Cutaneous findings in diabetes mellitus can be related primarily to the disease process, associated with the diabetic state, secondary to infection, manifestations of related diseases, or a response to therapy (Box 22.7).141–143 Type I, insulin-dependent diabetes mellitus (IDDM), used to be called juvenile, ketosis-prone, or brittle diabetes. Type II is non-insulin-dependent diabetes mellitus (NIDDM), which was formerly called the adult-onset form. Because both types may occur in either childhood or adult life, the designations Types I and II are preferable. Most children have IDDM, but there is a growing incidence of childhood NIDDM associated with obesity.144 Diabetes mellitus can also occur secondary to disorders that destroy the pancreatic islet cells, such as hemochromatosis and cystic fibrosis, or may occur in one of the insulin-resistance syndromes.

Epidemiology About 5% of the world population has diabetes,145 and about half of these patients have cutaneous manifestations.145,146 However, the prevalence of skin manifestation in childhood Type I diabetes is lower.142 Male to female ratios appear equal.

140. Mathur R, Alexander CJ, Yano J, et al. Use of metformin in polycystic ovary syndrome. Am J Obstet Gynecol. 2008;199:596–609. 141. Van Hattem S, Bootsma AH, Thio HB. Skin manifestations of diabetes. Cleve Clin J Med. 2008;75:772–787. 142. Pavlović MD, Milenković T, Dinić M, et al. The prevalence of cutaneous manifestations in young patients with type 1 diabetes. Diabetes Care. 2007;30:1964–1967. 143. Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol. 2006;24: 237–246.

BOX 22.7 CUTANEOUS CHANGES IN DIABETES MELLITUS

Skin disorders associated primarily with diabetes mellitus

>> Limited joint mobility syndrome >> Waxy skin syndrome >> Finger pebbles >> Pigmented pretibial patches >> Necrobiosis lipoidica diabeticorum >> Disseminated granuloma annularea >> Bullosis diabeticoruma >> Scleredema of Buschkea >> Kyrle’s diseasea

DIABETES MELLITUS

gluconeogenesis, has been noted to reduce obesity, lower serum lipids, improve fibrinolysis and induce ovulation in infertile women with PCOS.133,140 The thiazolidinediones (the ‘glitazones’) including troglitazone, rosiglitazone, and pioglitazone reduce insulin resistance through activation of PPARγ.133 Troglitazone has been removed from the US market because of hepatotoxicity. Although none of these agents has been studied for specific effects on acne, hirsutism, or androgenetic alopecia, they may turn out to be useful, although toxicity including cardiovascular morbidity needs to be considered.133 Because many patients with PCOS may be treated with these insulin-lowering agents, dermatologists should be familiar with them.

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Skin disorders secondary to complications of diabetes mellitus

>> Eruptive xanthomas >> Lipoatrophy/lipohypertrophy at injection site >> Infections – Candidiasis – Severe, recurrent staphylococcal infections – Malignant otitis externa (Pseudomonas) Associated cutaneous manifestations of diabetes mellitus

>> Vitiligo >> Acanthosis nigricans >> Hemochromatosis >> Lipodystrophy a

Rarely reported in childhood.

Presenting history Type I diabetes mellitus in childhood presents with a relatively short history, usually less than 1 month, of polyuria, polydipsia, polyphagia, and weight loss. Less often, there is frank diabetic ketoacidosis as an initial symptom with Kussmaul breathing, prostration, coma, and shock. Some skin manifestations of diabetes mellitus, notably necrobiosis lipoidica diabeticorum (NLD), may precede the onset of Type I diabetes mellitus.

Physical examination The cutaneous changes associated with diabetes mellitus are summarized in Box 22.7

144. Weigensberg MJ, Goran, MI. Type 2 diabetes in children and adolescents. Lancet. 2009;373:1743–1744. 145. Paron NG, Lambert PW. Cutaneous manifestations of diabetes mellitus. Dermatology. 2000;27:371–383. 146. Romano G, Moretti G, Di Benedetto A, et al. Skin lesions in diabetes mellitus: prevalence and clinical correlations. Diabetes Res Clin Pract. 1998;39:101–106.

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DIABETES MELLITUS

Figure 22.23  Necrobiosis lipoidica diabeticorum (NLD) on the anterior tibia of a 14-year-old girl. These lesions preceded the onset of her insulin-dependent diabetes mellitus.

Figure 22.22  Contractures of the fingers with inability to fully extend the digits and approximate the palms is the hallmark of the limited joint-mobility syndrome seen in type I diabetes. There is also a waxy thickening of the skin on the dorsa of the hands. (From Rosenbloom AL, Silverstein JH, Lezotte DC, et al. Limited joint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med. 1981;305:191–194. Copyright © 1981 Massachusetts Medical Society. All rights reserved.)

Primary skin disease associated with diabetes mellitus Diabetic hand, limited joint-mobility syndrome, waxy skin, and finger pebbles These changes occur in up to 30% of Type I diabetics in the first two decades.147–150 although a more recent study found only a 2.3% prevalence in childhood,142 perhaps related to better glycemic control. The limited joint-mobility syndrome consists of diffuse, although sometimes subtle, joint contractures of the hands with inability to fully extend the fingers (Fig. 22.22). There is thickened waxy skin, especially on the backs of the hands, and there may be stiffness of the large joints. There may be a pebbly appearance to the skin, but these finger pebbles are more common in adults.151 Limited joint mobility is seen in patients with poor growth and short stature. It has been associated with duration but not with severity of disease. The contractures are analogous to Dupuytren’s contractures in adults and appear to affect the fourth and fifth fingers most commonly. Histologically, the thick waxy skin shows increased dermal collagen. Although the changes may be described as scleroderma-like,152 147. Grgic A, Rosenbloom AL, Weber FT, et al. Joint contracture – common manifestation of childhood diabetes mellitus. J Pediatr. 1976;88: 584–588. 148. Rosenbloom AL, Silverstein JH, Lezotte DC, et al. Limited joint mobility in childhood diabetes mellitus indicates increased risk for microvascular disease. N Engl J Med. 1981;305:191–194. 149. Seibold JR. Digital sclerosis in children with insulin-dependent diabetes mellitus. Arthritis Rheum. 1982;25:1357–1361.

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there have been no reports of atrophy or pigmentary alterations. It has been postulated that accumulations of glycosylated proteins in the collagen matrix or increased fibroblast proliferation are responsible.

Diabetic dermopathy Pigmented pretibial patches or shin spots are seen in up to 50% of adult diabetics; they are rare, but do occur, in childhood.143 Lesions begin as small pretibial papules and evolve into 1–2 cm patches that have a brownish-red to yellow color and may be depressed. There is no waxy alteration of the epidermis such as seen in necrobiosis lipoidica diabeticorum (NLD). Histopathology is similar to that of the progressive pigmented purpuras with extravasated red blood cells (RBCs), hemosiderin, and mild perivascular lymphohistiocytic infiltrate. Increased deposits of acid mucopolysaccharides have been noted. The lesions of diabetic dermopathy do not evolve into NLD. They may resolve and often leave brown hyperpigmentation.

Necrobiosis lipoidica diabeticorum (NLD) NLD occurs more rarely in children with diabetes than in adults (2.3% in a recent pediatric series).142 NLD characteristically appears on the anterior tibiae (Fig. 22.23) but may be found on the upper extremities and on the trunk on rare occasions. The skin lesions may precede the onset of diabetes mellitus. The primary lesions are oval plaques that expand up to several centimeters in size from their origins as small erythematous papules. The borders are usually sharply demarcated, somewhat raised, and more erythematous than the center of the lesion. There is occasionally some scale at the borders. Centrally, there may be a waxy, translucent, atrophic epidermis with colors ranging from 150. Rosenbloom AL, Silverstein JH, Lezotte DC, et al. Limited joint mobility in diabetes mellitus of childhood: natural history and relationship to growth impairment. J Pediatr. 1982;101:874–878. 151. Huntley AC. Finger pebbles: A common finding in diabetes mellitus. J Am Acad Dermatol. 1986;14:612–617. 152. Buckingham BA, Uitto J, Sandborg C, et al. Scleroderma-like changes in insulin-dependent diabetes mellitus: clinical and biochemical studies. Diabetes Care. 1984;7:163–169.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

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or GA. GA may be long-standing but eventually resolves without scarring.

Diabetic skin changes primarily found in adults Bullosis diabeticorum Tense bullae on the distal portions of the extremities that appear without preceding trauma and usually resolve without scarring have been reported in adults with long-standing diabetes mellitus.159

Scleredema

toddler who had developed IDDM at age 1 year.

DIABETES MELLITUS

Figure 22.24  Large plaques of granuloma annulare on the abdomen of a

In scleredema adultorum of Buschke, broad areas of woody, hard, nonpitting edema with erythema typically appearing on the upper back have been noted in long-standing, poorly controlled adult diabetics who have many microangiopathic complications.

Perforating disorders red to brown to a characteristic yellow. Often, the atrophy is so prominent that large subcutaneous vessels are easily visible coursing under the surface of the plaque. A perforating form of NLD has been described in children.153 There is a tendency to ulceration with slow healing. Histologically, there is necrobiosis of collagen and infiltration of collagen bundles with palisading histiocytes and accumulations of mucin. This histology closely resembles granuloma annulare as well as rheumatoid nodule. Many treatments have been suggested for NLD, but it is often difficult to control.153 High-potency topical corticosteroids under occlusion and intralesional steroids have been tried with minimal success. In some cases, excision and grafting have improved the cosmetic appearance.154

Granuloma annulare The common childhood form of localized granuloma annulare (GA), consisting of discrete rings with raised papular borders that occur in countable numbers, does not correlate well with diabetes mellitus. Such patients with typical GA need not be studied for the presence of diabetes or glucose intolerance. In addition, because most children develop IDDM of rapid, rather than insidious, onset, a prospective glucose tolerance test (GTT) is not indicated in GA (Fig. 22.24). It is not clear whether the disseminated form of GA, especially in elderly patients, is associated with diabetes; estimates of 12–15% have been published,155,156 but one study of subcutaneous GA in children under age 10 years revealed diabetes in 6% (2/34).157 Lesions resembling GA have been noted on the anterior tibiae in proximity to, or in association with, typical lesions of NLD; rarely, these two disorders have been reported to coexist.158 It may be a matter of semantics whether such pretibial lesions are distinctly NLD and/

153. Hammami H, Youssef S, Jaber K, et al. Perforating necrobiosis lipoidica in a girl with type 1 diabetes mellitus: a new case reported. Dermatol Online J. 2008;14:11. 154. Marr TJ, Traisman HS, Griffith BH, et al. Necrobiosis lipoidica diabeticorum in a juvenile diabetic. Cutis. 1977;19:348–350. 155. Studer EM, Calza AM, Saurat JH. Precipitating factors and associated diseases in 84 patients with granuloma annulare: a retrospective study. Dermatology. 1996;193:364–368.

Disorders such as Kyrle’s disease (hyperkeratosis follicularis et parafollicularis in cutem penetrans) and/or reactive perforating collagenosis have been described in adults with DM, often when they are in renal failure and receiving dialysis.

Diabetic ulcers In long-standing IDDM, ulcerations of the distal lower extremities with eventual gangrene can occur on the basis of poor peripheral perfusion and secondary trauma if there is severe neuropathy. Diabetic ulcers are rare in childhood.

Skin disorders secondary to metabolic changes in diabetes mellitus Eruptive xanthomas In IDDM that is poorly controlled, there may be massive hypertriglyceridemia. In such cases, there may be sudden appearance of diffuse xanthomatosis. Lesions consist of firm, 1–3 mm redto-yellow papules that may coalesce (Fig. 22.25) or appear in linear array in areas of previous trauma to the skin (Köbner’s phenomenon). With control of the hyperlipidemia, the lesions resolve.

Local lipodystrophy at injection sites and local reactions to insulin Paradoxically, both lipoatrophy and/or lipohypertrophy may occur at sites of insulin injection. Hypertrophic lesions are composed of collagen mixed with adipose tissue and are often anesthetic and preferred by juvenile diabetics for injection sites.

156. Tan HH, Goh CL. Granuloma annulare: A review of 41 cases at the National Skin Centre. Ann Acad Med Singapore. 2000;29:714–718. 157. Grogg KL, Nascimento AG. Subcutaneous granuloma annulare in childhood: clinicopathologic features in 34 cases. Pediatrics. 2001;107:E42. 158. Schwartz ME. Necrobiosis lipoidica and granuloma annulare. Simultaneous occurrence in a patient. Arch Dermatol. 1982;118:192–193. 159. Paltzik RL. Bullous eruption of diabetes mellitus. Bullosis diabeticorum. Arch Dermatol. 1980;116:474–476.

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Although a few cases of this destructive infection have been reported in childhood,162 only one has been associated with diabetes.163

Other disorders associated with diabetes mellitus Vitiligo, psoriasis, and eczema were found in nearly 10% of a series of 64 patients with IDDM146 suggesting a possible autoimmune link between these disorders.

Lipodystrophies Congenital, acquired, partial, or total, lipodystrophies have been associated with diabetes mellitus, and underlying insulin resistance (see above). DISORDERS OF G PROTEIN SIGNAL TRANSDUCTION

Hemochromatosis Figure 22.25  Pink-yellow firm papules, here in linear array, on the ankle of a Type I diabetic patient in poor control. He had massively elevated triglycerides as the basis of his eruptive xanthomas.

However, absorption from these sites is erratic. Local cutaneous reactions at the site of injection of insulin used to occur in 15– 55% of patients.160 These are rare with the use of human recombinant insulin.

Infections associated with diabetes mellitus It is not established whether cutaneous fungal and bacterial infections are more common in diabetics or simply more severe when they occur. In one study of 142 children with Type 1 diabetes they were no more frequent than in a control group.142 Candida can be found in many locations: oral mucosa (thrush), vaginal mucosa (vaginitis), on the nail (onychomycosis), or surrounding soft tissues (paronychia), in the toe and the finger webs (blastomycosis erosio interdigitalis), or on moist flexural surfaces (intertrigo). Topical anticandidal therapy is usually effective. Recurrent staphylococcal furunculosis is common in diabetics. Patients may be intranasal Staphylococcus carriers or may have recurrent staphylococcal folliculitis, which then develops into more serious lesions. Chronic or intermittent systemic antibiotics, antibacterial cleansers, and intranasal antibiotic ointment may be helpful. Mucormycosis of the nasal cavity can cause perforation in poorly controlled disease, usually in elderly diabetics, and is often fatal. Diabetes mellitus has been found in 15% of a series of 157 children with zygomycosis.161 Malignant otitis externa due to Pseudomonas aeruginosa has been reported as a complication of diabetes in elderly patients.

160. Kahn CR, Rosenthal AS. Immunologic reactions to insulin: insulin allergy, insulin resistance, and the autoimmune insulin syndrome. Diabetes Care. 1979;2:283–295. 161. Zaoutis TE, Roilides E, Chiou CC, et al. Zygomycosis in children: a systematic review and analysis of reported cases. Pediatr Infect Dis J. 2007;26:723–727. 162. Joachims HZ. Malignant external otitis in children. Arch Otolaryngol. 1976;102:236–237.

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Either primary or secondary, excessive iron deposition can lead to destruction of pancreatic islet cells and produce so-called bronze diabetes, which is insulin dependent. Such patients have diffuse, deep hyperpigmentation, due not only to deposits of iron but also to hypermelanization. Hemochromatosis can be primary or secondary to multiple transfusion therapy for diseases such as thalassemia.

Pathophysiology and histogenesis There is a distinct familial predisposition to development of IDDM with evidence for complex inheritance patterns. There is however, an association of Type 1 diabetes with the HLA region on chromosome 6p21.164 Environmental triggers such as viral infections and autoimmune mechanisms appear to play a role.

Therapy The only treatment for Type I diabetes mellitus at this time is parenteral administration of human recombinant insulin. Current therapeutics are leaning toward more stringent control of hyperglycemia with either multiple daily injections or computer-controlled insulin pumps maintaining normal blood glucose levels.165

DISORDERS OF G PROTEIN SIGNAL TRANSDUCTION INTRODUCTION Several endocrine disorders have been attributed to mutations in G (guanine nucleotide) stimulating protein signal trans­ duction (Table 22.1). G proteins couple receptors for many hormones to effectors that regulate second messenger

163. Merritt WT, Bass JW, Bruhn FW. Malignant external otitis in an adolescent with diabetes. J Pediatr. 1980;96:872–873. 164. Concannon P, Rich SS, Nepom GT. Genetics of Type 1A diabetes. N Engl J Med. 2009;360:1646–1654. 165. Shalitin S, Phillip M. The use of insulin pump therapy in the pediatric age group. Horm Res. 2008;70:14–21.

A

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Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

B

C

Figure 22.26  Brachydactyly in a girl with pseudohypoparathyroidism with (A) short 4th and 5th metacarpals and the (B) ‘knuckle, knuckle, dimple, dimple’ sign when she makes a fist. Radiograph of the hand of an infant girl born with osteoma cutis showing short 4th and 5th metacarpals. She had (C) pseudo-pseudo hypoparathyroidism.

metabolism.166–168 Mutations in G proteins or their receptors may result in loss or gain of function. Loss-of-function mutations create hormone resistance. Gain-of-function mutations create hormone hypersecretion. Relevant to dermatology are two syndromes caused by mutations in the GNAS1 gene which codes for Gs-α: pseudohypoparathyroidism (Albright’s hereditary osteodystrophy) which results from a loss-of-function mutation causing resistance to parathyroid hormone (PTH); and polyostotic fibrous dysplasia with multiple endocrine abnormalities and café au lait spots (McCune–Albright syndrome), which results from a gain-of-function mutation causing excessive endocrine function, especially precocious puberty.

PSEUDOHYPOPARATHYROIDISM Pseudohypoparathyroidism (PHP1a), also known as Albright’s hereditary osteodystrophy, is an autosomal-dominant disorder which has a distinctive phenotype.168,169 Patients present with typical facies and body habitus and may exhibit signs of hypo­ calcemia. Typically, they have a round face with a broad, flat nasal bridge, short stature with brachydactyly (broad, short digits) and short fourth and sometimes fifth metacarpals and metatarsals causing dimpling of the knuckles, especially of the fourth and fifth fingers (Fig. 22.26). Patients have ectopic calcifications in the basal ganglia, calcinosis cutis, and, most diagnostically,

166. Bastepe M. The GNAS locus and pseudohypoparathyroidism. Adv Exp Med Biol. 2008;626:27–40. 167. Mantovani G, Spada A. Mutations in the Gs alpha gene causing hormone resistance. Best Pract Res Clin Endocrinol Metab. 2006;20:501–513. 168. Wilson LC. Albright’s hereditary osteodystrophy. J Pediatr Endocrinol Metab. 2006;19:S671–S673. 169. Prendiville JS, Lucky AW, Mallory SB, et al. Osteoma cutis as a presenting sign of pseudohypoparathyroidism. Pediatr Dermatol. 1992;9:11–18. 170. Izraeli S, Metzker A, Horev G, et al. Albright hereditary osteodystrophy with hypothyroidism, normocalcemia, and normal Gs protein activity: a

Figure 22.27  A large plaque of osteoma cutis in an infant boy who had pseudohypoparathyroidism.

osteoma cutis (Fig. 22.27). Osteoma cutis can present at birth or in the early years of life and may be an important first sign of PHP.169–173 Mental retardation was initially considered to be part of the syndrome. However, children treated early and aggressively with calcium and 25-hydroxy vitamin D appear to develop

family presenting with congenital osteoma cutis. Am J Med Genet. 1992;43:764–767. 171. Lucky AW, Tsang R. Clinical vignette: Pseudopseudohypoparathyroidism, presenting with osteoma cutis. Bone Mineral Res. 1997;12:995. 172. Kappy M, Kummer M, Tyson RW, et al. Pathological case of the month. Osteoma cutis/pseudohypoparathyroidism Arch Pediatr Adolesc Med. 1999;153:427–428. 173. Goeteyn V, De Potter, CR, Naeyaert JM. Osteoma cutis in pseudohypoparathyroidism. Dermatology. 1999;198:209–211.

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normally, suggesting that prolonged hypocalcemia was the cause of the delayed development.174 Concurrent hypothyroidism is usually found, although its onset may be delayed. This is not surprising because there is impaired sensitivity to both thyroid stimulating hormone (TSH) and thyrotropin releasing hormone (TRH) as a result of the loss-of-function mutation.175 Laboratory findings include hypocalcemia, hyperphosphatemia, and elevated serum levels of PTH. There is an absent urinary cyclic AMP response to PTH stimulation. Those with hypothyroidism have elevated levels of TSH. Radiographs of the hands reveal short fourth and fifth metacarpals. As noted above, the underlying causes are loss-of-function mutations of the gene that encodes Gs-α (GNAS1) located on chromosome 20q13.3.166–168 Therapy consists of prospective monitoring for development of hypocalcemia, hyperphosphatemia, and rising levels of serum PTH and TSH. These changes may occur in infancy or later in childhood, and require replacement with appropriate doses of calcium, vitamin D, and thyroid hormone. Pseudo-pseudohypoparathyroidism (PPHP) is the cumbersome term used to denote a phenotype identical to pseudohypoparathyroidism but without the hypocalcemia. Infants with normocalcemia who have congenital osteoma cutis or a primary relative with pseudohypoparathyroidism need to be prospectively and closely followed for development of hypocalcemia and hypothyroidism. Petrified ears have been reported in PPHP.176 The phenomenon of imprinting is seen with GNAS1 mutations: If the mutant GNAS1 allele is inherited from the mother the full PHP phenotype will be expressed; however, if the father’s allele is the affected one, progressive osseous heteroplasia (POH), a disorder with osteoma cutis without the PPH phenotype occurs.177 This phenomenon may be explained by tissue specific selective inactivation of either maternal or paternal alleles. PHP type1b expresses only the renal metabolic defect and has none of the clinical or dermatologic features of PHP1a. Type 1c has the same phenotype as 1a but has retained Gs activity and may be a subtype of 1a rather than a distinct entity.178

POLYOSTOTIC FIBROUS DYSPLASIA WITH MULTIPLE ENDOCRINE ABNORMALITIES AND CAFÉ-AU-LAIT SPOTS (McCUNE–ALBRIGHT SYNDROME) McCune–Albright syndrome (MAS) is a sporadic disorder characterized by polyostotic fibrous dysplasia, café-au-lait spots, and endocrine hyperfunction.179–181 It is rare, occurring with a preva-

174. Patten JL, Johns DR, Valle D, et al. Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright’s hereditary osteodystrophy. N Engl J Med. 1990;322:1412–1419. 175. Balavoine AS, Ladsous M, Velayoudom FL, et al. Hypothyroidism in patients with pseudohypoparathyroidism type Ia: clinical evidence of resistance to TSH and TRH. Eur J Endocrinol. 2008;159:431–437. 176. Strauss RM. Petrified ears associated with pseudopseudohypoparathyroidism. Br J Dermatol. 2008;158:409–410. 177. Shore EM, Ahn J, Jan de Beurs S, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med. 2002;346:99–106.

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Figure 22.28  Large, segmental café-au-lait macules with a ‘coast of Maine’ border in an infant with McCune–Albright syndrome (Courtesy Philippe Backeljauw, Cincinnati Children’s Hospital).

lence of 1/100 000 to 1/1 000 000. The signature skin manifestations are café-au-lait patches that tend to be large with irregular borders (like the ‘coast of Maine’) and segmental (Fig. 22.28). They often follow Blaschko’s lines and tend not to cross the midline. They usually appear on the same side as the skeletal abnormalities. The typical bone lesions of polystotic fibrous dysplasia are usually but not always multiple. Endocrine abnormalities consist of autonomous and excessive functioning of endocrine organs with nodular overgrowth and hormone elevations with low levels of stimulating hormones. Precocious puberty is the most common endocrine manifestation, but excessive growth hormone, prolactin and thyroid hormone, and nodular adrenal hyperplasia with neonatal Cushing syndrome are reported. Patients are also prone to renal phosphate wasting and fractures. Malignancies are rare. Abnormal radiographs and specific hormone tests can be useful and must be tailored to each clinical situation. These patients have somatic mutations of the GNAS1 gene and are thus mosaic. This disorder thus represents postzygotic rather than germline mutation and is thus not transmitted vertically. These gain-of-function mutations cause elevation of cyclic AMP levels. Specific clinical manifestations may appear at different times of life. One study showed increased c-AMP mediated expression of tyrosinase in melanocytes isolated from a pigmented patch in one patient.182 Therapy is directed towards

178. Aldred MA. Genetics of pseudohypoparathyroidism types 1a and 1c. J Pediatr Endocrinol Metab. 2006;19:S635–S640. 179. Dumitrescu CE, Collins MT. McCune Albright syndrome. Orphanet J Rare Dis. 2008;3:12. 180. Zacharin M. The spectrum of McCune Albright syndrome. Pediatr Endocrinol Rev. 2007;4:S412–S418. 181. Völkl TM, Dörr HG. McCune-Albright syndrome: clinical picture and natural history in children and adolescents. J Pediatr Endocrinol Metab. 2006;19:S551–S559. 182. Kim IS, Kim ER, Nam HJ, et al. Activating mutation of GSα in McCuneAlbright syndrome causes skin pigmentation by tyrosinase gene activation on affected melanocytes. Horm Res. 1999;52:235–240.

Figure 22.29  Severe nail candidiasis in a teenage girl with autoimmune polyglandular syndrome Type I (APS-1).

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MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

Figure 22.30  Mucous membrane and lip involvement with chronic candida in a child with APS-1.

specific hormonal abnormalities as they become manifest, with careful attention to early pubertal development.

AUTOIMMUNE POLYENDOCRINE SYNDROMES The autoimmune polyendocrine syndromes, also known as autoimmune polyglandular syndromes and autoim­ mune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndromes, have been subdivided into four types:183 Type 1 (APS-1)184 occurs in childhood as a rare autosomalrecessive disorder that has been localized to mutations of the autoimmune regulator gene AIRE located at 21q22.3 (Table 22.1). The major endocrine hallmarks are hypoparathyroidism, adrenal insufficiency, gonadal failure in females, and insulin dependent diabetes mellitus (IDDM). Patients with APS 2–4185 have no known specific genetic mutations: they occur later in midlife. APS 2 always has Addison disease,185 APS 3 primarily has autoimmune thyroid disease, and APS4 may have different combinations of the other types.185 There is wide variation of expression within and between families. Cutaneous signs of APS-1 include vitiligo, alopecia areata, and nail dystrophy (chronic mucocutaneous candidiasis). Severe mucocutaneous candidiasis of nails (Fig. 22.29) and mucous membranes (Fig. 22.30) is the hallmark of the disorder and is often refractory to conventional topical antifungal therapy and requires chronic oral antifungal treatment. Primary nail dystrophy is unlikely, despite the misnomer of ‘ectodermal dystrophy’ in the eponym APCED. Enamel hypoplasia may also occur.186 Other features are listed in Table 22.5. 183. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syndromes (APS). Acta Biomed. 2003;74:9–33. 184. Obermayer-Straub P, Strassburg CP, Manns MP. Autoimmune polyglandular syndrome Type I. Clin Rev Allergy and Immunol. 2000;18: 167–183.

Table 22.5  Autoimmune polyendocrine syndrome-1 (APS-1) (%) Cutaneous features   Mucocutaneous candidiasis   Alopecia   Vitiligo   Nail dystrophy

73–100 29–37 8–15 52

Endocrine features   Hypoparathyroidism   Adrenal failure   Gonadal failure   Parietal cell atrophy   Insulin dependent diabetes mellitus   Autoimmune thyroid disease

76–93 72–100 7–50 13–15 2–12 2–11

Other features   Enamel hypoplasia   Keratoconjunctivitis   Chronic hepatitis   Intestinal malabsorption

77 12–35 12–20 77

MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES The multiple endocrine neoplasia (MEN) syndromes are a group of autosomal-dominantly inherited disorders in which there are multiple tumors in a variety of endocrine organs. Most 185. Kahaly G. Polyglandular autoimmune syndromes. Eur J Endocrinol. 2009; 161:11–20. 186. Porter SR, Haria S, et al. Chronic candidiasis, enamel hypoplasia, and pigmentary anomalies. Oral Surg Oral Med Oral Pathol. 1992;74: 312–314.

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Table 22.6  Multiple endocrine neoplasia (MEN) syndromes

CARNEY COMPLEX

CUTANEOUS FEATURES

ENDOCRINE FEATURES

MEN 1

Angiofibromas Collagenomas Leiomyomas Lipomas Confetti-like hypopigmented macules Café-au-lait macules Gingival papules Melanoma

Parathyroid hyperplasia and adenomas Gastroenteropancreatic tumors Pituitary adenomas Adrenocortical tumors

MEN-2A (Sipple syndrome)

Lichen amyloidosis

Medullary carcinoma of the thyroid Pheochromocytoma Parathyroid hyperplasia

MEN-2B

Cutaneous neuromas Mucosal neuromas Café-au-lait macules Marfanoid habitus Elongated facies

Medullary carcinoma of the thyroid Pheochromocytoma

are associated with specific cutaneous findings.187–190 The major cutaneous and endocrine features are summarized in Table 22.6. MEN-1191–193 occurs in 0.01–2.5 : 100 000 in the population and has been attributed to a loss-of-function mutation of the tumor suppressor gene MEN-1 (which produces the protein menin) located on chromosome 11q13. It rarely presents in childhood. Endocrine features include primary hyperparathyroidism with parathyroid hyperplasia or adenomas, gastroenterohepatic tumors, especially those producing gastrin or insulin, pituitary adenomas, particularly prolactinomas, and more rarely adrenocortical tumors. Cutaneous manifestations of MEN-1190–193 include angiofibromas, which occur in 22–88% of patients in different series. These are smaller and less numerous than in tuberous sclerosis (TS)

187. Brandi ML, Gagal RF, Angeli A, et al. CONSENSUS: Guidelines for diagnosis and therapy of MEN Type 1 and Type 2. J Clin Endocrinol Metab. 2001;86:5658–5671. 188. Raue F, Frank-Raue K. Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens). 2009;8:23–28. 189. Puñales MK, da Rocha AP, Meotti C, et al. Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid. 2008;18:1261–1268. 190. Vidal A, Iglesias MJ, Fernández B, et al. Cutaneous lesions associated to multiple endocrine neoplasia syndrome type 1. J Eur Acad Dermatol Venereol. 2008;22:835–838. 191. Stratakis CA, Ball DW. A concise genetic and clinical guide to multiple endocrine neoplasias and related syndromes. J Pediatr Endocrinol Metab. 2000;13:457–465. 192. Darling TN, Skarulis MC, Steinberg SM, et al. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia Type I. Arch Dermatol. 1997;133:853–857. 193. Schussheim DH, Skarulis MC, Agarwal SK, et al. Multiple endocrine neoplasia type 1: New clinical and basic findings. Trends in Endocrinol and Metab. 2001;12:173–178.

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and are often located around the upper lip. Other skin signs such as collagenomas and confetti-like hypopigmentation also overlap with TS. Leiomyomas, lipomas, gingival papules and café-au-lait macules have been reported. Melanomas may occur more frequently.194 Allelic deletions of the MEN-1 gene have been demonstrated within several cutaneous tumors.195 Early genetic screening may improve outcome.196 The MEN-2 disorders result from activation mutations in the proto-oncogene RET, which encodes a tyrosine kinase receptor in neural crest-derived tissues (Table 22.1).197 MEN-2A is the most common and is characterized by medullary carcinoma of the thyroid (MCT) (>90%), pheochromocytoma (40–50%), and parathyroid hyperplasia (10–20%).188 The cutaneous hallmark is lichen amyloidosis.191,198 Hirschsprung’s disease has also been associated.199 The gene defect is a gain-of-function mutation in the RET extracellular domain. MEN-2B191 is the least common but is a very aggressive form of MEN-2. Patients also have MCT and pheochromocytomas as well as a Marfanoid habitus and multiple mucosal, cutaneous, and gastrointestinal ganglioneuromas (Fig. 22.31). Patients are tall, thin, and have elongated faces with thickened lips (Fig. 22.31A). Mucosal neuromas are usually present by age 3 and may be visible at birth. Such patients also have multiple café-aulait macules and lentigines. MEN-2B is also an autosomaldominant trait, but it has onset in early childhood. Screening of first-degree relatives for MCT should begin by age 1 year. These manifestations can be seen in early childhood. The genetic defect is a gain-of-function mutation in the RET intracellular domain. Early screening for the genetic mutation has superseded pentagastrin-calcitonin stimulation tests. Prophylactic thyroidectomy by age 5 is recommended,200 especially in patients with the specific mutations in which genotype–phenotype correlations have shown the highest risk for aggressive MTC.188 Finally, the familial MCT (FMTC) syndrome191 is the most benign and has few other endocrine or cutaneous manifestations and is also due to a mutation in the RET extracellular domain.

CARNEY COMPLEX Carney complex (CNC) was first described as such in 1985 as a syndrome consisting of ‘spotty skin pigmentation, myxomas,

194. Nord B, Platz A, Smoczynski K, et al. Malignant melanoma in patients with multiple endocrine neoplasia Type I and involvement of the MEN1 gene in sporadic melanoma. Int J Cancer. 2000;87:463–467. 195. Pack S, Turner ML, Zhuang Z, et al. Cutaneous tumors in patients with multiple endocrine neoplasia type I show allelic deletion of the MEN1 gene. J Invest Dermatol. 1998;110:438–440. 196. Pieterman CR, Schreinemakers JM, Koppeschaar HP, et al. Multiple endocrine neoplasia type 1 (MEN1): its manifestations and effect of genetic screening on clinical outcome. Clin Endocrinol (Oxf). 2009;70:575–581. 197. Raue F, Frank-Raue K. Multiple endocrine neoplasia type 2: 2007 update. Hormone Res. 2007;68:S101–S104. 198. Kousseff BG. Multiple endocrine neoplasia 2 (MEN2)/MEN 2A (Sipple syndrome). Dermatol Clin. 1995;13:91–97. 199. Moore SW, Zaahl MG. Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET. Pediatr Surg Int. 2008;24: 521–530. 200. Zenaty D, Aigrain Y, Peuchmaur M, et al. Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B. Eur J Endocrinol. 2009;160:807–813.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

22

Table 22.7  Carney complex (CNC) ENDOCRINE FEATURES

Lentigines (spotty skin pigmentation)a

Adrenal tumors (PPNAD) with Cushing syndromea

Cutaneous and mucosal myxomasa

Pituitary tumors with gigantism or acromegalya

Multiple epithelioid blue nevia

Precocious pubertya

Multiple common blue nevi

Testicular tumors (LCCSCT)a

Conjunctival pigmentation

Thyroid nodules and carcinomasa

Combined nevi

Hyperprolactinemia

Small café-au-lait macules Depigmented macules

OTHER FEATURES

Multiple skin tags

Cardiac myxomasa

Lipomas

Breast myxomasa

Pigmented schwannomas

Breast ductal adenomasa

Pilonidal sinus

Non-cutaneous psammomatous melanotic schwannomasa

CARNEY COMPLEX

A

CUTANEOUS FEATURES

Cardiomyopathy Osteochondromyxomasa a

Diagnostic criteria. PPNAD, primary pigmented nodular adrenocortical disease; LCCSCT, large-cell calcifying Sertoli cell tumors.

B

Figure 22.31  Patient with Type 2B multiple endocrine neoplasia (MEN 2B) syndrome showing (A) characteristic thick lips and mucosal neuromas on the tongue and (B) a cutaneous neuroma on the pinna.

endocrine overactivity and schwannomas.’201 It is closely related to other multiple lentigines syndromes as well as the MEN syndromes. Patients previously described as having LAMB and NAME syndromes undoubtedly had CNC.202 CNC is inherited as a rare autosomal-dominant trait; about 500 cases have been registered as of 2006.202,203 More than half of the cases are familial. Of these, more are from affected mothers than fathers. CNC has been diagnosed as early as at birth, but the mean age of diagnosis is 20 years. Lentigines are usually the first sign, More rarely, one of the endocrinopathies such as Cushing disease, precocious puberty or gigantism arises first. The main clinical findings are listed in Table 22.7.204 The lentigines are the ‘dark spots’ originally described and occur in about three-quarters of

201. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation and endocrine overactivity. Medicine (Balt). 1985;64:270–283. 202. Bertherat J. Carney complex (CNC). Orphanet J Rare Dis. 2006;1:21. 203. Stratakis CA, Kirschner LS, Carney JA. Genetics of endocrine disease. Clinical and molecular features of the Carney complex: Diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. 2001;86:4041–4046.

the patients, although nevocellular nevi and café-au-lait macules occur as well. The lentigines characteristically occur on the midface, the borders of the lips (Fig. 22.32) and on the genital skin of females. Buccal mucosal involvement is rarer (5–10%). Pigmentation of the conjunctivae is characteristic, in particular the lacrimal caruncle and the semilunar fold. Multiple epithelioid blue nevi are found on the face and trunk, and occur singly on the extremities.205 Depigmented macules also occur. Cutaneous myxomas are small, flesh-colored papules seen on the eyelids, external ear canals, mucosae, and elsewhere on the skin in one-third of the cases. Pigmented schwannomas of the skin are rare, but can metastasize and be fatal.205 The most common endocrine findings are in the adrenal, pituitary, gonads and thyroid.203,204,206,207 Primary pigmented nodular adrenocortical disease (PPNAD) is the hallmark of CNC and often manifests as Cushing disease. Growth hormone producing tumors of the pituitary can cause gigantism or acromegaly. Large-cell calcifying Sertoli cell tumors (LCCSCT) are also characteristic of CNC and are rarely found in other settings: ultrasound of the testes may reveal calcifications even in infancy. Testicular adrenocortical rests and Leydig cell tumors also occur. Thyroid nodules and carcinoma have been recently

204. Mateus C, Palangié A, Franck N, et al. Heterogeneity of skin manifestations in patients with Carney complex. J Am Acad Dermatol. 2008;59:801–810. 205. Carney JA, Stratakis CA. Epithelioid blue nevus and psammomatous melanotic schwannoma: The unusual pigmented skin tumors of the Carney complex. Semin Diagnost Pathol. 1998;15:216–224. 206. Stratakis CA. Genetics of Carney complex and related familial lentiginoses and other multiple tumor syndromes. Front Biosci. 2000;5:353–366. 207. Carney JA. The Carney complex (myxomas, spotty pigmentation, endocrine overactivity and schwannomas). Dermatol Clin. 1995;13:19–26.

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VITAMIN D RESISTANCE AND ALOPECIA

ANOREXIA AND BULIMIA NERVOSA

Figure 22.32  Carney complex. Facial and lip lentigines.

added to the list of endocrine tumors. Non-endocrine tumors include cardiac myxomas, occurring in half of the cases and possibly life-threatening breast myxomas and ductal adenomas, as well as psammomatous melanotic schwannomas of the upper GI tract and sympathetic chain, which may become malignant. Laboratory findings are myriad and reflect the particular manifestations of each patient. However, regular adrenal and testicular screening are recommended for identified patients. The genetics of CNC have been extensively studied and two loci have been identified: 2p16 and the more common 17q22–24. The latter locus involves a tumor suppressor gene (PRKARIA) which produces an effector molecule important in many endocrine signaling pathways.202,204 The differential diagnosis includes the other familial lentigines syndromes such as Peutz–Jeghers, LEOPARD, Noonan, Cowden, Ruvalcaba–Myhre–Smith (Bannayan–Zonana), multiple endocrine neoplasia and Laugier– Hunziker syndromes.206 Therapy is directed to specific manifestations of CNC as they appear. All first degree relatives should be screened. Pediatricians and dermatologists are in a unique position to recognize the cutaneous findings of this probably underdiagnosed condition.

208. Rosen JF, Fleischman AR, Finberg L, et al. Rickets with alopecia: an inborn error of vitamin D metabolism. J Pediatr. 1979;94:729–735. 209. Liberman UA, Halabe A, Samuel R, et al. End-organ resistance to 1,25-dihydroxycholecalciferol. Lancet. 1980;1:504–506. 210. Hochberg Z, Gilhar A, Haim S, et al. Calcitriol-resistant rickets with alopecia. Arch Dermatol. 1985;121:646–647. 211. Hewison M, O’Riordan JL. Hormone–nuclear receptor interactions in health and disease. Vitamin D resistance. Baillières Clin Endocrinol Metab. 1994;8:305–315. 212. Nicolaidou P, Tsitsika A, Papadimitriou A, et al. Hereditary vitamin D-resistant rickets in Greek children: genotype, phenotype, and long-term response to treatment. J Pediatr Endocrinol Metab. 2007;20:425–430. 213. Sultan Al-Khenaizan, Vitale P. Vitamin D-dependent rickets Type II with alopecia: two case reports and review of the literature. Int J Dermatol. 2003;42:682–685. 214. Nicolaidou P, Papadopoulou A, Georgouli H, et al. Calcium and vitamin D metabolism in hypocalcemic vitamin D-resistant rickets carriers. Horm Res. 2006;65:83–88.

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Of interest to dermatologists are the reports of several kindreds with clinical syndromes of hereditary vitamin D-dependent rickets (HVDDR) and alopecia.208–213 Affected individuals have rickets associated with elevated rather than decreased circulating levels of 1,25-dihydroxy vitamin D, the active form of vitamin D. This paradoxically high level of vitamin D is related to peripheral resistance to hormonal action. Homozygous mutations in the gene encoding the vitamin D receptor (VDR) have been documented. Heterozygous carriers have no clinical manifestations but higher circulating levels of 1,25-dihydroxy vitamin D.214 Patients may have hair at birth but, usually over a 6–7month period of time in association with onset of rachitic bone changes, striking hair loss progresses to total alopecia. Patients tend to be irritable and to have growth failure. In those few patients who have had scalp biopsies, no lymphocytic infiltrate was noted about the hair bulbs (such as seen in alopecia areata). Clinical response of the rickets to pharmacologic doses of vitamin D3, 25-hydroxy D3, 1,25-dihydroxy D3, or 1-α-hydroxy D3 was variable, suggesting more than one mechanism of action. In one case in which the rickets was documented to respond to therapy, no regrowth of hair occurred. There is evidence that vitamin D receptors are necessary for maintenance of the normal hair cycle,215 explaining the alopecia in some but not all affected patients. Vitamin D resistance should be added to the list of disorders that cause alopecia in infancy.

ANOREXIA AND BULIMIA NERVOSA Anorexia nervosa (AN) is a generalized disorder that occurs almost exclusively in females (F : M ratio is 20 : 1). It affects 1–3% of prepubertal and pubertal females and may persist into the third and fourth decades. It often coexists with bulimia nervosa (BN), which is binge eating and forced vomiting or laxative abuse. Anorexic patients develop an abhorrence of food intake, and often participate in excessive physical exercise. Cutaneous manifestations primarily reflect malnutrition (Fig. 22.33),216–218 but repetitive self-induced vomiting in patients with bulimia and concomitant self-inflicted injury in some patients can also produce characteristic skin findings. Cutaneous manifestations of AN and BN have been studied in several series of patients under psychiatric treatment,219–221 and those findings noted

215. Bouillon R, Verstuyf A, Mathieu C, et al. Vitamin D resistance. Best Pract Res Clin Endocrinol Metab. 2006;20:627–645. 216. Rapaport MJ. Pellagra in a patient with anorexia nervosa. Arch Dermatol. 1985;121:255–257. 217. Van Voorhees AS, Riba M. Acquired zinc deficiency in association with anorexia nervosa: case report and review of the literature. Pediatr Dermatol. 1992;9:268–271. 218. Strumia R. Dermatologic signs in patients with eating disorders. Am J Clin Dermatol. 2006;6:165–173. 219. Schulze UME, Pettke-Rank CV, Kreienkamp M, et al. Dermatologic findings in anorexia and bulimia nervosa of childhood and adolescence. Pediatr Dermatol. 1999;16:90–94. 220. Glorio R, Allevato M, De Pablo A, et al. Prevalence of cutaneous manifestations in 200 patients with eating disorders. Int J Dermatol. 2000;39:348–353. 221. Hediger C, Rost B, Itin P. Cutaneous manifestations in anorexia nervosa. Schweiz Med Wochenschr. 2000;130:565–575.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

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Table 22.8  Cutaneous manifestations of anorexia nervosa and bulimia nervosa

Cutaneous changes   Xerosis   Carotenodermia   Purpura   Calluses on dorsum of hand (Russell’s sign)a   Other self-inflicted injuries Acral changes   Acral coldness   Acrocyanosis   Periungual erythema   Brittle/dystrophic nails

PREVALENCE ON EXAMINATION (%) 71–97 24 Unknown 23–30 12 38 24–40 48 30

Hair changes   Hypertrichosis   Telogen effluvium   Dry scalp hair   Pili torti   Lanugo-like body hair

36–77 37–86 20–48 82b

Oral changes   Cheilitis and perlèche   Aphthae   Gum recession, erosiona   Enamel erosiona   Dental cariesa   Sialadenosis (enlarged parotid and salivary glands)a

15–76 9–18 37 5–12 5–47 5–13

DISORDERS OF PREGNANCY

FEATURE

a

In patients with BN. From Strumia 2006,218 Schulze et al. 1999,219 Glorio et al. 2000,220 Hediger et al. 2000.221 bFrom Lurie et al. 1996.222

on examination are listed in Table 22.8.218–222 The prevalence of each of these conditions varies with the stage (early, late, recovery) and duration of the illness, accounting for discrepancies between studies. Cutaneous xerosis, carotenodermia, and acral changes including coldness, cyanosis, and erythema are common. Hair changes of note are generalized hypertrichosis, telogen effluvium, dry scalp hair, and pili torti.222 Oral manifestations include cheilitis, perlèche, aphthae, gum recession and erosion, enamel erosion, and dental caries. Salivary glands are enlarged. Nails become brittle and dystrophic. Self-inflicted injuries are common, but calluses on the backs of the hands from repetitive forced vomiting (Russell’s sign) are most characteristic. Most of the changes are reversible with weight regain. It has been proposed that a body mass index (BMI) of 16 kg/m2 is the critical value when most skin manifestations become apparent.

Figure 22.33  A teenage girl with severe emaciation characteristic of anorexia nervosa.

DISORDERS OF PREGNANCY Julie Powell The disorders of pregnancy are considered in a textbook of pediatric dermatology because of the associated fetal morbidity and

222. Lurie R, Danziger Y, Kaplan Y, et al. Acquired pili torti – a structural hair shaft defect in anorexia nervosa. Cutis. 1996;57:151–156.

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BOX 22.8 PHYSIOLOGIC CUTANEOUS CHANGES OBSERVED DURING PREGNANCY

DISORDERS OF PREGNANCY

>> Pigmentary – Hyperpigmentation – Melasma (chloasma) >> Vascular – Spider telangiectasia – Venous varicosities – Palmar erythema – Vasomotor instability – Pyogenic granuloma – Gingival hypertrophy – Hemorrhoids >> Hair – Prolonged anagen cycle – Telogen effluvium (3 months postpartum) – Hirsutism >> Cholestasis – Jaundice – Pruritus gravidarum >> Striae distensae >> Glandular – Increased eccrine gland activity – Decreased apocrine function – Increased sebaceous function >> Nail – Transverse ridging – Brittleness – Distal onycholysis >> Tumors – Skin tags (molluscum fibrosum gravidarum, fibroma molle) – Dermatofibroma – Neurofibromas – Melanocytic nevi – Keloids – Leiomyoma

mortality and because of the high incidence of adolescent pregnancies. The literature is replete with discrepancies and controversies over nomenclature and classification of the disorders of pregnancy. This section discusses the major disorders likely to be seen and to affect the fetus.223–226 Cutaneous findings during

223. Shornick JK. Dermatoses of pregnancy. Semin Cutan Med Surg. 1998;17:172–181. 224. Vaughn Jones SA, Black MM. Pregnancy dermatoses. J Am Acad Dermatol. 1999;40:233–241. 225. Kroumpouzos G, Cohen LM. Dermatoses of pregnancy. J Am Acad Dermatol. 2001;45:1–19. 226. Ambros-Rudolph CM, Müllegger RR, Vaughn-Jones SA, et al. The specific dermatoses of pregnancy revisited and reclassified: Results of a

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BOX 22.9 SPECIFIC DISORDERS OF PREGNANCY

>> Pemphigoid gestationis (herpes gestationis)a >> PUPPP (also known as polymorphic eruption of pregnancy,

toxic erythema of pregnancy, toxemic rash of pregnancy, and late-onset prurigo of pregnancy)

>> Prurigo of pregnancy >> Pruritic folliculitis of pregnancy >> Atopic eruption of pregnancy (AEP) (including prurigo of pregnancy and pruritic folliculitis of pregnancy)

>> Cholestasis of pregnancya >> Impetigo herpetiformis (pustular psoriasis of pregnancy)a a

Associated with either fetal morbidity or mortality, or both.

pregnancy can be classified as (1) physiologic changes, (2) specific disorders seen only in pregnancy, and (3) effects of pregnancy on cutaneous disorders previously present. Physiologic skin changes225,227 that occur with pregnancy are listed in Box 22.8. These include disorders of pigmentation such as hyperpigmentation of pre-existing pigmented lesions (i.e., nevi, lentigines, linea nigra), melasma (which is also known as chloasma), and jaundice (which is a result of cholestasis of pregnancy). Cholestasis is also responsible for the common pruritus gravidarum that occurs in nearly 20% of otherwise normal pregnancies. Vascular changes are also common during pregnancy and include growth in number and size of spider telangiectases, varicosities (both large deep-vessel varicosities and stellate varicosities of the lower extremities), and palmar erythema. Pyogenic granulomas are commonly seen during pregnancy, as well as edema and hyperemia of the gingivae. Abdominal striae distensae develop in up to 90% of women during the sixth and seventh months of pregnancy.225 Hair changes during pregnancy include a prolonged anagen cycle of the hair with less loss of hair and consequent thickening during gestation followed by a predictable telogen effluvium 3 months postpartum. A telogen effluvium is seen in the newborn at approximately the same time. There is increased eccrine hyperhidrosis and heat intolerance associated with pregnancy, increased sebaceous activity, and decreased apocrine activity. Finally, besides pyogenic granulomas, other cutaneous tumors seem to be stimulated by pregnancy, including skin tags or larger similar lesions called molluscum fibrosum gravidarum or fibroma molle, dermatofibromas, keloids, leiomyomas, neurofibromas, and nevi. The specific skin disorders of pregnancy are listed in Box 22.9. The historical classification223–225 is being modified226,228 and the following highlights the major features of the most common conditions.

retrospective two-center study on 505 pregnant patients. J Am Acad Dermatol. 2006;54:395–404. 227. Elling SV, Powell FC. Physiological changes in the skin during pregnancy. Clin Dermatol. 1997;15:35–43. 228. Kroumpouzos G, Cohen LM. Specific dermatoses of pregnancy: An evidence-based systematic review. Am J Obstet Gynecol. 2003;188:1083–1092.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

Pemphigoid gestationis (PG) is the best characterized dermatosis of pregnancy229–231 and is important to exclude. This disorder closely resembles bullous pemphigoid (BP) and has been estimated to occur in 1 in 50 000 births, an incidence much lower than reported earlier. The term pemphigoid gestationis is proposed to avoid any confusion with a herpesvirus infection. PG has been reported to occur as early as 9 weeks’ gestation and as late as 6 days postpartum, but it usually occurs in the second trimester (mean onset, 21 weeks). There may be earlier onset in subsequent pregnancies. Individual lesions begin as intensely pruritic urticarial papules and plaques that develop into polycyclic wheals, target-like lesions, and ultimately vesicles and bullae that crust over. Rarely, they are pustular.232 The lesions begin around the umbilicus and rapidly progress to become generalized, usually sparing the face, mucous membranes, palms and soles. Earlier reports suggested a higher than expected infant mortality and prematurity rate,233 but this has been disputed.230,231 Infants born to affected mothers may have transient papulovesicular eruptions lasting several weeks.234–236 Histologically, lesions of PG are subepidermal bullae with a mixed perivascular inflammatory cell infiltrate237 and a predominance of C3 localized to the lamina lucida of the basement membrane zone. IgG can also be found, but in only about 25– 30% of patients.225,231 Thus, although there may be many features of pemphigoid gestationis that resemble bullous pemphigoid, one major difference is the rarity of IgG compared with C3. A circulating complement-fixing IgG, called HG factor, is not easily detected by routine indirect immunofluorescence (IF) but can be demonstrated in the majority of cases by using indirect complement-added IF.231 This antibody belongs to the IgG1 subclass and the antigen is a 180-kd protein similar to the bullous pemphigoid antigen (bullous pemphigoid antigen 2, BPAG2). HG factor can cross the placenta, has been found in cord blood, and probably accounts for the transient symptoms reported in some infants. Immunogenetic studies have shown a marked increase in the HLA antigens DR3 and DR4 in patients with HG; the most striking observation is the simultaneous presence of both DR3 and DR4 in about 45% of patients compared with only 3% in the general population.225,231 These observations suggest that both genetic (HLA type) and environmental (pregnancy) factors are involved in the pathogenesis of PG.

229. Yancey KB. Herpes gestationis. Dermatol Clin. 1990;8:727–735. 230. Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients with pemphigoid gestationis. Clin Exp Dermatol. 1999;24:255–259. 231. Engineer L, Bhol K, Ahmed AR. Pemphigoid gestationis: a review. Am J Obst Gynecol. 2000;183:483–491. 232. Bercovitch L, Bogaars HA, Murray DO. Pustular herpes gestationis. Arch Dermatol. 1983;119:91–93. 233. Lawley TJ, Stingl G, Katz SI. Fetal and maternal risk factors in herpes gestationis. Arch Dermatol. 1978;114:552–555. 234. Chorzelski TP, Jablonska S, Beutner EH, et al. Herpes gestations with identical lesions in the newborn. Passive transfer of the disease? Arch Dermatol. 1976;112:1129–1131. 235. Karna P, Broecker AH. Neonatal herpes gestationis. Pediatrics. 1991;119: 299–301. 236. Chen SH, Chopra K, Evans TY, et al. Herpes gestationis in a mother and child. J Am Acad Dermatol. 1999;40:847–849. 237. Hertz KC, Katz SI, Maize J, et al. Herpes gestationis. A clinicopathologic study. Arch Dermatol. 1976;112:1543–1548.

Therapy for pemphigoid gestationis is quite successful with systemic glucocorticosteroids. Such treatment may be responsible for the recent apparent decline in infant morbidity and mortality with this disease. Mild cases may respond to topical corticosteroids and oral antihistamines. There is no maternal risk in PG other than pruritus and discomfort. An increased association with Graves’ disease and other autoimmune disorders has been reported.225,231 Neonatal PG can occur in up to 10% of cases, but is mild and self-limited. There has been considerable controversy regarding the increase in fetal mortality and morbidity with PG. Most studies show a tendency for complications associated with low-grade placental insufficiency, such as prematurity and small-for-gestational-age infants; this does not seem to be altered by systemic corticosteroids. However, recent studies show no additional increase in fetal mortality and morbidity. A few cases of PG progressing to bullous pemphigoid have been reported.238

DISORDERS OF PREGNANCY

PEMPHIGOID GESTATIONIS (HERPES GESTATIONIS)

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PRURITIC URTICARIAL PAPULES AND PLAQUES OF PREGNANCY (POLYMORPHOUS ERUPTION OF PREGNANCY) Pruritic urticarial papules and plaques of pregnancy (PUPPP) were described as such in 1979 by Lawley, followed by massive confusion in the literature concerning the inclusion or exclusion of previously described but less well-documented disorders.239–245 PUPPP still seems to be the preferred acronym in the USA at this time but the name polymorphic eruption of pregnancy (PEP) is also widely used; these incorporate toxic erythema of pregnancy, toxemic rash of pregnancy, and late-onset prurigo of pregnancy. PUPPP is the most common of the specific dermatoses of pregnancy. This pruritic disorder tends to occur in the last trimester of pregnancy, usually in a primigravida. In contrast to pemphigoid gestationis, it does not recur with subsequent pregnancies. The incidence is estimated to be as frequent as 1 in 120 to 1 in 240 pregnancies, and its common occurrence in mild forms probably accounts for the lack of reported cases. Lesions begin as pruritic urticarial papules, primarily within abdominal striae around the umbilicus (Fig. 22.34). The papules progress to plaques, polycyclic wheals, and target-like lesions. Rarely, tiny vesicles are seen. The abdomen and proximal portions of the extremities are most often affected. In contrast to pemphigoid gestationis, these do not develop large vesicles or

238. Jenkins RE, Vaughan Jones SA, Black MM. Conversion of pemphigoid gestationis to bullous pemphigoid – two refractory cases highlighting this association. Br J Dermatol. 1996;135:595–598. 239. Lawley TJ, Hertz HC, Wade TR, et al. Pruritic urticarial papules and plaques of pregnancy. JAMA. 1979;241:1696–1699. 240. Callen JP, Hanno R. Pruritic urticarial papules and plaques of pregnancy (PUPPP). J Am Acad Dermatol. 1981;5:401–405. 241. Petropoulou H, Georgala S, Katsambas AD. Polymorphic eruption of pregnancy. Int J Dermatol. 2006;45:642–648. 242. Rudolph CM, Al-Fares SA, Vaugh-Jones SA, et al. Polymorphic eruption of pregnancy: clinicopathology and potential trigger factors in 181 patients. Br J Dermatol. 2006;154:54–60. 243. Ohel I, Levy A, Silberstein T, et al. Pregnancy outcome of patients with pruritic urticarial papules and plaques of pregnancy. J Matern Fetal Neonatal Med. 2006;19:305–308. 244. Regnier S, Fermand V, Levy P, et al. A case-control study of polymorphic eruption of pregnancy. J Am Acad Dermatol. 2008;58:63–67. 245. Aronson IK, Bond S, Fiedler VC, et al. Pruritic urticarial papules and plaques of pregnancy: clinical and immunopathologic observations in 57 patients. J Am Acad Dermatol. 1998;39:933–939.

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of urinary cortisol and estriol, but this has not been further substantiated.223–225 Prurigo of pregnancy is now thought to be a result of physiologic pruritus in patients with an atopic tendency. Liver function tests should be performed to exclude cholestasis. There are no adverse effects to mother or infant. The disease may last for weeks to months and resolves postpartum. Recurrence in subsequent pregnancies is variable. Treatment is usually satisfactory with mid-potency topical corticosteroids and oral antihistamines.

PRURITIC FOLLICULITIS OF PREGNANCY

DISORDERS OF PREGNANCY

Figure 22.34  Pruritic urticarial papules and plaques of pregnancy: periumbilical striae involved.

bullae. To date, there has been a single report of an infant with papular lesions born to a mother with PUPPP.246 However the diagnosis of PUPPP in the infant was not well substantiated and the neonate is usually unaffected. There appears to be no increased infant morbidity or mortality.243 Association with excessive maternal weight gain and with multiple gestation pregnancies has been recognized.242–244 Histologically, lesions show upper dermal inflammation and epidermal spongiosis with a mixed perivascular infiltrate including prominent eosinophils. In contrast to pemphigoid gestationis, there is no evidence for an immune etiology and direct and indirect immunofluorescence are negative. Lesions often respond well to high-potency topical steroids and oral antihistamines, and rarely are systemic steroids needed for relief of pruritus.

PRURIGO OF PREGNANCY This is the current term used to describe a heterogeneous group of disorders including Besnier’s prurigo gestationis, Spangler’s papular dermatitis of pregnancy247,248 and Nurse’s early onset prurigo,249 because of extensive clinical overlap between these conditions.225 Its incidence is approximately 1 in 300 pregnancies. It is similar to nodular prurigo in non-pregnant individuals and typically presents as an intensely pruritic papular disorder on the extensor surfaces of the limbs and on the abdomen. Lesions are 0.5–1.0 cm in size, with or without a central crust. Histopathologic features are nonspecific, showing a chronic upper dermal inflammatory infiltrate with occasional epidermal involvement and negative direct and indirect IF. Spangler described an association with a higher than expected level of urinary human chorionic gonadotropin (HCG) and low levels

246. Uhlin SR. Pruritic urticarial papules and plaques of pregnancy. Involvement in mother and infant. Arch Dermatol. 1981;117:238–239. 247. Spangler AS, Reddy W, Bardawil WA, et al. Papular dermatitis of pregnancy. A new clinical entity? JAMA. 1962;181:577–581. 248. Michaud RM, Jacobson D, Dahl MV. Papular dermatitis of pregnancy. Arch Dermatol. 1982;118:1003–1005.

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This disorder, which presents as its name describes, with pruritic follicular inflammation, was described in 1981 by Zoberman and Farmer.250 It presents as widespread erythematous, follicular papules and pustules occurring in the fourth to ninth month of gestation and carries no fetal risk. Histologically, there is an acute sterile folliculitis with negative immunofluorescence, and cultures are negative. It bears some resemblance to steroid acne; increased levels of androgens were reported in one case. Some authors think that this condition should be included in the PUPPP or polymorphic eruption of pregnancy category.251 Therapy with 1% hydrocortisone, 10% benzoyl peroxide, or UVB has been effective.

ATOPIC ERUPTION OF PREGNANCY (AEP) This term has recently been proposed by Ambros-Rudolph et al.226 as a distinct disease complex comprising prurigo of pregnancy, pruritic folliculitis of pregnancy as well as eczema of pregnancy, because of the considerable clinical and histopathological overlap of these conditions. In their review of 505 pregnant patients, AEP was the most common pruritic dermatosis in pregnancy, occurring in close to 50% of patients. Pre-existing atopic dermatitis was present in only 20% of these patients. In comparison with the other specific dermatoses of pregnancy, symptoms of AEP occur earlier in gestation with equal involvement of the trunk and extremities. Skin manifestations can be eczematous (in 2 3 of cases) or prurigo-type. There is no specific association with parity or gestation, and no fetal risk. It is speculated that the Th2 shift associated with pregnancy may favor the exacerbation of atopic dermatitis during pregnancy and the manifestation of AEP. Because eczema is so common both in pregnant and non-pregnant women, it is still unclear if AEP deserves to be considered a specific dermatosis of pregnancy.

IMPETIGO HERPETIFORMIS (PUSTULAR PSORIASIS OF PREGNANCY) This generalized pustular disorder represents pustular psoriasis exacerbated by pregnancy.223–225 It is no longer included in the specific disorders of pregnancy by many authors. It can occur in any trimester and often in patients without a prior family or

249. Nurse DS. Prurigo of pregnancy. Aust J Dermatol. 1968;9:258–267. 250. Zoberman E, Farmer ER. Pruritic folliculitis of pregnancy. Arch Dermatol. 1981;117:20–22. 251. Kroumpouzos G, Cohen L. Pruritic folliculitis of pregnancy. J Am Acad Derm. 2000;43:132–134.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

Cholestasis of pregnancy (CP) Although it does not cause primary skin lesions but only secondary lesions from scratching, CP is included in the specific dermatoses of pregnancy in recent reviews because of the risk of fetal complications.228,226 The incidence of CP ranges from 70 per 10 000 pregnancies in the USA to about 150 per 10 000 pregnancies in Scandinavia and South America. Hormonal, genetic, environmental and alimentary factors all appear to play a role in its pathogenesis. This condition begins in the 3rd trimester with moderate to severe pruritus, limited to the palms and soles or generalized. Skin lesions are usually absent or appear as secondary excoriations or prurigo. Jaundice develops in about 20% of cases. Fetal risks include distress, stillbirth, and preterm delivery as a result of placental anoxia. Elevated serum bile acids are the most sensitive marker of this condition and mild perturbations in liver function tests are common. In mild cases, treatment is symptomatic with emollients and topical antipruritics. Antihistamines are rarely helpful. UVB and dexamethasone can be effective. Cholestyramine can reduce symptoms by binding bile acids in milder cases but may lead to coagulopathy by precipitating vitamin K. Ursodeoxycholic acid (UDCA) appears more effective than cholestyramine with more rapid and sustained effect on pruritus.

SYSTEMIC DISORDERS EXACERBATED BY PREGNANCY There is a group of disorders that seem to be aggravated by pregnancy (Box 22.10). These include metabolic conditions such as porphyria cutanea tarda,252,253 and acrodermatitis enteropathica;253 autoimmune diseases including systemic lupus erythematosus, systemic sclerosis,254 polymyositis/dermatomyositis, and pemphigus; Ehlers–Danlos syndrome and pseudoxanthoma elasticum; neurofibromatosis255 and tuberous sclerosis; erythema

252. Goerz G, Hammer G. Porphyria cutanea tarda and pregnancy. Dermatologica. 1983;166:316–318. 253. Perez-Maldonado A, Kurban AK. Metabolic diseases and pregnancy. Clin Dermatol. 2006;24:88–90. 254. Saar P, Hermann W, Müller-Ladner U. Connective tissue diseases and pregnancy. Rheumatology (Oxford). 2006;45:iii30–iii32.

BOX 22.10 CUTANEOUS DISORDERS AGGRAVATED BY PREGNANCY

Autoimmune

>> SLE, systemic sclerosis >> Dermatomyositis/polymyositis >> Pemphigus vulgaris, vegetans, foliaceus Metabolic

>> Porphyria cutanea tarda >> Acrodermatitis enteropathica Infectious

>> Condyloma acuminata >> Fungal (Candida, Pityrosporum) >> AIDS

DISORDERS OF MINERALS AND CO-FACTORS

personal history of psoriasis. Patients may become extremely ill with fever, chills, nausea, vomiting, diarrhea, and hypocalcemic tetany. Indeed, hypocalcemia has become a hallmark of acute exacerbations of this disease. Individual lesions are millimetersized pustules that coalesce into large lakes of pus, desquamate, and recur in crops. The lesions often begin in flexural areas, spreading centrifugally; the face, hands, and feet are spared. Postinflammatory hyperpigmentation is common. Histopathologic features are the same as pustular psoriasis and direct immuno­ fluorescence is negative. There is some response to systemic steroids, usually at doses of 15–30 mg/day of prednisone. Serum calcium and albumin levels should be monitored closely as risks to the mother include tetany, seizures, and delirium. Stillbirth and placental insufficiency are still frequently seen even if the disease appears well controlled with corticosteroids. Remission occurs postpartum but recurrence in further pregnancies is common.

22

Miscellaneous

>> Ehlers–Danlos syndrome >> Pseudoxanthoma elasticum >> Neurofibromatosis >> Tuberous sclerosis >> Erythema nodosum

nodosum; and various infections. Some other conditions, such as atopic dermatitis, psoriasis, acne vulgaris, hidradenitis suppurativa, rheumatoid arthritis and sarcoidosis, may either improve or deteriorate during pregnancy.225

DISORDERS OF MINERALS AND CO-FACTORS ZINC Epidemiology Human clinical zinc deficiency states have been recognized only relatively recently. Three types of zinc deficiency have been described: (1) a rare autosomal-recessive disorder, acrodermatitis enteropathica; (2) nutritional zinc deficiency, found sporadically in premature and full-term infants and endemically in adolescents in some Middle Eastern countries; and (3) iatrogenic zinc deficiency associated with total parenteral nutrition (TPN). This last cause is now rare because of heightened awareness of necessary zinc supplementation in TPN. Although clinical descriptions of acrodermatitis enteropathica have appeared in the literature for decades, Moynahan256 was the first to associate zinc deficiency with the clinical syndrome. Subsequently, the more subtle forms of zinc deficiency that are not genetically

255. Swapp GH, Main RA. Neurofibromatosis in pregnancy. Br J Dermatol. 1973;88:431–435. 256. Moynahan EJ. Acrodermatitis enteropathica: a lethal inherited human zinc deficiency disorder. Lancet. 1974;2:399–400.

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inherited have been recognized. Several excellent reviews are available.257–264

Presenting history

DISORDERS OF MINERALS AND CO-FACTORS

Infants with acrodermatitis enteropathica present with a classic triad of diarrhea, periorificial and acral dermatitis and alopecia, often with extreme irritability and depression. Onset is approximately 1–2 weeks after weaning or 4–10 weeks of age in bottlefed infants. Left untreated, severe failure to thrive and death may ensue. Frequent secondary bacterial and fungal infections are not uncommon. Acquired nutritional zinc deficiency has been reported in both bottle- and breast-fed premature infants265–268 and in full-term infants as well.269,270 These children present with cutaneous eruptions, alopecia, irritability, and failure to thrive. Adolescents, primarily in the Middle East, have been noted to have growth failure and delayed pubertal maturation.271 In the past, premature infants receiving TPN272 appeared with symptoms similar to nutritionally deprived children. In some adults and children, disturbances in taste appear secondary to zinc deficiency. Two children have been reported with alopecia, trichorrhexis nodosa, and dry, scaly skin all of which responded to zinc supplementation despite normal serum zinc levels, adding further confusion to the clinical diagnosis of zinc deficiency.273

Physical examination Infants with zinc deficiency have a classical erythematous, scaly, psoriasiform, and sometimes vesiculoerosive eruption located peri-orificially (Fig. 22.35A) (i.e., around the mouth, eyes, and genital area). Similar lesions may occur on the distal portions of the extremities (Fig. 22.35B), but these are not always present in infancy. In premature infants, scaly, red, macerated plaques in the neck folds are characteristic. Refractory diaper dermatitis may be the presenting complaint (Fig. 22.35C). Nail changes, consisting of paronychia as well as dystrophy of the nail plate, may occur. Secondary staphylococcal and candidal superinfections are very common, and Candida may not respond to topical

257. Sehgal VN, Jain S. Acrodermatitis enteropathica. Clin Dermatol. 2000;18: 745–748. 258. Prasad AS. Zinc: An overview. Nutrition. 1995;11:93–99. 259. Gordon EF, Gordon RC, Passal DB. Zinc metabolism: basic, clinical, and behavioral aspects. J Pediatr. 1981;99:341–349. 260. Ackland ML, Michalczyk A. Zinc deficiency and its inherited disorders. A review. Genes Nutr. 2006;1:41–50. 261. Kay RG. Zinc and copper in human nutrition. J Hum Nutr. 1981;35:25–36. 262. Maverakis E, Fung MA, Lynch PJ, et al. Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol. 2007;56:116–124. 263. Di Silvestro RA, Cousins RJ. Physiological ligands for copper and zinc. Annu Rev Nutr. 1983;3:261–288. 264. Van Wouwe JP. Clinical and laboratory diagnosis of acrodermatitis enteropathica. Eur J Pediatr. 1989;149:2–8. 265. Zimmerman AW, Hambidge KM, Lepow ML, et al. Acrodermatitis in breast-fed premature infants: evidence for a defect of mammary zinc secretion. Pediatrics. 1982;69:176–183. 266. Heinen F, Mathern D, Pringsheim N, et al. Zinc deficiency in an exclusively breast-fed preterm infant. Eur J Pediatr. 1995;154:71–75. 267. Stevens J, Lubitz C. Symptomatic zinc deficiency in breast-fed term and premature infants. J Paediatr Child Health. 1998;34:97–100. 268. Moore MEC, Moran JR, Green HL. Zinc supplementation in lactating women: evidence for mammary control of zinc secretion. J Pediatr. 1984;105:600–602. 269. Piela Z, Szuber M, Mach B, et al. Zinc deficiency in exclusively breast-fed infants. Cutis. 1998;61:197–200. 270. Lee MG, Hong KT, Kim JJ. Transient symptomatic zinc deficiency in a full-term breast-fed infant. J Am Acad Dermatol. 1990;23:375–379.

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therapy unless the zinc deficiency is corrected. If the disorder is left untreated, the dermatitis appears first and, after a period of several weeks, near-total alopecia develops. In addition, photophobia, blepharitis and conjunctivitis can be seen, possibly leading to corneal opacity. Diarrhea may present before or after the cutaneous changes. The affected child is typically irritable with failure to thrive. The Middle Eastern adolescents who have been reported have similar acral and periorificial cutaneous findings, but they also have short stature and delayed puberty.271

Laboratory findings Low levels of plasma zinc are pathognomonic of acrodermatitis enteropathica. Blood for zinc levels must be carefully collected in special acid-washed or plastic tubes, so that exogenous zinc present on ordinary glassware will not contaminate the specimen. In milder forms of zinc deficiency, plasma levels may be misleadingly normal,269 although there may be a clinically favorable response to zinc. Another useful associated laboratory finding is low serum alkaline phosphatase, a zinc-dependent metalloenzyme.274 Investigational testing of immune function has revealed anergy, hypogammaglobulinemia,273 abnormal cell-mediated immunity,275,276 as well as monocyte and neutrophil chemotaxis defects.277,278

Pathophysiology and histogenesis The clinical signs and symptoms of all the zinc deficiency states correct dramatically upon replacement with zinc.258–262 In autosomal-recessive acrodermatitis enteropathica (OMIM 201100), the genetic defect has been mapped to chromosome 8q24.3;279 the defective gene SLC39A4,280 encodes the zinc transporter Zip4. This leads to defective zinc absorption in the duodenum and jejunum. The observation that acrodermatitis enteropathica does not usually occur during breast-feeding but one to two weeks after weaning and the fact that breast milk seems more beneficial than cow’s milk in this disorder has led

271. Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency, anemia, hepatosplenomegaly, dwarfism, hypogonadism and geophagia. Am J Med. 1961;31:532–546. 272. Arlette JP, Johnston MM. Zinc deficiency dermatosis in premature infants receiving prolonged parenteral alimentation. J Am Acad Dermatol. 1981;5:37–42. 273. Slonim AE, Sadick N, et al. Clinical response of alopecia, trichorrhexis nodosa, and dry, scaly skin to zinc supplementation. J Pediatr. 1992;121: 890–895. 274. Weismann K, Hyer H. Serum alkaline phosphatase activity in acrodermatitis enteropathica: an index of the serum zinc level. Acta Derm Venereol (Stockh). 1978;59:89–90. 275. Oleske JM, Westphal ML, Shore S, et al. Zinc therapy of depressed cellular immunity in acrodermatitis enteropathica. Its correction. Am J Dis Child. 1979;133:915–918. 276. Chandra RK. Acrodermatitis enteropathica: zinc levels and cell-mediated immunity. Pediatrics. 1980;66:789–791. 277. Businco L, Menghi AM, Rossi P, et al. Zinc-dependent chemotactic defect in an infant with acrodermatitis. Arch Dis Child. 1980;55:966–968. 278. Weston WL, Huff JC, Humbert JR, et al. Zinc correction of defective chemotaxis in acrodermatitis enteropathica. Arch Dermatol. 1977;113:422–425. 279. Wang K, Pugh EW, Griffen S, et al. Homozygosity mapping places the acrodermatitis enteropathica gene on chromosomal region 8q.24.3. Am J Hum Genet. 2001;68:1055–1060. 280. Kury S, Dreno B, Bezieau S, et al. Identification of SCL39A4, a gene involved in acrodermatitis enteropathica. Nat Genet. 2002;31:239–240.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

B DISORDERS OF MINERALS AND CO-FACTORS

A

22

Figure 22.35  Acrodermatitis enteropathica. (A) Periorificial lesions; (B) acral C

bullous and erosive lesions; (C) recalcitrant and erosive diaper dermatitis. (All courtesy Dr A. Hernández-Martín.)

to extensive studies of zinc metabolism in human milk.265,268 Although the zinc content of human milk is not significantly greater than that of cow’s milk, its bioavailability in human milk is higher. However, the concentration of zinc in human breast milk declines rapidly during the postpartum period making human milk alone an insufficient source of zinc after approximately 5–6 months postpartum. Control of zinc levels in human milk is independent of maternal plasma zinc, as shown by the failure to increase milk zinc levels by maternal ingestion of zinc.265,268 Individual abnormalities in breast-milk zinc excretion have resulted in the development of zinc deficiency states in both premature and full-term breast-fed infants.265–270 Conversely, it is believed that the Middle Eastern adolescents with symptomatic zinc deficiency develop it on the basis of concurrent ingestion of high amounts of a zinc-binding ligand, phytate, present in high quantities in these areas and perhaps in the local clay, which is often ingested. Phytate binds the zinc and renders it unavailable for absorption. In developed countries, groups at risk of dietary zinc deficiency include vegetarians, alcoholics and patients with malabsorption syndromes such as celiac sprue,

Crohn’s disease and short bowel syndrome. Finally, in TPNassociated zinc deficiency and in sick premature infants, the zinc deficiency state occurs because of a combination of factors. These include inadequate intake as well as enhanced losses and need for zinc in severe illness and/or stress, as plummeting plasma zinc levels are associated with such stressful events as sepsis. Absorption of zinc is in the duodenum and proximal small intestine and excretion is primarily intestinal with a small component being excreted in sweat. Thirty percent of ingested zinc is absorbed. In blood, 80% of zinc is in red blood cells in carbonic anhydrase. Zinc is an essential mineral that has been found to be a component of the catalytic site of hundreds of metalloenzymes. Notable enzymes include carbonic anhydrase, carboxypeptidases A and B, alkaline phosphatase, alcohol dehydrogenase, retinene reductase, lactate dehydrogenase, glutamate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, and superoxide dismutase. Thus, zinc deficiency has profound widespread metabolic effects. Zinc may interact with essential fatty acid metabolism mediated via prostaglandins.281,282 Zinc also seems to play an important role in wound healing.

281. Horrobin DF, Cunnane SC. Interactions between zinc, essential fatty acids and prostaglandins: relevance to acrodermatitis enteropathica, total parenteral nutrition, the glucagonoma syndrome, diabetes, anorexia nervosa and sickle cell anaemia. Med Hypoth. 1980;6:277–296.

282. Cunnane SC. Maternal essential fatty acid supplementation increases zinc absorption in neonatal rats: relevance to the defect in zinc absorption in acrodermatitis enteropathica. Pediatr Res. 1982;16:599–603.

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The histopathology of zinc deficiency is not specific and is indistinguishable from other ‘deficiency dermatoses’ such as niacin/vitamin B3 deficiency (pellagra) and glucagonomaassociated necrolytic migratory erythema.283 It shows a chronic dermatitis with possible neutrophilic infiltration of the epidermis and intraepidermal vesicle formation.

Differential diagnosis Zinc deficiency in infants resembles severe seborrheic dermatitis as well as essential fatty acid and biotin deficiencies. Secondary candidal infection may be mistakenly thought to be the primary disorder. An acrodermatitis enteropathica-like eruption has been reported as a presenting sign of cystic fibrosis,284,285 acquired immune deficiency syndrome, and organic aciduria.286 DISORDERS OF MINERALS AND CO-FACTORS

Therapy and prognosis Left untreated, acrodermatitis enteropathica can progress to a fatal outcome. Before the discovery of zinc deficiency, 8-hydroxyquinoline (diodoquin) was found empirically to provide partially successful therapy. It is now speculated that the mechanism of action of diodoquin is to enhance intestinal zinc absorption. Zinc supplementation has a rapid and dramatic effect that reverses all cutaneous, GI, and neurologic manifestations of the disease. In acrodermatitis enteropathica, zinc may need to be supplemented for a lifetime, or at least during times of metabolic stress such as pregnancy. In transient zinc deficiency associated with prematurity TPN or malnutrition there is gradual lessening of the need for zinc supplementation as the underlying medical problems are resolved. There is no evidence that zinc supplementation will enhance growth or intellectual function or improve hair growth in children with normal levels of plasma zinc. The daily dietary requirements for zinc and suggested replacements in deficiency states are listed in Table 22.9.

COPPER Two disorders of copper metabolism are of interest to pediatric dermatologists: Wilson’s disease and Menkes’ steely hair disease (kinky hair syndrome).287,288 They are discussed separately.

Wilson’s disease (hepatolenticular degeneration) Wilson’s disease (WD)287–289 was first described in 1912 as an autosomal-recessive trait distinguished by toxic copper accumulation in several organ systems, especially the liver and the brain. It occurs in approximately 1 : 30 000–1 : 100 000 births. Chronic liver disease, occasionally progressing to rapid massive hepatic

283. Gonzalez JR, Botet MV, Sanchez JL. The histopathology of acrodermatitis enteropathica. Am J Dermatopathol. 1982;4:303–311. 284. Hansen RC, Lemen R, Revsin B. Cystic fibrosis manifesting with acrodermatitis enteropathica-like eruption. Arch Dermatol. 1983;119: 51–55. 285. Zedek D, Morrell DS, Graham M, et al. Acrodermatitis enteropathica-like eruption and failure to thrive as presenting signs of cystic fibrosis. J Am Acad Dermatol. 2008;58:S5–S8. 286. De Raeve, De Meirieir L, Ramet J, et al. Acrodermatitis enteropathica-like cutaneous lesions in organic aciduria. J Pediatr. 1994;124:416–420.

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Table 22.9  Elemental zinc requirements and replacementa CLINICAL STATE

PO (mg/day)

IV µg/ kg/day

REFERENCE

0–6 months

2



262

7 months to 3 years

3



262

4–8 years

5



262

9–13 years

8



262

Females, 14–18 years

9



262

Females, >18 years

8



262

Males, ≥13 years

11



262

Pregnant females (14–18 years)

12



262

Pregnant females (>18 years)

11



262

Premature, sick,   on TPN



40–200

274

Acrodermatitis enteropathica

3 mg/kg/ day



262

Adult on TPN



20

272

a

50 mg elemental zinc, 200 mg zinc sulfate. 1 mg elemental zinc per 2.8 mg zinc acetate.

failure, is the presenting sign in the first decade of life. Later, in the second and third decades, CNS copper accumulation, especially in the basal ganglia, causes neurological symptoms including parkinsonian features and seizures. Psychiatric symptoms such as personality changes, depression and psychosis can also occur. Hemolytic anemia, joint symptoms, renal stones, and renal tubular acidosis are less common findings. The visible sign in WD is the Kayser–Fleischer ring, a brownish-green pigmentation of copper deposition in Descemet’s membrane of the cornea. It first appears at the upper and lower poles. Early on, it is visible only with a slit lamp. By the time CNS manifestations are present, it is usually visible. Blue lunulae may also be seen in the nails. Laboratory studies reveal low plasma ceruloplasmin with high plasma and urinary levels of copper. Liver biopsy specimens also show an accumulation of copper. Radioactive copper studies show failure of normal copper incorporation into ceruloplasmin. The gene mutated in WD, ATP7B,288 has been mapped to chromosome 13q14.3. The basic defects are thought to be abnormal biliary copper excretion and failure of normal copper incorporation into ceruloplasmin in the liver.287,290

287. Culotta VC, Gitlin JD. Disorders of copper transport. In: Scriver CR, Beaudet AL, Sly WS, et al. eds. The metabolic and molecular bases of inherited disease, 8th ed. New York: McGraw Hill; 2001:3105–3118. 288. De Bie P, Wijmenga C, Klomp LWJ. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet. 2007;44:673–688. 289. Waggoner DJ, Barthikas TB, Gitlin JD. The role of copper in neurodegenerative disease. Neurobiol Dis. 1999;6:221–230. 290. Menkes JH. Menkes disease and Wilson disease: two sides of the same copper coin. Part II: Wilson disease. Eur J Paediatr Neurol. 1999;3:245–253.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

Menkes’ kinky hair disease Menkes’ disease (MD),287,288 also known as steely hair disease, trichopoliodystrophy, X-linked copper malabsorption, and X-linked copper deficiency, was first described clinically as an X-linked disease in 1962 by Menkes et al.291 but its relationship to copper deficiency was not noted until a decade later by Danks et al.292 The incidence has been estimated in Australia as 1 in 35 000 births,293 but in Northern Europe the incidence was found to be only 1 in 298 000 live births.294 The clinical features of this disorder of copper storage, which results in systemic copper deficiency for many vital tissues, illustrate the ubiquity and importance of copper. The MD gene, ATP7A, has been located on chromosome Xq13.3 and codes for an intracellular copper binding P-type ATPase similar to that in Wilson’s disease, but this isomer is not present in the liver.287,295 Affected infants, often born prematurely, may have normal appearance and development for the first 2–3 months of life. In retrospect, hypothermia and prolonged jaundice are common. Gradually, there is loss of normal psychomotor development, severe hypotonia, and seizures. Cutaneous findings include a striking appearance of the hair, resembling steel wool. The hair is usually light, almost depigmented, with a spangled appearance. Under the microscope, the main finding is pili torti. Trichorrhexis nodosa, brush-like breaks along the hair shaft, may also occur. In careful studies of obligate female heterozygotes, variable levels of pili torti have been found. The face is characteristically pudgy, with a cupid’s bow upper lip and horizontal fuzzy eyebrows. There is generalized marked pigment dilution, with the patient having fairer skin, hair, and eye color than in firstdegree relatives. In addition to kinky hair, there are kinky tortuous blood vessels due to abnormalities of the internal elastic lamina of large and small arteries. Bones are fragile, and fractures, often resembling those seen in child abuse, may be present.296 Inguinal hernias are common. Infants rarely survive beyond the first decade and invariably show progressive deterioration before death. Most patients are males because this is an X-linked recessive disease. However, several female patients have now been 291. Menkes HJ, Alter M, Steigleder GK, et al. A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics. 1962;29:764–779. 292. Danks DM, Campbell PE, Stevens BJ, et al. Menkes’ kinky hair syndrome. An inherited defect in copper absorption with widespread effects. Pediatrics. 1972;50:188–201. 293. Hart DB. Menkes’ syndrome: an updated review. J Am Acad Dermatol. 1983;9:145–152. 294. Tonnesen T, Kleijer WJ, Horn N. Incidence of Menkes disease. Hum Genet. 1991;86:408–410. 295. Menkes JH. Menkes disease and Wilson disease: two sides of the same copper coin. Part I: Menkes disease. Eur J Paediatr Neurol. 1999;3:147–158. 296. Adams PC, Strand RO, Bresnan MJ, et al. Kinky hair syndrome: serial study of the radiological findings with emphasis on the similarity to the battered child syndrome. Radiology. 1974;112:401–407.

Table 22.10  Some important copper-containing enzymes ENZYME

FUNCTION

Cytochrome oxidase

Mitochondrial electron transport

δ-Amino levulinate dehydrase

Hemoglobin synthesis

Ceruloplasmin

Catecholamine metabolism

Tyrosinase

Melanin formation

Superoxide dismutase

Protection from free radicals

Monoamine oxidases

Catecholamine metabolism

Lysyl oxidase

Collagen and elastin production

Dopamine β-hydroxylase

Catecholamine metabolism

Peptidylglycine α-amidating monooxygenase

Neuropeptide and peptide hormone processing

DISORDERS OF MINERALS AND CO-FACTORS

Therapy may be successful with the chelating agent, penicillamine. Cutaneous complications of this treatment include elastosis perforans serpiginosa and pemphigus foliaceous and/or vulgaris as well as cutaneous adverse drug reactions; nephrotic syndrome is also a possible complication. Other treatment options include ammonium tetrathiomolybdate, triethylene tetramine dihydrochloride, and zinc acetate. Fulminant liver failure may require liver transplantation.

22

reported, presumably clinically affected because of unfortunate random inactivation of a large percentage of their normal X chromosomes (Lyonization).297 A mild form of MD has been described with less severe neurological defects and a longer lifespan.288 Laboratory findings include low levels of serum copper and ceruloplasmin, although incorporation of copper into ceruloplasmin appears normal.287,293,295,298 Anemia is common. Intestinal biopsies show high levels of copper in the brush border of the intestinal mucosa. The abnormalities in this disorder reflect the numerous enzymes that are dependent on copper (Table 22.10).289,298,299 Thus the anemia, connective tissue and bone abnormalities, and pigment dilution are readily understood as direct abnormalities of δ-amino levulinate dehydrase, lysyl oxidase, and tyrosinase, respectively. It is believed that the poor CNS development may be a result of abnormal catecholamine metabolism in the brain. Arterial abnormalities are due to abnormal elastin tissue on the internal elastic lamina of arteries. There also is an abnormality of cross-linking of free sulfhydryl groups in hair, which may account for the pili torti. Although MD was initially thought to be a simple disorder of copper deficiency due to malabsorption of copper, the high levels of copper found in intestinal mucosal cells as well as in the kidney put it more in the category of a copper storage disease. Indeed, cultured fibroblasts from affected individuals accumulate copper in vitro, providing a basis for possible prenatal diagnosis.300,301 Prenatal screening is possible by demonstrating accumulation of copper in chorionic villus sampling in the first trimester or in cultured amniotic fluid cells in the second and now with genetic mutation analysis. 297. Gerdes AM, Tonnesen T, Horn N, et al. Clinical expression of Menkes syndrome in females. Clin Genet. 1990;38:452–459. 298. Lucky AW, Hsia YE. Distribution of ingested and injected radiocopper in two patients with Menkes’ kinky hair disease. Pediatr Res. 1979;13:1280–1284. 299. Kay RG. Zinc and copper in human nutrition. J Hum Nutr. 1981;35:25–36. 300. Kivirikko KI, Peltonen L. Abnormalities in copper metabolism and disturbances in the synthesis of collagen and elastin. Med Biol. 1982;60:45–48. 301. Peltonen L, Kuivaniemi H, Palotie A, et al. Alterations in copper and collagen metabolism in the Menkes syndrome and a new subtype of the Ehlers–Danlos syndrome. Biochemistry. 1983;22:6156–6163.

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Ultrastructural studies of the skin have shown abnormal elastin fibrils with deficiency of mature elastin but normalappearing collagen.302 Biochemical studies of collagen biosynthesis in cultured fibroblasts showed not only copper accumulation, but low lysyl oxidase activity, similar to the abnormality found in Ehlers–Danlos syndrome type IX.301 Treatment with both oral and parenteral replacement of copper has not been uniformly successful but works best with early intervention.303,304 The prognosis is poor for survival beyond the first few years of life.

Biotin deficiency and multiple carboxylase deficiencies DISORDERS OF MINERALS AND CO-FACTORS

Biotin (vitamin H) is an essential cofactor in many metabolic pathways, such as gluconeogenesis, amino acid catabolism and fatty acid synthesis. It is found in many foods, such as liver, meats, egg yolks, yeast and tomatoes. Skin disorders secondary to biotin deficiency were first reported in the 1940s when diets high in raw eggs were popular.305 Avidin, a component of egg white, binds biotin and renders it biologically unavailable. More recently, several inborn errors of metabolism, the multiple carboxylase deficiencies, have also been identified as causing biotindependent skin and neurologic disease.306

Epidemiology Biotin deficiency can occur as an acquired or dietary deficiency in children and adults, or more frequently as an inborn error of metabolism. The two major metabolic syndromes associated with multiple carboxylase deficiency are inherited autosomal recessively: neonatal (early-onset) multiple carboxylase deficiency (OMIM 253270) presents in the first weeks of life and is associated with a deficiency of the enzyme holocarboxylase synthetase; the juvenile (late infantile) form (OMIM 253260) occurs after the second or third month of life and is caused by deficiency of biotinidase, an enzyme necessary for the recycling of endo­ genous biotin.307 There is no sex predilection. Recently, an autosomal recessive defect in biotin transport has been described.308

Presenting history Acquired dietary biotin deficiency has been produced experimentally in adult volunteers.305 After the 5th week of a biotinfree diet, symptoms included depression, lassitude, somnolence, hallucination, muscle pains, hyperesthesia, anorexia, and nausea.

302. Oakes BW, Danks DM, Campbell PE. Human copper deficiency: ultrastructural studies of the aorta and skin in a child with Menkes’ syndrome. Exp Mol Pathol. 1976;25:82–98. 303. Tang J, Donsante A, Desai V, et al. Clinical outcomes in Menkes disease patients with a copper-responsive ATP7A mutation. G727R. 2008;95: 174–181. 304. Kaler SG, Holmes CS, Goldstein DS, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med. 2008;358:605–614. 305. Sydenstricker VP, Singal SA, Briggs AP, et al. Observations on the ‘egg white injury’ in man. JAMA. 1942;118:1199–1200. 306. Wolf B. Disorders of biotin metabolism. In: Scriver CR, Beaudet AL, Sly WS, et al. eds. The metabolic and molecular bases of inherited disease, 8th ed. New York: McGraw-Hill; 2001:3935–3964. 307. Wolf B. Biotinidase: its role in biotinidase deficiency and biotin metabolism. J Nutr Biochem. 2005;16:441–445. 308. Mardach R, Zempleni J, Wolf B, et al. Biotin dependency due to a defect in biotin transport. J Clin Invest. 2002;109:1617–1623.

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In the inherited neonatal and juvenile forms of multiple carboxylase deficiency, vomiting, seizures, developmental delay or regression, hypotonia, and later ataxia are prominent symptoms.306–311 Optic atrophy and hearing loss can occur with biotinidase deficiency.307 Neurologic findings can also be found in the acquired form secondary to total parenteral alimentation.312–314

Physical findings In the neonatal form of multiple carboxylase deficiency, the earliest signs in the first weeks of life are a sharply marginated seborrheic rash on the scalp, eyebrows, and eyelids that can spread to perioral, perianal, and other flexural areas.310 There is associated crusting and erosion, but there are no pustules or vesicles. Over several months, hair thinning can progress to total and even universal alopecia. Prominent fissures on the feet, in the perianal area, and on the cheeks have been reported. There has been associated blepharitis and keratoconjunctivitis with photophobia. Significant cutaneous manifestations may be absent in patients with an early demise. The juvenile (or late infantile) onset and the acquired forms of biotin deficiency secondary to TPN have similar signs but they present at later ages (i.e., over 2–3 months in the juvenile form and at the time of TPN). In one family with juvenile onset disease,311 three affected children developed neurologic and cutaneous signs at 2–3 months of age. These children had distinctive, sharply marginated, brightly erythematous periorificial scaly plaques with secondary Candida infection as well as severe alopecia. Of note, there are reported cases of well-documented multiple carboxylase deficiency without mention of cutaneous findings. The variability in severity of symptoms is highlighted by a recent report of asymptomatic family members of affected patients.309 Secondary candidiasis is a frequent complication in patients with biotin deficiency and is often difficult to treat despite topical antifungal medication until biotin therapy is instituted.

Laboratory findings Metabolic acidosis, often lactic acidosis, ketosis, and hyper­ ammonemia are all reported. Specific elevations of the urinary organic acids β-methylcrotonyl glycine, β-hydroxyisovaleric acid, and tiglylglycine can aid in diagnosis. Plasma levels of biotin are unreliable indicators of this disorder, unless they are diagnostically low. Holocarboxylase synthetase deficiency can be demonstrated in cultured fibroblasts or peripheral blood

309. Baykal T, Gokcay G, Gokdemir Y, et al. Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases. J Inherit Metab Dis. 2005;28:903–912. 310. Mock DM. Skin manifestations of biotin deficiency. Semin Dermatol. 1991;10:296–302. 311. Williams ML, Packman S, Cowan MJ. Alopecia and periorificial dermatitis in biotin-responsive multiple carboxylase deficiency. J Am Acad Dermatol. 1983;9:97–103. 312. Sweetman L, Surh L, Baker H, et al. Clinical and metabolic abnormalities in a boy with dietary deficiency of biotin. Pediatrics. 1981;68:553–558. 313. Mock DM, Baswell DL, Baker H, et al. Biotin deficiency complicating parenteral alimentation: diagnosis, metabolic repercussions, and treatment. J Pediatr. 1985;106:762–769. 314. Navarro PC, Guerra A, Alvarez JG. Cutaneous and neurologic manifestations of biotinidase deficiency. Int J Dermatol. 2000;39: 363–365.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

>> Dietary deficiency ± avidin binding >> Total parenteral nutrition >> Multiple carboxylase deficiencies – Neonatal (holocarboxylase synthetase deficiency) – Juvenile (biotinidase deficiency)

lymphocytes of affected children. The diagnosis of biotinidase deficiency is made by measuring the enzyme activity in serum and screening has become standard practice in many states in the USA as well as in many countries, despite potential pitfalls of standard fluorometric and colorimetric tests (false-positive and false-negative results).307

Etiology and pathogenesis

have been found.316–320 Both neonatal and juvenile forms are inherited as autosomal-recessive disorders, occurring as frequently as 1 in 60 000 births.320

Therapy All cutaneous findings, including the alopecia, are rapidly responsive to biotin therapy. In biotinidase deficiency, the hearing loss, visual anomalies and developmental delay do not appear to be reversible once they occur, despite biotin therapy, thus the importance of early diagnosis. Pharmacologic doses of biotin of 5–20 mg/day in infants and children have been employed in most cases, although some authors believe that 100 µg/day supplementation may be adequate.

Differential diagnosis

DISORDERS OF MINERALS AND CO-FACTORS

BOX 22.11 BIOTIN DEFICIENCY STATES

22

The clinical findings of biotin deficiency are nearly indistinguishable from essential fatty acid and zinc deficiencies, including location and appearance of the skin manifestations as well as secondary refractory candidiasis.

There are at least three different mechanisms whereby a patient may be biotin deficient (Box 22.11). First, dietary deficiency of biotin coupled with binding of available biotin with avidin can occur.305,312 One such case was reported in an 11-year-old developmentally delayed boy who subsisted on formula supplemented with raw eggs.315 Second, there may be biotin deficiency due to inadequate replacement during total parenteral nutrition,313 but this is now a rare occurrence. In such cases, the etiology is clear, although there may be individual variation of response to standard biotin supplementation in TPN fluids. Differentiation from essential fatty acid and zinc deficiencies can be extremely difficult clinically. In fact, since one of the key enzymes in long-chain fatty acid synthesis, acetyl CoA carboxylase, contains biotin, there may be a common mechanism.311 Of note, some children who have responded well to biotin therapy (after failure on zinc and essential fatty acid supplementation) had normal plasma biotin levels, making diagnosis of this deficiency difficult. The third and most important etiology of biotin responsive disease is the group of multiple carboxylase deficiencies.306–311 These involve poor activity of any or all of four carboxylases: 3-methylcrotonyl CoA carboxylase (MCC), propionyl CoA carboxylase (PCC), pyruvate carboxylase (PC), and acetyl CoA carboxylase (ACC). These four enzymes are biotin dependent, with biotin acting as an obligatory cofactor.306 In the neonatal form, diagnosis of a deficient holocarboxylase synthetase can be made in cultured skin fibroblasts or peripheral blood lymphocytes with defects localized to over thirty loci.315 Holocarboxylase synthetase is necessary for biotinylation or attachment of biotin to the other carboxylase enzymes. In the juvenile (late infantile) form, total and partial deficiencies of the enzyme biotinidase

This X-linked recessive disorder of purine metabolism, known also as Lesch–Nyhan syndrome, is characterized by the total absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT).321 The HPRT gene has been mapped to chromosome Xq26-Q27 and over 200 mutations have been characterized. The condition occurs only in males, with female carriers being unaffected, and can present anywhere from early infancy to later life with some degree of genetic heterogeneity. Besides mental retardation, choreoathetosis, and dysarthria, the striking manifestation of this disorder is compulsive, uncontrollable self-mutilation, primarily of the lips, mucous membranes, and hands. This behavior is unwanted by the patient but appears to be uncontrollable, and the patients are often grateful for external restraints. There is no absence of pain, and it is one of the few disorders, if not the only one, in which there is massive destruction of tissue rather than callous formation or chronic dermatitis from biting or compulsive picking of the skin. Biochemically, the disorder is characterized by massive elevation of uric acid and, in later life, renal stones and gouty tophi can be present. Of interest, a milder defect of the same enzyme produces no neurologic signs, but early and severe renal disorders and gout. Therapy aimed at reducing the uric acid is advised but has no effect on the neurologic manifestations; unfortunately, there is no significant curative treatment for this disorder. Recently, botulinum toxin injections of the facial perioral muscles has proved helpful in controlling the self-mutilation.322

315. Suzuki Y,Yang X, Aoki Y, et al. Mutations in the holocarboxylase synthetase gene HLCS. Hum Mutat. 2005;26:285–290. 316. Wolf B, Grier RE, Parker WD Jr, et al. Deficient biotinidase activity in late-onset multiple carboxylase deficiency. N Engl J Med. 1983;208:161. 317. Wolf B, Jensen KP, Barshop B, et al. Biotinidase deficiency: Novel mutations and their biochemical and clinical correlates. Hum Mutat. 2005;25:413 318. Wolf B, Grier RE, Allen RJ, et al. Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. Clin Chim Acta. 1983; 131:273–278.

319. Wolf BW, Heard GS. Biotinidase deficiency. Adv Pediatr. 1991;38: 1–21. 320. Weber P, Scholl S, Baumgartner ER. Outcome in patients with profound biotinidase deficiency: relevance of newborn screening. Dev Med Child Neurol. 2004;46:481–484. 321. Nyhan WL. Lesch–Nyhan disease. Nucleosides, Nucleotides, Nucleic Acids. 2008;27:559–563. 322. Gutierrez C, Pellene A, Micheli F. Botulinum toxin: Treatment of self-mutilation in patients with Lesch-Nyhan syndrome. Clin Neuropharmacol. 2008;31:180–183.

Hypoxanthine-guanine phosphoribosyltransferase deficiency

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Essential fatty acid Deficiency

PROTEIN ENERGY MALNUTRITION

Essential fatty acid (EFA) deficiency does not occur naturally in humans. It has been observed secondary to nutritional deficiencies that are induced either by abnormal diets or severe malabsorption in individuals who have had large portions of their intestine resected and require low-fat diets to prevent severe diarrhea. It has also been observed in individuals who were treated with TPN before the need for replacement of EFAs was recognized. The two major EFAs are linoleic and linolenic acids, and, although arachidonic acid has also been considered essential, it can be metabolized from linoleic acid. Hopefully, with increased awareness of EFA deficiency in the situations noted above, this will become a rare if not extinct disorder. EFA deficiency may be one of the factors responsible for the malnutritionassociated rash of cystic fibrosis.323

Pathophysiology and histogenesis Descriptions of EFA deficiency are sparse, but our major clinical understanding of the disorder comes from studies in the late 1950s and early 1960s324,325 in which over 400 infants were fed diets with graded deficiencies of linoleic acid for 6–12 months. Skin changes were noted to be most striking in infants with the lowest levels of linoleic acid and were most easily seen in black infants, but were present in all races. After several weeks of either fat-free or low linoleic acid diets, the skin became dry, leathery, and scaly with underlying erythema. The intertriginous areas became exudative. Although there was no increase in bacterial infections in the linoleic acid-deficient group, the children who did develop infections seemed to tolerate them less well. In one instance, a child with full-blown clinical symptoms showed reversal of these after two weeks of oral supplementation of linoleic acid. However, after the supplement was discontinued, the condition relapsed within six weeks to the previous clinical state. Histologic differences were not apparent in the skin between linoleic acid-deficient and normal children. In most other scattered case reports, the skin is referred to as ‘dry,’ ‘flaky,’ or ‘scaly.’ Other manifestations of EFA deficiency include growth failure, alopecia, poor wound healing, and, at least in animal studies, impaired reproduction, abnormal liver and kidney function, capillary fragility, and increased susceptibility to infection.326

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is also the presence of 5, 8, 11-icosatrienoic acid, a lipid not usually found in measurable levels in the circulation, and elevated levels of palmitoleic and oleic acids. The trienoic/tetraenoic ratio is >0.4.327,328 Essential fatty acids are C18, C20, or C22 fatty acids with two to six methylene interrupted unsaturated bonds.329 The two major EFAs are linoleic and linolenic acids. These cannot be synthesized de novo in humans, and can be obtained only through the diet. Arachidonic acid can be metabolized from linoleic acid and is important as a precursor to the prostaglandins, leukotrienes, and thromboxane. Major functions of the EFAs are thought to be multiple because they provide a structural role for fluidity in phospholipid membranes, they serve as energy stores or sebum precursors in triglycerides, and they are also found in sterol esters in the skin. It has been argued that their most important role is as a precursor to prostaglandins. Clinical studies have indicated that reversal of abnormalities noted in EFA deficiency, such as dry, flaking skin, and increased transepidermal water loss, can be improved with oral, parenteral, or even topical applications of linoleic acid. For example, in one study (in adults) topical application of sunflower seed oil to one arm provided increased epidermal linoleic acid, decreased transepidermal water loss, and reversed the scaliness of the skin. This was seen in contrast to the contralateral arm treated with olive oil.330 However, controlled studies on premature neonates showed no effect of topical application of safflower oil.331 Animal studies332 have shown that topical linoleic acid directly corrected skin signs of EFA deficiency (dryness, scaling of skin and scalp) even when prostaglandin synthesis was blocked with indomethacin; this suggests that the linoleic acid effect was a direct one, not mediated via prostaglandins. Such studies have not yet been confirmed in humans. It should be noted that there are many well-documented cases of biochemical EFA deficiency where there are no cutaneous manifestations.

Differential diagnosis Differential diagnosis will include other nutritional deficiencies and indeed there may be coexistence of multiple deficiencies in individuals with poor diet (i.e., protein calorie malnutrition syndromes) or specific malnutrition due to illness. Therapy involves replacing linoleic acid orally, parenterally, or topically, but most important is the awareness of potential EFA deficiency in situations of poor nutrition.

Laboratory findings

PROTEIN ENERGY MALNUTRITION

Laboratory findings in EFA deficiency include decreased levels of plasma linoleic acid, linolenic acid, and arachidonic acid. There

The term protein energy malnutrition refers in a general sense to a variety of nutritional disorders due to limited intake,

323. Darmstadt GL, McGuire J, Ziboh VA. Malnutrition-associated rash of cystic fibrosis. Pediatr Dermatol. 2000;17:337–347. 324. Hansen AE, Haggard ME, Boelsche AN, et al. Essential fatty acids in infant nutrition. III. Clinical manifestations of linoleic acid deficiency. J Nutr. 1958;66:565–576. 325. Hansen AE, Wiese HF, Boelsche AN, et al. Role of linoleic acid in infant nutrition. Clinical and chemical study of 428 infants fed on milk mixtures varying in kind and amount of fat. Pediatrics. 1963;31:171–192. 326. Paulsrud JR, Pensler L, Whitten CF, et al. Essential fatty acid deficiency in infants induced by fat-free intravenous feeding. Am J Clin Nutr. 1972;25:897–904. 327. Caldwell MD, Jonsson HT, Othersen HB Jr. Essential fatty acid deficiency in an infant receiving prolonged parenteral alimentation. J Pediatr. 1972;81:894–898.

328. Friedman Z, Danon A, Stahlman MT, et al. Rapid onset of essential fatty acid deficiency in the newborn. Pediatrics. 1976;58:640–649. 329. Horrobin DF. Essential fatty acids in clinical dermatology. J Am Acad Dermatol. 1989;20:1045–1053. 330. Prottey C, Hartop PJ, Press M. Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin. J Invest Dermatol. 1975;64:228–234. 331. Lee EJ, Gibson RA, Simmer K. Transcutaneous application of oil and prevention of essential fatty acid deficiency in preterm infants. Arch Dis Child. 1993;68:27–28. 332. Elias PM, Brown BE, Ziboh VA. The permeability barrier in essential fatty acid deficiency: Evidence for a direct role for linoleic acid in barrier function. J Invest Dermatol. 1980;74:230–233.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

A

PROTEIN ENERGY MALNUTRITION

malabsorption, or an excessive catabolic state. The two bestknown syndromes include kwashiorkor and marasmus, which, although less common in the USA, are endemic worldwide. Other causes of exogenous starvation include anorexia nervosa and iatrogenic causes when inadequate replacement is given during TPN for a variety of disorders. Malabsorption syndromes including cystic fibrosis, celiac sprue, liver disease, and intractable diarrhea can cause loss of protein, fat-soluble vitamins, and a variety of minerals. Catabolic states such as malignancies, or renal and hepatic failure, can also cause negative nitrogen balance that leads to starvation. In developed countries, protein energy malnutrition is rarely encountered in the absence of chronic disease but has been described occasionally with Crohn’s disease, food faddism or nutritional ignorance.333 The clinical features of kwashiorkor and marasmus are discussed below. Specific features of vitamin deficiencies are discussed separately.

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KWASHIORKOR Kwashiorkor is a form of protein energy malnutrition in which there is a specific protein intake deficiency with normal caloric intake. It is defined as a total body weight of 60–80% of that expected for age and height with either edema or hypoalbuminemia or both. This usually occurs in impoverished areas in children in the first 5 years of life at or after the time of weaning when breast-milk, the only source of protein, is removed. Such children are usually fed on a diet of carbohydrate staples such as maize. To date, the best clinical descriptions of kwashiorkor remain those of Cicely Williams, put forth in 1933.334 Williams described children in the Gold Coast of Africa who, after weaning, went on to a diet consisting nearly entirely of maize. Classic symptoms include irritability, diarrhea, and edema of the hands and feet. After 1 week to 10 days, cutaneous findings become apparent. There is generalized hyperpigmentation from ‘dark glossy brown’ to ‘dull reddish muddy’ color, and occasional depigmentation is also seen. Specific signs include the appearance of small black patches over pressure points on the extensor surfaces of the ankles, knees, and above the wrists and elbows that gradually spread to the legs, forearms, knees, and elbows in a ‘crazy pavement of thickened epidermis.’ As the older patches mature, they strip off very readily leaving a pink raw surface exposed underneath; this is called the ‘enamel paint,’ ‘flaky paint,’ or ‘peeling paint’ appearance (Fig. 22.36A). There is also desquamation at the corners of the mouth and eyes with photophobia. The mucous membranes begin to erode. The thickened black patches of desquamating skin appear first in areas of pressure. In addition, erosions in intertriginous areas with fissuring occur. Most striking in these children is extreme irritability, apathy, and dejection. Edema can be massive and appear as anasarca (extreme generalized edema). The edema contributes to a large protruding abdomen (Fig. 22.36B), which is also due to hepatomegaly secondary to fatty infiltration of the liver. Edema also accounts for the puffy cheeks and moon-faced appearance.

The hair becomes dry, hypopigmented, and sparse. When children are treated following a bout of kwashiorkor, there is repigmentation of the hair shaft leading to the classical ‘flag sign.’ A band of depigmented hair along the hair shaft marks the span of time during which there has been relative protein malnutrition. Other hair findings include a change in the character of the hair to a softer, finer, and sometimes, straight shaft in normally curly or kinky hair. Ultrastructural studies of such hair has revealed oval shafts with asymmetric loss of the cuticle at the ends of the oval. This weathering of the cuticle is apparently responsible for the dull lusterless look of the hair. No abnormalities in distribution or relative amounts of sulfur-containing amino acids have been found.335 Copper and zinc levels in hair of children with kwashiorkor have been apparently normal.336 The lightening of hair color (hypochromotrichia) is associated

333. Heath ML, Sidbury R. Cutaneous manifestations of nutritional deficiency. Curr Opin Pediatr. 2006;18:417–422. 334. Williams CD. A nutritional disease of childhood associated with a maize diet. Arch Dis Child. 1933;8:423–433.

335. Gummer CL, Dawber RPR, Harman RRM, et al. Kwashiorkor: an electron histochemical study of the hair shaft. Br J Dermatol. 1982;106:407–410. 336. Bradfield RB, SooHoo T, Baertl JM. Effect of hypochromotrichia on hair copper and zinc during kwashiorkor. Am J Clin Nutr. 1980;33:1315–1317.

B

Figure 22.36  Kwashiorkor: (A) classical flaky paint desquamation (Courtesy of Amy Paller); (B) bronze color, edema, protuberant abdomen (Courtesy Hélène Decaluwe MD, Sainte-Justine Hospital, Montreal).

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with a reduction in the total melanin content of scalp hair, possibly through reduced intake or availability of tyrosine.337 Nails are thin and soft. The cutaneous findings in kwashiorkor are quite striking and specific and are all reversible with therapy.338 The introduction of ready-to-use therapeutic food (RUTF) which can be administered by non-medical personnel in rural under­ served areas has made a large impact on successful therapy. Protein energy malnutrition in developed countries occurs predominantly in chronically ill patients such as those with cystic fibrosis. However, several recent cases have been reported in North America in infants without chronic disease intentionally on unorthodox diets because of suspected milk allergy or intolerance, food faddism, nutritional ignorance, or food aversion.339–341 A recent report of two infants presenting with skin changes, edema and hypoalbuminemia while being fed only a rice-based beverage because of a perceived milk allergy illustrates this problem.342 The diagnosis of kwashiorkor in these children was missed initially because of their chubby appearance, due to the edema.342 The most important diagnostic sign is the characteristic skin eruption. The histopathology is distinctive but not pathognomonic, being similar in other nutritional deficiencies: it shows superficial perivascular lymphocytic infiltrate, pallor of keratinocytes in a band across the upper epidermis, and confluent parakeratosis. A psoriasiform pattern can also be seen. Pathophysiological features are still not precisely defined. Increased lipid peroxidation seems to play an important role. The differential diagnosis includes other nutritional deficiencies (with which it often co-exists) such as zinc, essential free fatty acid, or multiple carboxylase deficiency; immunodeficiencies; metabolic disorders; and Langerhans cell histiocytosis.

MARASMUS In contrast to kwashiorkor, marasmus represents total calorie starvation and is often seen in younger children under 1 year of age. These children are emaciated with extensive loss of subcutaneous fat and muscle (Fig. 22.37), but they remain alert as opposed to those with kwashiorkor, who are more irritable and apathetic. Rare cutaneous findings may include thin, dry, and elastic skin. However, striking desquamation, hair changes, pigmentary changes, and edema are absent.

VITAMINS VITAMIN A Vitamin A (retinol) is a fat-soluble vitamin found in green leafy vegetables, animal fats, milk, and liver. Although the infant’s liver stores are quite low at birth, vitamin A derived from colostrum, breast milk, and cow’s milk rapidly saturates this primary reser-

337. McKenzie CA, Wakamatsu K, Hanchard NA, et al. Childhood nutrition is associated with a reduction in the total melanin content of scalp hair. Br J Nutr. 2007;98:159–164. 338. Latham MC. The dermatosis of kwashiorkor in young children. Semin Dermatol. 1991;10:270–272. 339. Buno IJ, Mordei JG, Weston WL. The enamel paint sign in the dermatologic diagnosis of early-onset kwashiorkor. Arch Dermatol. 1998; 134:107–108. 340. Eastlack JP, Grande KK, Levy ML, et al. Dermatosis in a child with kwashiorkor secondary to food aversion. Pediatr Dermatol. 1999;16:95–102.

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Figure 22.37  Marasmus (Courtesy Hélène Decaluwe MD, Sainte-Justine Hospital, Montreal).

voir. Ultimately, a supply is established that provides enough vitamin A for the body’s needs for a 12-month period. In the setting of a well-balanced diet, vitamin A deficiency is not encountered. If, however, intake of retinol is inadequate, symptoms may develop as early as 2–3 years of age. In infants and young children, in whom the pilosebaceous follicles are immature, very dry cracked skin is found. Follicular hyperkeratosis (phrynoderma) may develop, particularly on the shoulders, buttocks, and the extensor surface of the extremities. Acneiform eruptions have been described in adolescents, involving the anterolateral surfaces of the arms and back, sparing the face and abdomen. Enhanced keratinization of mucosal surfaces transforms nonkeratinized mucosa into hyperkeratotic white patches. Associated findings may include metaplasia of the salivary ductal epithelium and xerostomia. Ocular changes are among the earliest manifestations of vitamin A deficiency. Initial changes include impairment of dark adaptation and night blindness. Later, conjunctival and corneal dryness develop as a result of keratinizing metaplasia. Keratomalacia (wrinkling and clouding of the cornea) and Bitot spots (dry, silver-gray plaques on the bulbar conjunctiva) may accompany photophobia. Vitamin A deficiency may produce both mental and physical retardation and apathy. Vitamin A is also essential for normal immune functions.343 Anemia with or without hepatosplenomegaly is usually present. Increased intracranial pressure and hydrocephalus may occur. Normal values of vitamin A are agerelated: from 0 to 6 months, serum levels should exceed 20 mg/ dl, and from 6 months to adulthood they should fall within the

341. Liu T, Howard RM, Mancini AJ, et al. Kwashiorkor in the United States. Fad diets, perceived and true milk allergy, and nutritional ignorance. Arch Dermatol. 2001;137:630–636. 342. Katz KA, Mahlberg MH, Honig PJ, et al. Rice nightmare: Kwashiorkor in 2 Philadelphia-area infants fed Rice Dream beverage. J Am Acad Dermatol. 2005;52:S69–S72. 343. Stephensen CB. Vitamin A, infection, and immune function. Annu Rev Nutr. 2001; 21:167–192.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

THIAMINE (B1) Deficiency of vitamin B1 (thiamine) leads to beriberi. This water-soluble vitamin plays an important role in pyruvate metabolism; in the setting of poor vitamin intake, both lactate and pyruvate accumulate. These byproducts interfere with carbohydrate metabolism, and a high carbohydrate diet accentuates the pre-existing vitamin deficiency state.345 Thiamine is present in many foods, including breast milk and cow’s milk, pork, vegetables, cereals, fruits, eggs, yeast, and unmilled cereal grains. It is absent in oils, fats, and refined sugars. Both heat and alkalinity destroy the vitamin, and loss into the water used for boiling is high. When GI or liver disease is present, absorption of thiamine is often poor. Minimum daily require-

344. Schwartz KB. Vitamins. In: Walter A, Watkins JM, eds. Nutrition in Pediatrics: Basic Science and Clinical Application, 2nd ed. London: BC Decker, Hamilton; 1996: pp. 115–135. 345. Ferguson MM, Dagg JH. Nutritional disorders. In: Jones JH, Mason DK, eds. Oral Manifestations of Systemic Disease. Philadelphia: WB Saunders; 1980: p. 211. 346. Curran JS, Barness LA. Vitamin deficiencies and excesses. In: Behrman RE, Kliegman RM, Jenson HB, eds. Textbook of Pediatrics, 16th ed. Philadelphia: WB Saunders; 2000.

ments are elevated with fever, stress, surgery, dialysis, use of diuretics, and folate deficiency. Nonspecific systemic indications of thiamine deficiency include fatigue, apathy, irritability, depression, drowsiness, poor concentration, anorexia, nausea, and abdominal discomfort. Characteristic developments that appear later are polyneuritis, muscular weakness, cardiac failure, mental changes, and growth retardation. Neurologic sequelae of beriberi include decreased tendon reflexes, loss of vibratory sense, ptosis, hoarseness, ataxia, and loss of coordination and deep sensation. Prolonged deprivation of thiamine may induce signs of increased intracranial pressure, meningismus, and coma.346 A plump, pale child who appears flabby, listless, and dyspneic characterizes the ‘dry’ form of beriberi. These children have a rapid heart rate and hepatomegaly. When ‘wet’ beriberi occurs, peripheral edema develops secondary to high-output biventricular cardiac failure. Skin breakdown may ensue. These children appear undernourished, pale, edematous, and dyspneic. Vomiting and tachycardia are associated features. The skin is waxy and may develop changes as a consequence of peripheral neuropathy. Although no pathognomonic oral changes are seen in beriberi, glossodynia has been reported. The diagnosis is based on the characteristic clinical findings. Lowered erythrocyte transketolase activity and clinical improvement in response to thiamine help confirm the diagnosis. Prevention is possible if the daily diet includes 0.5 mg thiamine for infants and 0.7–1.5 mg for older children. When hyperalimentation is required, up to 3 mg/day may be necessary. A high carbohydrate intake should be avoided when thiamine deficiency is present.347 Therapy should be directed at correcting dietary inadequacies. Thiamine supplementation should include both mother and child when the infant is being breast-fed. Oral administration of 10 mg thiamine daily will correct beriberi provided absorption is not diminished by GI disturbance. Intramuscular or intravenous thiamine is indicated when cardiac failure is present. Fortunately, the cardiac changes are reversible. Infants suffering from beriberi often have other vitamin deficiencies and the entire B complex should be provided.

VITAMINS

range of 30–80 mg/dl. Infants require at least 500 IU/day, whereas older children and adults require 600–1500 IU/day of either vitamin A or carotene. Both vitamin A and carotene (which is broken down to vitamin A following ingestion) are absorbed with fats. Absorption may be grossly diminished when fat maldigestion or malabsorption occurs as a result of GI disease or surgery.344 Celiac disease, hepatic and pancreatic diseases, iron-deficiency anemia, chronic infectious diseases, or chronic ingestion of mineral oil impair vitamin A absorption. Premature infants also absorb vitamin A and fat less efficiently than do full-term infants. Low dietary intake of fat also minimizes vitamin A absorption. Diagnosis is based on dietary history and dark adaptation tests; ophthalmologic examination for conjunctival xerosis is helpful. Treatment is based on the severity of the ophthalmologic impairment and ranges from 5000 to 25 000 IU vitamin A in oral or intramuscular forms. In the setting of xerophthalmia, 5000 IU/kg per 24 hours orally for 5 days should be followed by daily intramuscular injections of 25 000 IU vitamin A in oil until recovery. Keratomalacia requires that doses between 50 000 and 100 000 IU be given parenterally. Children with malabsorption syndrome, celiac disease, or cystic fibrosis should be given supplements of 2000 IU in a water-miscible preparation of vitamin A per day (i.e., 1 IU vitamin A = 0.3 units of retinol). Vitamin A excess can be seen in children chronically receiving high doses of vitamins. Manifestations of hypervitaminosis A include lethargy and anorexia. The skin becomes dry and itchy, with follicular keratosis; cheilitis and hair loss are also observed. These mucocutaneous changes are similar to those encountered with isotretinoin therapy. No treatment is necessary other than discontinuation of the vitamin supplement. Infants should not receive more than 20 000 IU/day, as vitamin A toxicity may occur. Toxicity has been reported with intakes as low as 18 000 IU/day over a period of a few weeks and from a single dose of 300 000 IU.343 Supplements of vitamin A (400 000 IU) are effective in decreasing morbidity and mortality due to measles.

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RIBOFLAVIN (B2) Riboflavin (vitamin B2) is the coenzyme of flavin mononucleotide and flavin-adenine dinucleotide and essential for redox reactions. Deficiency (oculo-orogenital syndrome) is rarely encountered without concomitant deficiencies of the other B vitamins. Poor dietary intake accounts for most cases of ariboflavinosis, but riboflavin status is not dependent exclusively on dietary intake of the vitamin.348 Certain nondietary factors can modify riboflavin status. Respiratory infection, certain diseases, drugs and hormones can influence riboflavin metabolism, and poor absorption may play a role in the setting of biliary atresia

347. Vidal S, Andrianjatovo JJ, Dubau B, et al. Postoperative encephalopathies: thiamine deficiency, an unrecognized etiology. Ann Fr Anesth Reanim. 2001;20:40–43. 348. Lakshmi AV. Riboflavin metabolism – relevance to human nutrition. Indian J Med Res. 1998;108:182–190.

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or hepatitis. Minimum daily requirements are higher during increased physical activity and in patients with GI disease, hyperthyroidism, fever, and in patients receiving probenecid, tricyclic antidepressants or phenothiazine, or the antagonist galactoflavin.346 Riboflavin levels are lowered during phototherapy for neonatal hyperbilirubinemia and during psoralen and ultraviolet A light (PUVA) therapy for psoriasis. Although destruction of riboflavin is accelerated in the presence of light, patients receiving phototherapy do not show clinical evidence of vitamin deficiency. Diets high in carbohydrates accentuate ariboflavinosis, but foods such as liver, kidney, brewer’s yeast, milk, cheese, eggs, and green leafy vegetables contain large amounts of riboflavin. Cow’s milk provides five times as much of the vitamin as does breast milk. None of the oral, ocular, or cutaneous sequelae of ariboflavinosis are pathognomonic. When several of the clinical stigmata appear simultaneously, they suggest the deficiency. Among the earliest and most frequently encountered clinical signs is angular cheilitis, which begins with painless gray papules at the corners of the mouth. As the papules enlarge, they ulcerate and become indolent fissures. Similar lesions may develop at the ocular canthi and nasolabial folds. During the early stages of ariboflavinosis, the fungiform papillae become flattened and swollen, giving the dorsal surface of the tongue a pebbly or granular appearance. With ongoing vitamin deficiency, a progressive papillary atrophy develops and an irregular denudation of the papillae occurs. Rarely, the edema at the bases of the papillae modifies the color of the tongue to a deep purple-red, hence the name magenta cobblestone tongue. Ocular features of riboflavin deficiency include superficial keratitis, conjunctival edema, lacrimation, blepharospasm, disturbances of vision, changes in iris pigment, and photophobia. Fine, greasy scale mimicking seborrheic dermatitis (dyssebacea) is found on the nasal ala, nasal vestibule, nasolabial and nasomaxillary folds, cheeks, and chin. A normochromic, normocytic anemia with an associated bone marrow hypoplasia represents the hematologic aberration. The erythrocyte glutathione reductase activation test confirms the diagnosis. Oculo-orogenital syndrome is thought to result from riboflavin deficiency. It has been described in adult prisoners of war but not in children. Measurement of riboflavin stores is possible by determining the erythrocyte glutathione reductase activity. Urinary excretion of riboflavin below 30 mg/24 hours is considered low.346 Ariboflavinosis is preventable if the daily intake for infants is 0.6 mg and for older children and adults 1–2 mg.346 A balanced diet is important to ensure adequate intake. If vitamin deficiency is detected, 3–10 mg riboflavin can be given daily by mouth. If no alteration in clinical staus occurs within a few days, 2 mg should be given intramuscularly three times a day.346

PANTOTHENIC ACID Pantothenic acid, like biotin, is synthesized by the bacterial flora within the gut. The vitamin is required for the synthesis of coenzyme A, and this plays an essential role in metabolism. Deficiency states occur when nutrition is poor, as with protein energy malnutrition. Manifestations of inadequate pantothenic acid include fatigue, muscle cramps, headaches, incoordination, paresthesias, vomiting, and diarrhea. No characteristic skin or mucous membrane changes are attributable to a deficiency of this vitamin.

NIACIN (B3)

The three forms of vitamin B6 are pyridoxol, pyridoxal, and pyridoxamine. Pyridoxine is a cofactor for numerous enzymes of amino acid metabolism (transaminases, hydroxylases, synthetases) and the transformation of linolic acid to arachidonic

Niacin, one component of the vitamin B complex, is unlike other vitamins in that humans are capable of synthesizing it from tryptophan, an essential amino acid. Liver, lean pork, salmon, poultry, and red meat are good sources of niacin. Pellagra is a deficiency disease caused by inadequate intake of niacin (nicotinic acid). Pellagra (pelle for ‘skin’ and agra for ‘rough’) is limited primarily to populations whose major dietary intake is maize (which is low in tryptophan) and millet (which may interfere with tryptophan metabolism due to its high leucine content) or who suffer from malnutrition due to psychic alterations.349 Some drugs may cause pellagroid skin and mucosal reactions.350

349. Ballmer-Weber BK, Braathen LR, Ballmer PE. Erythem nach Fehlernährung und Sonnenexposition. Schweiz Med Wochenschr. 1999;129:1492–1495.

350. Heyer G, Simon M, Schell H. Dosisabhängige pellagroide Hautreaktion durch Carbamazepin. Hautarzt. 1998;49:123–125.

PYRIDOXINE (B6 GROUP)

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acid. Pyridoxol is present in plant foods, the remaining two in animal products.345 As pyridoxine is widely distributed in nature, deficiency does not occur in the presence of a balanced diet. Malabsorption states, as in celiac disease, may play a role in the development of B6 deficiency. Riboflavin deficiency can cause conditioned deficiency of vitamin B6 and the mucocutaneous lesions observed in these two vitamin deficiencies could be due to impaired skin collagen maturity. The metabolic antagonists of pyridoxine (desoxypyridoxine, and isonicotinic acid hydrazide (isoniazid)), as well as oral contraceptives, hydralazine, and penicillamine may induce a vitamin deficiency state. Clinical findings that develop when vitamin B6 levels are inadequate include dermatitis, glossitis, and neurologic and GI disturbances. A scaly eruption mimicking seborrhea develops around the eyes, nose, and mouth. The onset of glossitis is heralded by a scalding sensation in the mouth, followed by reddening and hypertrophy of the filiform papillae at the tip and on the margins and dorsum of the tongue. Pain and edema are associated features. Angular cheilitis and a generalized stomatitis may also be present.345 Additional clinical aberrations include peripheral neuropathy, dizziness, weakness, seizures, nausea, and vomiting. Although the anemia of pyridoxine deficiency is uncommon in infants, it is of a microcytic, hypochromic nature when present. The determination of vitamin B6 levels is based on erythrocyte pyridoxal phosphate concentrations or erythrocyte aspartate transaminase levels. Provided the infant’s diet contains 0.5– 1.5 mg, intake is adequate to prevent vitamin deficiency. Adults require 1.5–2.0 mg/day.346 Intake must be supplemented when drug use induces the deficiency state. Among the pyridoxineresponsive inherited disorders are seizures from B6 dependency, B6-dependent anemia, homocystinuria, xanthinuric aciduria cystathionuria, and pyridoxine-responsive chronic anemia.

Cutaneous manifestations of endocrine, metabolic, and nutritional disorders

VITAMIN B12 Vitamin B12 is ubiquitous in foods, and most cases of deficiency are due to failure of absorption. Inadequate intake does result, however, from diets lacking in milk, eggs, and animal products as in strict vegetarianism (vegans), or the breast milk of mothers with pernicious anemia. Infants with kwashiorkor or marasmus are not usually B12-deficient. Juvenile pernicious anemia, a rare condition, differs from the adult form in that gastric acid secretion is normal. The ability to secrete gastric intrinsic factor is lost, possibly as a result of genetic influences, as parental consanguinity is common in such cases. Symptoms of juvenile pernicious anemia may appear between 9 months and 3 years of age. Congenital transcobalamine deficiency predisposes to vitamin B12 deficiency in older children. Intestinal causes of poor absorption of vitamin B12 include surgical resection of the terminal ileum for regional enteritis or tuberculosis, overgrowth of intestinal bacteria in diverticula or blind loops of bowel, and infestation with the fish tapeworm Diphylobothrium latum in the upper small intestine. Glossopyrosis antedates swelling and pallor of the tongue when vitamin B12 levels are inadequate. The filiform and fungiform papillae are lost, in either a focal or diffuse pattern, leaving a smooth, red, painful dorsal surface (Hunter’s or Moeller’s glossitis). These oral changes may precede significant anemia. Neurologic sequelae include ataxia, paresthesias, hyporeflexia, clonus, Babinski responses, and even coma.346 A symmetric but patchy hyperpigmentation may develop over the joints of the hands and feet. Diagnosis of vitamin B12 deficiency is based on characteristic changes in the peripheral blood smear and bone marrow. Radioassay of vitamin B12 levels in the serum may also be employed. Therapy should include oral therapy only if poor oral intake is causing the deficiency, as most cases result from malabsorption of the vitamin. Intramuscular injection of hydroxycobalamin, which is retained more efficiently than cyanocobalamin, effects a prompt clinical response and rapidly replenishes body stores. If chronic replacement is required, 1000 µg injected every 2 months provides a wide margin of safety.344,346 The liver stores vitamin B12; if gastric absorption ceases, stores are generally adequate for 6–10 years. Daily metabolic requirements may be as little as 2–5 µg of vitamin B12.

VITAMINS

The earliest symptoms of pellagra include lassitude, anorexia, numbness, dizziness, and paresthesias.345 The tongue is often the focus of clinical changes, with both edema and glossitis noted as prominent features. The swollen papillae at the tip and lateral margins gradually atrophy and disappear, leaving a slick red dorsal surface. The entire tongue gradually becomes enlarged, painful, and erythematous. The lateral surfaces may become deeply ulcerated, and superinfection is common. The buccal and vaginal mucosae are also susceptible to deep ulceration and secondary infection. The classical triad of dermatitis, diarrhea, and dementia develops only after months of niacin or tryptophan deficiency. Tissue stores of niacin are generally large and the symptom complex of pellagra is often not well developed in infants and children.346 The dermatitis may develop suddenly or insidiously following exposure to an irritant or to bright sunlight. Areas exposed to heat, friction, or pressure are also susceptible to the development of pellagrous dermatitis. Early lesions are pruritic and burning and have sharp margination. A symmetric distribution of erythematous patches with or without vesicles develops. The underlying skin may be slightly edematous. The facial lesions, which are often large and thick, can become pustular. Welldemarcated lesions around the neck, called Casal’s necklace, are rarely present in the absence of dermatitis elsewhere. Dermatitic skin becomes rough, hard, brittle, cracked, and dark reddish-brown to black. Areas that have healed may remain hyperpigmented. Painful fissures occasionally develop on the digits and palms.351 Children infested with parasites or suffering from other chronic diseases demonstrate more severe effects as a result of niacin deficiency. GI manifestations include vomiting and diarrhea or diarrhea alternating with constipation. Other dietary deficiencies as well as anemia may exist simultaneously. Changes in the nervous system occur late in the course of the illness and are associated with irritability, anxiety, and apathy.346 The posterior and lateral columns are demyelinated when niacin deficiency is prolonged. The diagnosis of pellagra is suspected in the clinical setting of glossitis, GI problems, and a symmetric dermatitis. Clinical response to niacin remains an important diagnostic parameter. N-Methylnicotinamide, a normal metabolite of niacin, is nearly absent in the urine of pellagrous patients. Included in the differential diagnosis of pellagrous dermatitis are carcinoid syndrome, Hartnup’s disease, and isoniazid-induced alteration of tryptophan metabolism. Prevention of pellagra is possible if 8  mg niacin is provided in the daily diet of infants and 9–20  mg/day for older children. The addition of 50–300  mg niacin daily brings about rapid reversal of pellagra. If the vitamin deficiency is severe or GI absorption poor, 100  mg niacin may be given by the intravenous route. Within 30 minutes, flushing and a sensation of increased local heat may be noted. These side-effects are not present when nicotinamide (niacinamide) is used, but with large doses of that medication, cholestatic jaundice and hepatotoxicity may supervene.346

22

VITAMIN C (ASCORBIC ACID) Vitamin C (ascorbic acid) is a hydrosoluble vitamin that is not synthesized in the human body. Dietary intake is essential and recommended daily allowance is 40–50 mg/day for children and 60 mg/day for adults. Its main sources are fresh fruit and vegetables. Vitamin C is important in collagen formation and various enzymatic processes as well as an antioxidant. Inadequate dietary intake of vitamin C results in the metabolic deviations and clinical manifestations known as scurvy. Deficient ascorbic acid leads to the production of functionally defective collagen as a result of failure of hydroxylation of procollagen,

351. Yoshikawa K. Vitamin and dermatology. Nippon Rinsho. 1999;57:2385–2389.

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proline, and lysine. Abnormal collagen is responsible for widespread changes affecting principally the bones, teeth, and supporting tissues of blood vessels. Scurvy is rare in the USA and Europe, but most cases in the pediatric age group occur between the ages of 6 and 24 months.352 At birth, scurvy is extremely rare, and breast-fed infants usually receive adequate vitamin C. Infants fed with formula may require additional supplementation. Deficiency may occur with peculiar dietary habits, food fads, or parental ignorance.353–355 The need for vitamin C increases with febrile illnesses, particularly those of an infectious nature or accompanied by diarrhea. Exposure to cold, iron deficiency, and protein depletion also increases metabolic demands for ascorbate.346 Mucous membrane changes in scurvy are most noticeable after the teeth have erupted. Patients under 6 months of age and those who have become edentulous often lack the mucosal changes entirely. Redness, swelling, and tiny hemorrhages become evident at the tips of the interdental papillae. The gums may become bluish-purple and spongy, swelling to the point of concealing the upper incisors. Gradual loss of periodontal bone may follow with loosening and, ultimately, loss of the teeth.352,354 Follicular hyperkeratosis with broken corkscrew hairs represents one of the most distinctive and earliest signs of scurvy.352,353 The enlarged follicles are reddened by the congestion and proliferation of the surrounding blood vessels. The anterior forearms, abdomen, and lower extremities show the most marked follicular hyperkeratosis, with the follicles of the lower extremities having the greatest tendency to become hemorrhagic. These petechiae are prominent in hair-bearing areas due to defective collagen within the supporting tissue of the blood vessels. Bone pathology as a result of scurvy includes fractures of the cartilaginous matrix, decreased osteoid formation, and large subperiosteal or marrow hemorrhages. Epiphyseal separation may result. The femur and tibia are the long bones most often affected. Generalized tenderness and increasing irritability frequently accompany the bony alterations. The legs may assume a ‘frog position,’ with semiflexion at the hips and knees and the feet rotating outwardly. Overall growth is impeded. Vitamin C deficiency in infants, known as Möller–Barlow disease, shows particularly pronounced petechiae and hemorrhages in the gastrointestinal and urinary tracts. Systemic features of scurvy include low-grade fever, anemia, lethargy, and poor wound healing. When scurvy is severe, cardiac hypertrophy, bone marrow depression, adrenal atrophy, and degeneration of skeletal muscles may occur.355 The diagnosis of scurvy is based on a history of poor ascorbate intake in the setting of characteristic clinical changes. Laboratory evaluation of serum or leukocyte vitamin C levels can be employed to confirm the diagnosis. The differential diagnosis includes leukemia, meningococcemia, thrombocytopenic pur­

pura, suppurative arthritis, osteomyelitis, and other vitamin deficiencies. Therapy consists of a daily oral intake of 100–200 mg ascorbic acid. Recovery is generally rapid.

Vitamins K1 and K2 are naphthaquinone derivatives that participate in oxidative phosphorylation and hepatic synthesis of coagulation factors II (prothrombin), V, VII, IX, and X. Protein C, protein S, and osteocalcin are also vitamin-K-dependent. The production of these coagulation components is dependent both on normal hepatic function and on adequate dietary intake of vitamin K1. This naturally occurring fat-soluble form of vitamin K is found in varying concentrations in hog’s liver, soybeans, alfalfa, spinach, and tomatoes. The intestinal bacteria synthesize vitamin K2, but alteration of the gut flora by antibiotics may hinder its manufacture, with resultant diminution of prothrombin production. Low levels of vitamin K are frequently encountered in newborn infants, particularly those of low birth weight, as a result of inadequate intake and an uncolonized GI tract. Breast milk serves as a less valuable source of the vitamin than does cow’s milk. Infants with diarrhea, particularly if breast-fed, are susceptible to the development of a deficiency state. Other GI diseases predisposing to inadequate levels of vitamin K are biliary obstruction, fistulas, sprue, and other malabsorption diseases. By acting as competitive antagonists of vitamin K, drugs such as coumarin, salicylates, isoniazid, and cholestyramine produce thrombocytopenia.356 The clinical stigmata of thromcytopenia due to inadequate vitamin K include ecchymoses of the skin and bleeding from the gums. The ecchymoses may become confluent at sites of pressure or trauma. The gums are not friable despite their tendency to be hemorrhagic. Diagnosis of vitamin K deficiency is based on these clinical changes and a prolonged prothombin time. Mild cases in infants are amenable to oral administration of 1–2 mg vitamin K daily. When the hemorrhagic state is severe, a daily dose of 5 mg vitamin K1 should be given parenterally. Use of large doses of synthetic vitamin K analog (but not vitamin K1) can produce hyperbilirubinemia and kernicterus in the glucose-6-phosphate dehydrogenase-deficient newborn as well as the premature infant.346 If liver damage is the source of hypothrombinemia, both vitamin K1 and whole blood are often required to correct the deficiency.

352. Ellis CN, Vanderveen EE, Rasmussen JE. Scurvy: a case caused by peculiar dietary habits. Arch Dermatol. 1984;120:1212–1214. 353. Levin NA, Greer KE. Scurvy in an unrepentant carnivore. Cutis. 2000;66:39–44. 354. Fuchs J. Vitamine und Haut. Ther Umsch. 1994;51:489–495.

355. McLaren DS. Cutaneous changes in nutritional deficiencies. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al. eds. Dermatology in General Medicine, 2nd ed. New York: McGraw-Hill; 1979: p. 1024. 356. Bor O, Akgün N, Yakut A, et al. Late hemorrhagic disease of the newborn. Pediatr Int. 2000;42:64–66.

VITAMIN K

ACKNOWLEDGMENT The section on vitamin deficiency is courtesy of Dr. Adelaide Hebert.

Nancy K. Barnett, William L. Weston, Alfons Krol, Michael Shishov, Kaleo Ede,  Stanford T. Shulman, Elizabeth Swanson, Michelle Jeffries and Patricia A. Treadwell

CONNECTIVE TISSUE DISEASES AND ARTHRITIDES

23



EPIDEMIOLOGY

Lupus erythematosus (LE) is a chronic inflammatory disorder of unknown origin involving multiple organ systems. The clinical signs and symptoms, primarily the result of small vessel vasculopathy, can be protean and episodic. Advances in serologic technology, as well as the establishment1 and revision2,3 (first in 1977 and again in 1999) by the American College of Rheumatology (ACR) of criteria for the diagnosis of systemic lupus erythematosus (SLE), have provided clinicians with clinical and laboratory guidelines for the early diagnosis of SLE (Box 23.1). Four of these criteria must be present to establish a diagnosis of SLE but these can occur serially and so it is important to monitor children over years for evolving SLE.4 These laboratory and clinical guidelines, together with aggressive treatment, have improved the prognosis of childhood SLE. During the late 1950s and early 1960s, childhood SLE was viewed as a usually fatal disease. Now early diagnosis and the use of steroid and immunosuppressive therapy have dramatically improved the survival of childhood SLE patients, although it can still frequently be more severe than its adult counterpart.5,6

Approximately 25% of SLE begins during the first two decades of life.7 The peak incidence of the occurrence of SLE in childhood is early adolescence.8 A study has demonstrated that 60% of childhood SLE occurs between the ages of 11 and 15 years; 35% begins between 5 and 10 years; and 5% of cases occur before the age of 5;5 SLE is rare under 1 year.6 The frequency of SLE among white male and female children is 3 : 4 until puberty, at which time a striking increased predominance in female to male (9 : 1) involvement occurs.9 The exact incidence and prevalence of childhood SLE are unknown because no central registry exists, but the prevalence has been estimated to be 5–10 per 100 000; a racial difference in the frequency of childhood SLE exists: black, Hispanic, and Asian children have at least a two- to three-fold increased frequency of SLE compared with whites.10–13 Tucker9 reports an incidence of 9.4 per 100 000 in white females compared with almost 20 per 100 000 in black females before age 10, and the frequency of SLE at puberty rises at a disproportionately greater level among black, Asian, and Hispanic females than white females.10 There is some evidence to suggest that the disease process may also be more severe among black and Hispanic children. The children with lupus nephritis have a slightly earlier age of onset (approximately 10 years) and a higher mortality and morbidity than their white counterparts.14

1.

8.

LUPUS ERYTHEMATOSUS Nancy K. Barnett

2. 3. 4. 5. 6. 7.

Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25: 1271. Hochberg MC. Updating the American College of Rheumatology Revised Criteria for the Classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725. ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42(4):599. Lehman TJ. Systemic lupus erythematosus in children. UptoDate Online 2008; www.uptodate.com (Accessed 10 September 2008). Kornreich HK, Hanson V. The rheumatic diseases of childhood. Curr Probl Pediatr. 1974;4:3. Dale RC, Tang SP, Heckmatt JZ, et al. Familial systemic lupus erythematosus and congenital infection-like syndrome. Neuropediatrics. 2000;31(3):155. Fish AJ, Blau EB, Westberg NG, et al. Systemic lupus erythematosus within the first two decades of life. Am J Med. 1977;62:99.

LUPUS ERYTHEMATOSUS

Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

9. 10. 11. 12. 13. 14.

Lo JT, Tsai MJ, Wang LH, et al. Sex differences in pediatric systemic lupus erythematosus: a retrospective analysis of 135 cases. J Microbiol Immunol Infect. 1999;32(3):173. Tucker LB. Caring for the adolescent with systemic lupus erythematosus. Adolesc Med. 1998;9(1):59. Lehman TJA. Systemic lupus erythematosus in childhood and adolescence. In: Wallace DJ, Hahn BH, eds. Dubois lupus erythematosus, ed 4. Philadelphia: Lea & Febiger; 1993:431. Siegel M, Lee SL. The epidemiology of systemic lupus erythematosus. Semin Arthritis Rheum. 1973;3:1. Lehman TJA, McCurdy D, Spencer C, et al. Prognostic value of antibodies to Ro/SSA, La/SSB, and RNP in children with systemic lupus erythematosus. Arthritis Rheum. 1990;33:S154. Schaller J. Lupus in childhood. Clin Rheum Dis. 1982;8:219. Tejani A, Nicastri AD, Chen CK, et al. Lupus nephritis in black and Hispanic children. Am J Dis Child. 1983;137:481.

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BOX 23.1 REVISED CRITERIA FOR THE CLASSIFICATION OF SLE (1982) 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis: peripheral non-erosive arthritis involving two or more joints 6. Serositis: pleuritis or pericarditis 7. Renal disorder: proteinuria or cellular casts 8. Neurologic disorder: seizures or psychosisa

LUPUS ERYTHEMATOSUS

9. Hematologic disorder: hemolytic anemia or leukopenia, 4000/mm3 or lymphopenia, 1500/mm3 ×2 or thrombocytopenia, 100 000/mm3 without offending drugs 10. Immunologic disorder: positive LE preparation or anti-DNA or anti-Sm or false-positive serologic test for syphilis for 6 months (using the Treponema pallidum immobilization or fluorescent treponemal antibody absorption test)b 11. ANA: in the absence of drugs known to be associated with ‘drug-induced lupus’ syndrome a Item 8 revised in 1999 to include 19 central and peripheral nervous system syndromes.3 b Item 10 revised in 1997 to delete positive LE preparation and add positive finding of antiphospholipid antibodies based on: (1) an abnormal serum level   of IgG or IgM anticardiolipin antibodies; (2) a positive test result for lupus anticoagulant using a standard method; or (3) a false positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test.2 (From Tan AM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271.)

SLE is the most common form of LE among children. Benign and chronic cutaneous lupus (discoid,15–17 subacute cutaneous (SCLE),18 linear,19 chilblain20 and other variants, i.e., cutaneous lupus with no clinical evidence of systemic disease) are relatively unusual in children, whereas renal disease and central nervous system disease are prominent in childhood SLE.13,21–23 It is likely that less severe forms of SLE are underreported.

15. Bansal C, Ross AS, Cusack CA. Chronic cutaneous lupus in childhood: a report of two cases and review of the literature. Int J Dermatol. 2008;47:525. 16. Sampaio MC, deOliveira ZN, Machado MC, et al. Discoid lupus erythematosus in children. A retrospective study of 34 patients. Pediatr Dermatol. 2008;25:163. 17. Evans-Ramsey T, Frieden IJ. Arcuate plantar plaques as the initial sign of chronic cutaneous lupus in a child. J Am Acad Dermatol. 2003;49:270. 18. Rai VM, Balachandran C. Subacute cutaneous lupus erythematosus (SCLE) presenting in childhood. Dermatol Online J. 2005;11:27. 19. Engelman DE, Katz EA, Maize JC. Linear cutaneous lupus erythematosus in the lines of Blaschko. Pediatr Dermatol. 2007;24:125. 20. Lee-Kirsch M, Gong M, Schulz H, et al. Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet. 2006;79(4):731. 21. Yancy CL, Doughty RA, Athreya BH. Central nervous system involvement in childhood systemic lupus erythematosus. Arthritis Rheum. 1981;24:1389. 22. Cameron JS. Lupus nephritis in childhood and adolescence. Pediatr Nephrol. 1994;8(2):230. 23. Laitman RS, Glichklich D, Sablay LB, et al. Effective long term normalization of serum complement levels on the course of lupus nephritis. Am J Med. 1989;87:132.

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ETIOLOGY The etiology of SLE is unknown but is thought to be multi­ factorial, with evidence being accumulated for the roles of viral, hormonal, environmental, and immunogenetic factors. Studies have demonstrated a more compelling role for immunogenetic factors. Several studies demonstrate an aggregation of autoimmune diseases and autoimmune phenomena among 1st-degree relatives of patients with LE.24 Studies on the occurrence of LE in monozygotic and dizygotic twins present the most striking evidence for a genetic association. In one study, the concordance in monozygotic twins for SLE was approximately 70% and in another study, approximately 25%.25,26 The concordance among dizygotic twins ranges between 2% and 9%. It has been observed that when identical twins develop SLE, the age of onset of the disease is closer and the occurrence is at a younger age compared with siblings who develop SLE. However, even in monozygotic twins, SLE of childhood has presented with different clinical manifestations and different degrees of nephritis, emphasizing the multifactorial etiology of SLE and how much still needs to be learned about causation.27 SLE is associated with an increased frequency of the HLA-DR2 and DR3 phenotypes. The relative risks of developing SLE associated with the presence of these phenotypes are small. Studies indicate that the anti-Ro(SSA) antibody response is associated with the HLA-DR2 and DR3 phenotypes. If one subtracts the anti-Ro(SSA) antibody positive patients from the total lupus cohorts, the association of LE with the HLA-DR2 and DR3 phenotypes disappears. This suggests that the anti-Ro(SSA) antibody response and not the clinical presentation of LE is associated with these HLA phenotypes. Furthermore, in a study of 34 families with children who had SLE, Lehman et al. demonstrated that anti-Ro(SSA) antibodies were detected more frequently in daughters of anti-Ro(SSA) antibody positive mothers than among daughters of anti-Ro(SSA) negative mothers.28 Further proof, even at the molecular level, of a genetic component to SLE is found in the work by Reveille et al. which demonstrates that antibody responses produced by alleles at a usually hypervariable DQ locus are so specific that they determine glutamine to be at position 34 on the outer domain of the β-chain of the HLA-DQ molecule, and a leucine residue at position 26 on the α-chain in nearly all patients with the anti-Ro(SSA) and anti-La (SSB) antibody response.29

24. Arnett FC, Reveille JD, Wilson RW, et al. Systemic lupus erythematosus: current state of the genetic hypothesis. Arthritis Rheum. 1984;14:24. 25. Block SR, Lockshin MD, Winfield JB, et al. Immunologic observations on 9 sets of twins either concordant or discordant for SLE. Arthritis Rheum. 1976;19:545. 26. Deapen DM, Escalante A, Weinrib L, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992; 35:311. 27. Huang WC, Lien SH, Chan DM, et al. Monozygotic twins concordant for idiopathic thrombocytopenic purpura and discordant for systemic lupus erythematosus and lupus nephritis. Eur J Pediatr. 2007;166(5): 497. 28. Lehman TJA, Reichlin M, Harley JB. Familial concordance for antibodies to Ro/SSA among female relatives of children with systemic lupus erythematosus: evidence for a supergene hypothesis. Arthritis Rheum. 1990;33:125A. 29. Reveille JD, MacLeod MJ, Whithington K, et al. Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQBI chain genes promote the Ro(SSA)/La(SSB) autoantibody responses. J Immunol. 1991;146:3871.

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23

Figure 23.1  (A) Erythematous discoid lupus erythematosus in a child with no systemic disease (Courtesy Dr B. Krafchik). (B) Erythematous   discoid lupus erythematosus in a girl (Courtesy   Dr A. Torrelo).

LUPUS ERYTHEMATOSUS

B

A

Other studies have demonstrated a very close immunogenetic relationship between some anti-Ro(SSA) positive females presenting with primary Sjögren syndrome or with subacute cutaneous LE. The patients all shared an increased frequency of HLA-B8, DR3, DQ2, and DRw52 phenotypes30,31 and are at risk of giving birth to a child with neonatal lupus (see below). An association of the -308A allele (found with increased tumor necrosis factor alpha production), HLA-DROB1*02 and HLA-DRB1*03 has been noted in neonatal lupus and in a cohort of SCLE patients.32 Further evidence demonstrating the strong genetic relationship with LE have come from a study of patients with hereditary deficiencies of various components of the complement system.33 Those patients possessing homozygous deficiencies of the early complement components (i.e., C1q, C1r, C1s, C4, C2) have an increased frequency of LE (many beginning in childhood)31 when compared with those patients with homozygous complement deficiencies of the late complement components (i.e., C3, C5, C6, C7, and C8). C2 and C4 are encoded for by class III alleles located in the major histocompatibility complex of chromosome 6. Furthermore, the lupus-like disease process that homozygous C2 and C4 patients develop is characterized by the frequent presence of anti-Ro(SSA) antibodies.34 The most common complement deficiency associated with the development of LE is null alleles for the fourth component of complement, most commonly C4AQ0.35 As noted above, gender differences emerge strikingly in adolescence, becoming more common in the female by 5 : 1. Studies have suggested that there may be an effect of sex hormones with estrogen or lower testosterone predisposing to the development of SLE.35 Although the pathogenesis of LE is multifactorial, these studies demonstrate that immunogenetic factors most likely play a sub-

stantial role in the pathogenesis of LE in some patients. Positional candidate genes have been suggested on chromosome 136 and a genetic mutation of T-cell regulation may allow apoptosis with impaired regulation of B-cell clones producing autoantibodies in susceptible individuals.37 The first monogenic form of cutaneous lupus, a chilblain type, has been mapped to chromosome 3p in a kindred with clinical symptoms in children as young as 1 year of age.20

30. Provost TT, Watson R. Anti-Ro(SSA) HLA-DR3 positive women: the interrelationship between some ANA negative, SS, SCLE and NLE mothers and SS/LE overlap female patients. J Invest Dermatol. 1993;100:14s. 31. Stone NM, William A, Wilkinson JD, et al. Systemic lupus erythematosus with C1q deficiency. Br J Dermatol. 2000;142:521. 32. Clancy RM, Backer CB, Yin X, et al. Genetic association of cutaneous neonatal lupus with HLA Class II and tumor necrosis factor alpha. Arthritis Rheum. 2004;50(8):2598. 33. Arnett FC, Reveille JD. Genetics of systemic lupus erythematosus. Rheum Dis Clin North Am. 1992;18(4):865–892.

34. Provost TT, Arnett F, Reichlin M. C2 deficiency, lupus erythematosus, an anti-cytoplasmic antibodies. Arthritis Rheum. 1983;26:1279. 35. Petty RE. Etiology and pathogenesis of rheumatic disease of adolescence. Adolesc Med. 1998;9(1):11. 36. Tsao BP. Lupus susceptibility genes on human chromosome 1. Int Rev Immunol. 2000;19:319. 37. Andrade F, Casciola-Rosen L, Rosen A. Apoptosis in systemic lupus erythematosus. Rheum Dis Clin North Am. 2000;26:215. 38. George P, Tunnessen WW Jr. Childhood discoid lupus erythematosus. Arch Dermatol. 1993;129:613.

PHYSICAL EXAMINATION The true frequency of occurrence of various manifestations in childhood LE is difficult to obtain. Children with milder forms of LE (i.e., lacking cerebral and renal disease) may be under­ reported. Furthermore, the early recognition of LE and the institution of aggressive therapy with corticosteroids, and other medication have undoubtedly modified the frequency of their occurrence. Classic discoid lupus erythematosus (DLE) lesions are the most common cutaneous manifestation in childhood SLE.38 The term discoid is employed as a morphologic descriptive term meaning coin-shaped. Unfortunately, this term has been used to mean benign cutaneous lupus as opposed to SLE and this misuse of the term discoid has created a great deal of confusion. It is important to realize that DLE lesions can be seen in the total absence of serologic and clinical data of systemic involvement (Fig. 23.1A), and can also be seen as cutaneous manifestations in patients with classic SLE (Fig. 23.1B). Although benign cutaneous lupus (DLE) can be similar to its adult counterpart in presentation and chronicity, there may be some significant differences. Some authors note a lack of female predominance, a low incidence of photosensitivity, and an

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increased risk of progression to SLE.38 There are increasing reports of these cases15,16 sufficient to dispute the lack of female predominance but this is still controversial because the cases in children may be underreported.39 This is also true of lupus erythematosus tumidus (LET).40 LET consists of erythematous, edematous, non-scarring plaques in sun-exposed areas without systemic disease. DLE lesions are characterized by erythematous, sharply demarcated, round plaques demonstrating adherent scale formation, follicular plugging, telangiectasia, and scarring. These lesions are most prominent in the sun-exposed areas occurring frequently on the face and scalp. In 55% the DLE lesions can involve the malar eminence producing a classical butterfly dermatitis in which the involvement of the malar eminences is the wings of the butterfly and involvement of the nose is the body of the butterfly (Fig. 23.1B). In addition to the classic DLE and rare LET lesions, childhood patients may have an urticaria-like or a papular malar dermatitis in which there is little, if any, scaling, telangiectasia, follicular plugging, or scar formation. This type of lesion occurs primarily on sun-exposed surfaces and is known as subacute cutaneous lupus erythematosus (SCLE). Patients with SCLE have few systemic disease manifestations and are often anti-Ro positive.18 SLE patients may have both nasal and oral ulcerations, as well as scarring or non-scarring alopecia (25%). Petechiae or purpuric lesions, nail fold telangiectasia, or small digital icepick infarcts (Fig. 23.2) may be manifestations of an underlying vasculopathy

accompanying the lupus disease process. Urticaria-like vasculitic lesions can also occur, as well as livedo reticularis, and rarely bulla formation. Erythema nodosum and lupus panniculitis are other skin manifestations that may be seen in SLE. Fever and arthralgias/arthritis are common presenting features in childhood SLE. The arthritis is a non-deforming polyarthritis that can affect all joints but is most often small joints that are involved.4 In addition, weight loss, lymphadenopathy (50%), fatigue, abdominal pain, night sweats, proximal muscle weakness (20%) and Raynaud phenomenon (20%) have been described. Raynaud phenomenon is characterized by a triphasic reaction triggered by cold exposure or emotional distress. An initial blanching of the digits is followed by cyanosis and painful reactive hyperemia upon rewarming. Small icepick-like scars representing infarcts may occur on the fingertips (Fig. 23.2) and distal part of the toes. Pulmonary involvement such as pleuritis is commonly detected in childhood SLE, occurring in two-thirds of patients.41 Cardiac disorders affect as many as 50% of childhood SLE patients.42 These include pericarditis, myocarditis, and vasculitis affecting the coronary arteries. In addition, non-bacterial thrombotic endocarditis with focal necrosis (Libman–Sacks endocarditis) has also been reported. Some 50% of childhood SLE patients have central nervous system involvement,21 now known as neuropsychiatric SLE (NPSLE). The American College of Rheumatology has defined 19 neuropsychiatric manifestations of the central and peripheral nervous systems, including seizures, alteration in mental status, psychosis, and peripheral neuropathy.43 Less severe complaints such as headache are frequent and in adolescents poor school performance and social withdrawal may be difficult to distinguish from depression.4 Up to 60–80% of childhood SLE patients develop clinical renal disease.13,22,44 This is usually detected at the onset of the disease or within the first 2 years. In some patients, especially with anti-dsDNA antibodies and hypocomplementemia, direct immunofluorescence examination of the kidney may demonstrate a significant immunologic insult in the absence of hematuria or proteinuria. Nephritis occurs more frequently in childhood SLE than in adult disease and can be a devastating complication of childhood LE. The prognosis of childhood lupus nephritis has improved with early recognition and aggressive steroid and/or immunosuppressive treatment and only about 5% of patients currently progress to renal failure. Like adult LE patients, the survival rates for childhood lupus nephritis have dramatically improved during the past 20 years.44,45 There has been a report of children with SLE with gastro­ intestinal complaints (19%), emphasizing that as in adults the manifestations of the disease are widespread in all organ systems.46

39. Magana M, Vazquez R. Discoid lupus erythematosus in childhood. Pediatr Dermatol. 2000;17(3):241. 40. Kuhn A, Richter-Hintz D, Osliislo C, et al. Lupus erythematosus tumidus – a neglected subset of cutaneous lupus erythematosus: a report of 40 cases. Arch Dermatol. 2000;136(8):1033. 41. Delgado EA, Malleson PN, Pirie GE, et al. Pulmonary manifestations of childhood onset systemic lupus erythematosus. Semin Arthritis Rheum. 1990;29:285. 42. England JA, Lucas RV Jr. Cardiac implications in children with systemic lupus erythematosus. Pediatrics. 1983;72:724.

43. ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42(4):599. 44. Abeles M, Urman JD, Weinstein A, et al. Systemic lupus erythematosus in the younger patient: survival studies. J Rheumatol. 1980;7:515. 45. Lehman TJ, Edelbert BS, Onel KB. Combined intravenous methotrexate and cyclophosphamide for refractory childhood lupus nephritis. Ann Rheum Dis. 2004;63:321. 46. Richer O, Ulinski T, Lemelle I, et al. Abdominal manifestations in childhood onset systemic lupus erythematosus. Ann Rheum Dis. 2007;66:174.

Figure 23.2  Face eruption in a child with LES and typical palmar erythema (Courtesy Dr A. Torrelo).

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Serologic examination is the most important laboratory evaluation of children suspected of having LE.47 As in adult LE, the following laboratory tests have played a significant role in the early detection of SLE. The antinuclear antibody (ANA) determination is almost always positive in SLE when human substrates derived from tissue culture (Hep-2, Kb, etc.) cells are employed to detect the ANA. If, however, heterologous tissues (e.g., rat kidney, mouse liver) are employed as ANA substrates, approximately 5–10% of SLE patients may fail to demonstrate a significant ANA titer. The human tissue culture or tumor cell lines provide a much more sensitive substrate for the detection of the ANA. Studies indicate that anti-Ro antibodies, unlike autoantibodies against Sm, U1RNP, or La(SS-B), are directed against epitopes unique to human-derived Ro(SSA) macromolecules. These antibodies show variable or occasionally no cross-reactivity with nonhuman sources of the Ro(SSA) macromolecule.48 This fact, in all probability, explains the high frequency of anti-Ro(SSA) antibody positivity in lupus patients previously found to have insignificant ANAs (‘ANA-negative SLE’) when heterologous substrates were employed in the detection of ANAs. Five distinct patterns have been associated with ANAs. These are the speckled pattern, the most non-specific; a homogeneous pattern, associated with antinucleoprotein antibodies; a shaggy or peripheral pattern, associated with the presence of anti-nDNA antibodies; a centromere pattern predominantly associated with CREST (calcinosis, Raynaud, esophageal dysmotility, sclerodactyly, and telangiectases) syndrome; and a nucleolar pattern, commonly detected in patients with progressive systemic sclerosis. Because patients with lupus erythematosus make autoantibodies against many different nuclear autoantigens, less significance is now placed on the pattern of the ANA. However, if a shaggy or peripheral pattern is detected, a specific test to determine the presence or absence of native DNA antibodies should be performed. ANA determination is a screening test and is not specific for LE. ANAs can be detected in various connective tissue diseases and in approximately 5–10% of the general population. It was previously held that the magnitude of a titer has no relationship to the presence of LE, but a recent study in children suggests that an ANA of 1 : 160 correlates with autoimmune disease.49 When one detects a significant ANA titer, especially >1 : 640, other ANA profile serologic tests should be performed and definite clinical and historic features should be detected before a probable diagnosis of SLE is made since a diagnosis of SLE evokes a tremendous amount of anxiety in both the patient and family. Children suspected of having SLE should be examined for the presence of anti-native (ds, double stranded) DNA antibodies. These antibodies are highly specific for SLE (95%) and are found in approximately 70% of SLE patients. Low levels can be found

47. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989;44:93. 48. Reichlin M, Reichlin MW Autoantibodies to the Ro(SSA) particle react preferentially with the human antigen. In: Talal N, ed. Second International Symposium on Sjögren’s Syndrome. London: Academic Press; 1989:51. 49. Perilloux BC, Shetty AK, Leiva LE, et al. Antinuclear antibody (ANA) and ANA profile tests in children with autoimmune disorders: a retrospective study. Clin Rheumatol. 2000;19(3):200.

in a number of autoimmune disorders juvenile idiopathic arthritis (JIA), mixed connective tissue disease (MCTD) and rarely in drug induced lupus including that caused by the biologics etanercept and infliximab. Lupus patients with anti-dsDNA antibodies have a more guarded prognosis and a high frequency of renal disease. The presence of anti-dsDNA antibodies and hypocomplementemia, even in the absence of hematuria and proteinuria, almost always indicates a significant immunologic insult occurring in the kidney. It has been the early detection of these patients with anti-dsDNA antibodies that has played a major role in the reduction of mortality associated with this group of patients. Following the anti-dsDNA antibody titer level can help in disease management because it correlates well with SLE disease activity Anti-single-stranded DNA (ssDNA) antibodies are found in approximately 80% of patients with LE. These antibodies, unlike anti-dsDNA antibodies, are not specific for LE. They can be seen at a moderate level in a variety of other conditions such as rheumatoid arthritis, drug-induced lupus, Sjögren’s syndrome and healthy individuals. They are not a good measure of disease activity in SLE. Complement-fixing single-stranded DNA antibodies in the absence of anti-dsDNA antibodies have been associated with the presence of renal disease. In addition to anti-DNA antibodies, SLE patients frequently make autoantibodies directed against small nuclear ribonuclear proteins (snRNPs). The first description of these antinuclear antibodies were anti-SM antibodies. These antibodies, like antidsDNA antibodies, are specific for SLE and occur in approximately 20% of SLE patients. Anti-Sm antibodies rarely occur alone and are almost always seen in the presence of anti-nRNP (U1RNP) antibodies. Unlike anti-Sm antibodies, anti-nRNP antibodies can occur alone. They have been seen in a lupus disease process in which there is an increased frequency of sclerodactyly, esophageal dysmotility, pulmonary disease, and Raynaud phenomenon. A small percentage (approximately 5%) of scleroderma and dermato­ myositis/polymyositis patients possess these antibodies. Some patients possessing this antibody system have been described previously as having the mixed connective tissue disease syndrome. A follow-up study of patients with the MCTD syndrome has indicated that over a 10-year period, most of these patients evolve into a classical scleroderma or, more likely, LE disease.50 A third antibody directed against ribonuclear proteins is the anti-Ro(SSA) antibody. They are found in approximately 30% of SLE patients and 40–45% of Sjögren syndrome patients as detected by gel double diffusion. LE patients with anti-Ro(SSA) antibodies generally have a disease process that is characterized by intense photosensitive cutaneous LE lesions in 90% of patients.51 Frequently, they give a history of burning through window glass, indicating that low-energy, long-wave ultraviolet light is capable of activating or aggravating their disease process. Approximately 40% of patients develop either papulosquamous

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LABORATORY FINDINGS

23

50. Bennett RM. Definition and diagnosis of mixed connective tissue disease. UptoDate Online. 2008; www.uptodate version 16.2 (Accessed 31 May 2008). 51. Mond CB, Peterson MGE, Rothfield N. Correlation of anti-Ro antibody with photosensitivity rash in systemic lupus erythematosus patients. Arthritis Rheum. 1989;32:202.

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Table 23.1  Prevalence of autoantibodies in 23 untreated SLE patients with disease onset prior to age 18 AUTOANTIBODIES nDNA

Sm

nRNP

Ro(SSA)

La(SS-B)

Patients (n = 23)

11

8

7

5

3

Percentage

48

35

30

22

13

Data from Barnett N, Sills E, Provost TT, unpublished observations.

LUPUS ERYTHEMATOSUS

or widespread annular polycyclic lesions. Of these patients, 30– 50% have features that satisfy the minor criteria of the American College of Rheumatology for the diagnosis of SLE.52,53 These patients have been described under the term SCLE. In addition, some of the patients previously were reported under the rubric of ‘antinuclear antibody negative’ SLE patients. The anti-La(SS-B) antibody is found in approximately 10% of patients with SLE and is most often found in association with anti-Ro(SSA) antibodies. In adult lupus patients, antiphospholipid antibodies (anticardiolipin lupus anticoagulant) occur frequently (30–50%).54 These antibodies may also occur in the absence of LE as a primary antiphospholipid syndrome. The autoantibodies are associated with an increased frequency of arterial and venous thrombosis involving all organs, including the brain and heart. They have been reported in children and associated with clotting, menorrhagia and stroke.55 Cutaneous manifestations include acrocyanosis and livedo reticularis with and without ulceration. They have an increased frequency of thrombocytopenia, Libman– Sachs endocarditis, and central nervous system disease. Laboratory tests involving direct immunofluorescence, gel double diffusion, and enzyme-linked immunosorbent assay (ELISA) technologies have proved invaluable in the early diagnosis of children suspected of having LE. Lehman et al. reported that there may be an increased prevalence of single-stranded DNA, nRNP, and Sm in adult, as compared with childhood SLE populations.56,57 Others find the incidence in childhood of these antibodies is roughly the same as it is in adult SLE in a small population (Table 23.1). Serologic profiles for children under the age of 1 are not available in sufficient numbers to detect the prevalence of these autoantibodies. Monitoring of SLE activity is best performed by frequent physical examination and determination of serum complement (C3/ C4) levels.58 The clinical onset of disease activity, especially renal

52. Sontheimer RD, Maddison PJ, Reichlin M, et al. Serologic and HLA associations of subacute cutaneous lupus erythematosus: a clinical subset of lupus erythematosus. Ann Intern Med. 1982;97:664. 53. Watson RM, Talwar P, Alexander E, et al. Subacute cutaneous lupus erythematosus – immunogenetic associations. J Autoimmun. 1991;4:73. 54. Asherson RA, Cervera R. Antiphospholipid syndrome. J Invest Dermatol. 1993;100:21s. 55. Descloux E, Durieu I, Cochat P, et al. Systemic lupus erythematosus: prognostic impact of antiphospholipid antibody. Rheumatology. 2008; 47:183. 56. Lehman TJA, Hanson V, Singsin BH, et al. The role of antibodies directed against double stranded DNA in the manifestations of systemic lupus erythematosus in childhood. J Pediatr. 1980;96:657. 57. Lehman TJA, Hanson V, Zvaifler N, et al. Antibodies to non-histone nuclear antigens and anti-lymphocyte antibodies among children and

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disease, is frequently heralded by the gradual development of hypocomplementemia. Studies from one institution have demonstrated that therapeutic attempts to normalize complement levels are associated with a much better prognosis than treatment designed to treat only symptoms.58,23 Total complement activity is measured by a functional hemolytic assay (CH50). Complement can also be measured using single radioimmunodiffusion techniques examining for C3 and C4. Frequently C4 levels are depressed when C3 levels are normal. The most likely explanation for this dichotomy is the presence of one or more null alleles for C4 rather than low-grade complement consumption. Other laboratory procedures are of value in monitoring childhood SLE patients. The erythrocyte sedimentation rate (ESR) usually increases with disease activity, although there are exceptions. Thrombocytopenia, coagulation abnormalities (secondary to circulating anticoagulants), a Coomb’s positive hemolytic anemia, and leukopenia are also seen alone or in combination in as many as 90% of active childhood SLE patients.58 Routine urinalysis, serial complement determinations, antidsDNA antibody levels, and a renal biopsy are important procedures in monitoring childhood lupus patients suspected of having renal disease. Frequent blood pressure determinations are indicated in childhood SLE patients with active renal disease to detect the onset of a complicating hypertension. Renal biopsies have proven to be of immense value in the management of children with lupus nephritis. Four pathologic types of nephritis have been detected. These include mesangial lupus nephritis, membranous lupus nephropathy, focal glomerulonephritis, and diffuse proliferative glomerulonephritis. The diffuse proliferative glomerulonephritis carries the worst prognosis. This is a common type of nephritis seen in childhood SLE. The indications for renal biopsy can be found in a review by Garrin et al.59 Imaging techniques such as MRI and CT may help to delineate the disease processes in SLE.60 Bosma et al.61 detected brain parenchyma abnormalities in adolescents with neuropsychiatric SLE with magnetization transfer imaging (MTI). Chest X-rays have not been particularly helpful in discriminating LE from infectious processes in children.62

PATHOGENESIS The pathogenesis of various features of LE is becoming better understood and is reviewed by Petty.35 Evidence indicates that the glomerulonephritis is the result of immune complex formation with complement activation. Circulating immune complexes had been thought to play the primary role. It is now thought, that both double-stranded, as well as single-stranded

58. 59. 60. 61.

62.

adults with systemic lupus erythematosus and their relatives. J Rheumatol. 1984;11:644. Schaller JG. Diagnosis and management of rheumatic diseases in adolescence. Adolesc Med. 1998;9(1):1. Garrin EH, Shulman ST, Donnelly WH, et al. Systemic lupus erythematosus glomerulonephritis in children. Paediatrica. 1981;10:351. Hanlon R, King S. Overview of the radiology of connective tissue disorders in children. Eur J Radiol. 2000;33(2):174. Bosma GP, Rood MJ, Zwinderman AH, et al. Evidence of central nervous system damage in patients with neuropsychiatric systemic lupus erythematosus demonstrated by magnetization transfer imaging. Arthritis Rheum. 2000;43(1):48. Chantarojanasiri T, Sittirath A, Preutthipan A, et al. Pulmonary involvement in childhood systemic lupus erythematosus. J Med Assoc Thai. 1999;82:S144.

DNA, but not ribonuclear proteins [Sm, nRNP (U1RNP), Ro(SSA), and La(SS-B)] may preferentially bind to the collagen molecules along the glomerular basement membrane.63 Once having bound the anti-DNA antibodies can bind to these various forms of DNA (in situ immune complex formation). This observation is one explanation for the increased frequency of renal disease associated with anti-DNA antibodies compared with the frequency of renal disease in lupus patients possessing antibodies against Sm, nRNP (U1RNP), Ro(SSA), and La(SS-B). Another reason for the increased frequency of renal disease associated with anti-dsDNA antibodies compared with the frequency of renal disease associated with anti-U1RNP and Ro(SSA) antibodies may be related to the fact that lupus patients generally produce small quantities of anti-dsDNA antibodies. Thus, immune complexes involving anti-dsDNA tend to be formed in antigen excess. These immune complexes are small and soluble and escape clearance by the reticuloendothelial system. Antibodies directed against various riboprotein macromolecules, however, generally are present in large quantities. The immune complexes, in contradistinction to DNA immune complexes, are formed in antibody excess. These complexes generally are large and insoluble, and are easily removed by the reticuloendothelial system. In addition to anti-DNA and anti-RNP antibodies, lupus patients make antibodies against a variety of cell surface markers on platelets, neutrophils, and red blood cells. It is conceivable that these autoantibodies play a direct role in the development of cytopenias seen in LE. Petty indicates enhanced phagocytosis by the reticuloendothelial system as the cause of low platelets and leukopenia, with the antibodies being serologic markers.35 Cutaneous lupus lesions (DLE and SCLE) demonstrate an inflammatory mononuclear infiltrate characterized by the predominance of activated T cells (CD4 and CD8).64 Because the scarring discoid lesions most commonly occur in the total absence of autoantibodies, it is conceivable that this inflammatory lesion is the result of the T-cell inflammatory infiltrate. The deposition of immunoglobulin and complement has been shown to develop after the cutaneous lupus lesion is formed. At times, heavy deposition of immunoglobulin and complement at the dermal–epidermal junction can be seen in the total absence of clinical as well as histologic evidence of inflammation or an inflammatory cell infiltration. This implies that immune complex formation at the dermal–epidermal junction does not play a primary role in the pathogenesis of the cutaneous lupus lesions. Studies of neonatal lupus erythematosus (NLE) have provided good evidence to suggest that like the lesions of SCLE, the lesions of NLE are antibody mediated, perhaps by antibody-dependent cellular cytotoxicity. These studies have demonstrated that UV light may be an exogenous trigger for tumor necrosis factor alpha keratinocyte apoptosis in genetically susceptible individuals having-308A allele, HLA-DRQB1*02 and HLA-DRB1*03.32

The vasculitic lesions, including palpable purpura, urticariallike, livedo reticularis with ulceration, as well as nodular vasculitis are thought to be primarily the result of immune-complex mediated mechanisms. Immunoglobulin and complement deposition can be seen in and about affected blood vessels. Evidence exists that another mechanism could also potentially be involved. Studies indicate that some patients with SLE make autoanti­ bodies reactive against non-HLA-derived endothelial cell surface markers.65 Thus, a Gell and Coombs’ type II antibody-mediated complement-dependent (cytotoxic) immunologic mechanism in addition to type III (immune complex) type of immunologic mechanism may be involved in some of the vasculopathies seen in SLE. The alopecia that is seen in patients with SLE appears to arise from at least three different mechanisms. The most obvious is the presence of a scarring DLE lesion in the scalp resulting in destruction of the hair follicles. A second possible mechanism frequently seen in children with acute onset SLE is a diffuse alopecia most likely the result of a telogen effluvium secondary to the catabolic effects of the acute lupus disease process. A third type of alopecia, so-called lupus hair, is probably related to the catabolic effects of the lupus disease process. In this case, the patient develops characteristic thinning of the hair, especially around the periphery of the scalp, and most commonly observed at the temple and forehead area. The alopecia is characterized by thin, short hairs that easily fragment. It is likely that this type of alopecia, which is seen in patients with acute onset of SLE or recurrence of SLE, is the result of catabolic effects on the normal growth of the hair, producing weakened hairs that easily break resulting in shortened broken hairs. Bullous lesions, which are rare in SLE, can also arise via three potential mechanisms.66 Blisters can arise from widespread dissolution of the dermal–epidermal junction caused by liquefaction degeneration to the point of mimicking toxic epidermal necrolysis. This may be seen in anti-Ro(SSA) positive patients following intense ultraviolet light or sunlight exposure. The second form of bullous disease associated with LE probably results from a low-grade vasculopathy involving the blood vessels high in the papillary portion of the dermis resulting in neutrophilic papillary dermal microabscesses resembling dermatitis herpetiformis. These blisters have been reported to be responsive to dapsone therapy. The third form of bullous formation in LE was described by Gammon et al.66,67 These investigators determined that some lupus patients make an autoantibody against type VII collagen in the anchoring fibrils. This autoantibody results in destruction of the normal integrity of the dermal– epidermal junction producing subepidermal blister formation. This type of bullous formation in LE can be very recalcitrant to therapy. The role of ultraviolet light in the pathogenesis of cutaneous lupus lesions is unknown. Data by Lehmann et al. indicate that

63. Izui S, Lambert PH, Miescher PA. In vitro demonstration of a particular affinity of glomerular basement membrane and collagen for DNA. J Exp Med. 1976;144:428. 64. Synkowski DR, Provost TT. Characterization of the inflammatory infiltrate in lupus erythematosus lesions using monoclonal antibodies. J Rheumatol. 1983;19:920. 65. Cines DB, Lyss AP, Reeber M, et al. Presence of complement fixing anti-endothelial cell antibodies in systemic lupus erythematosus. J Clin Invest. 1984;73:611.

66. Gammon WR, Briggaman RA. Bullous SLE: a phenotypically distinctive but immunologically heterogeneous bullous disorder. J Invest Dermatol. 1993;100:28s. 67. Gammon WR, Briggaman RA, Inman AO III, et al. Evidence supporting a role for immune complex mediated inflammation in the pathogenesis of bullous lesions of systemic lupus erythematosus. J Invest Dermatol. 1983;81:320.

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both short-wave ultraviolet light (UVB), as well as long-wave (UVA) are capable of activating or aggravating lupus lesions.68 Their studies have confirmed that patients with SCLE appear to be the most photosensitive. The exact mechanism of how ultraviolet light induces formation of a cutaneous lupus lesion is unknown. Evidence is accumulating that UVB-induced cytokine damage occurs in the presence of Ro antibody in certain genetically susceptible individuals in both SCLE and neonatal lupus.32 The anticardiolipin antibody is found as a serologic marker in SLE and results in a false positive VDRL test. It causes primary antiphospholipid antibody syndrome69 and has an unknown substrate, but does bind to beta 2 glycoprotein 1.69,70 This results in intravascular coagulation and vessel endothelium adhesion causing thromboses.25 Inflammatory mediators affect pleuro/pericardial disease in SLE but no specific serologic markers have been identified.35

DIFFERENTIAL DIAGNOSIS Childhood SLE is often misdiagnosed as juvenile rheumatoid arthritis (JRA) (see below). Other differentials include infections such as infectious mononucleosis and viral conditions and rheumatic fever (which can usually be distinguished by the documentation of the Jones’ criteria, as well as a history of a recent streptococcal infection) are in the differential. Bacterial endocarditis must be distinguished from LE by clinical evidence of embolic phenomena, as well as positive blood cultures. Septicemia with arthritis especially secondary to a gonococcal or a meningococcal infection should be differentiated and may easily be confused with SLE septic arthritis. The purpuric dermatosis plus positive blood cultures help distinguish these two entities from LE.9,71 A serum sickness-like drug reaction can be confused with LE. In this case, a careful drug history plus discontinuation of the suspected offending drug should reveal the appropriate diagnosis. The drug-induced lupus-like states associated with isoniazid, hydralazine, and procainamide drugs are associated with a polyserositis, but generally no skin or renal disease.72 High-titer antihistone antibodies (directed predominantly against H2A/ H2B histones) are present and ANA may be directed toward single-stranded DNA as opposed to the double-stranded DNA of true SLE. However, a lupus-like state, including skin disease, renal disease, and anti-dsDNA antibodies, can occur in patients receiving D-penicillamine. Complement levels are usually normal in drug-induced SLE. In the last decade a lupus-like syndrome has been increasingly reported in adolescents on minocycline for acne.73 Occasionally the early onset of juvenile dermatomyositis in which the myositis is not a prominent feature (amyopathic der-

68. Lehmann P, Hölze E, Kind P, et al. Experimental reproduction of skin lesions in lupus erythematosus by UV-A and UV-B radiation. J Am Acad Dermatol. 1990;22:181. 69. Gattornd M, Buoncampagni A, Molinari AC, et al. Antiphospholipid antibodies in paediatric lupus erythematosus, juvenile chronic arthritis and overlap syndromes: SLE patients with both lupus anticoagulant and high-titre anticardiolipin antibodies are at risk for clinical manifestations related to the antiphospholipid syndrome. Br J Rheumatol. 1995;34:873. 70. McNeil HP, Simpson RJ, Chesterman CN, et al. Antiphospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation beta 2 glycoprotein 1 (apolipoprotein). Proc Natl Acad Sci USA. 1990;87(11):4120–4124.

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matomyositis) can be confused with LE. Dermatomyositis can also be photosensitive and histologically indistinguishable from LE. Serologically, the presence of lupus-specific autoantibodies such as anti-dsDNA and anti-Sm can be of great help in establishing a diagnosis of lupus. Myositis-specific antibodies, if present, or elevated muscle enzymes (see below) help to establish the diagnosis of dermatomyositis. Secondary syphilis characterized by arthralgias, fever, lymphadenopathy, and a papulosquamous disease process may be confused with LE. The diagnosis would be established by the demonstration of a positive Venereal Disease Research Laboratory (VDRL) test and confirmation by a fluorescent treponemal antibody (FTA) determination. In LE, it is possible to have the speckled positive FTA that represents staining of the nuclei of the treponema. This speckled pattern of staining is in reality a positive ANA determination. The staining pattern on the FTA for syphilis is a homogeneous staining of the treponema. Hence the FTA pattern for syphilis is homogeneous but speckled in the false positive FTA of LE.

THERAPY Corticosteroids have assumed the major therapeutic role in the treatment of childhood SLE. High doses of corticosteroids are employed until the anti-dsDNA antibodies and complement levels are normalized and the clinical state is improved. Prednisone is usually preferred. A tuberculosis skin test is advised before therapy is started. The corticosteroids are very slowly tapered to the lowest dose capable of controlling the disease symptoms, and maintaining normalized complement levels. Both alternate day and single morning dose corticosteroids have been shown to be therapeutically effective in treating lupus and minimizing the side-effects of infection, aseptic necrosis, Cushingoid features, and osteoporosis. High dose pulse corticosteroids have been shown to be effective in providing rapid control of acutely ill SLE patients. DEXA-scans can be used to document osteopenia and osteoporosis which may be steroid-induced or possibly part of the disease process.4,74 Immunosuppressive agents such as azathioprine (Imuran) and cyclophosphamide are generally reserved for individuals with severe renal disease or severe systemic involvement of other vital organs, especially the central nervous system. Steroids plus immunosuppressive agents have been shown to be more effective than steroids alone in the treatment of lupus nephritis.15 The combination of steroids and immunosuppressive agents permits lower doses of steroids to be used. While steroid exposure may risk growth failure, severe infections and avascular necrosis, these other immunosuppressive agents also have significant potential side-effects including sterility and hemorrhagic cystitis

71. Ansell BM. Rheumatic disease mimics in childhood. Curr Opin Rheumatol. 2000;12(5):445. 72. Cush JJ, Goldings EA. Drug induced lupus: clinical spectrum and pathogenesis. Am J Med Sci. 1985;290:36. 73. Akins E, Miller LE, Tucker LB, et al. Minocycline related lupus-like syndrome: Possible association with anti-neutrophil cytoplasmic antibodies [abstract]. Arthritis Rheum. 1997;40:A962. 74. Compeyrot-Lacassagne S, Tyrell PN, Atenade E, et al. Prevalence and etiology of low bone mineral density in juvenile systemic lupus erythematosus. Arthritis and Rheum. 2007;56:1966.

(cyclophosphamide), chemical hepatitis (azathioprine), and a propensity to infection, aplastic anemia and malignancy (azathioprine and cyclophosphamide). They should be employed only in the most severe cases with great caution, and treatment should be individualized by histologic class as discussed by Niaudet.75 Pulse intravenous cyclophosphamide (Cytoxan) has been especially effective and relatively non-toxic in the treatment of diffuse proliferative lupus glomerulonephritis76,77 and as a steroid-sparing agent. Other immunosuppressive drugs, metho­ trexate, chlorambucil and mycophenolate mofetil (CellCept) have been employed in the management of childhood lupus and can be used to achieve control if steroids have been unsuccessful. The combination of intravenous methotrexate and cyclophosphamide has been used successfully for refractory lupus nephritis in children.45 Renal transplant is a reasonable therapeutic choice for pro­ gressive end-stage lupus nephritis unresponsive to therapy. Lupus nephritis rarely recurs in the new organ75 and dialysis poses the risk of predisposing to sepsis. For milder renal disease standard antihypertensive and renal medical management is appropriate. The chimeric antiCD20 monoclonal antibody rituximab has been effective alone and in combination with cyclophosphamide for severe refractory SLE but dose and length of therapy as well as the extent of adverse events has not been established.4,78,79 Other experimental treatments being investigated for catastrophic refractory SLE include intravenous immunoglobulin (IVIG), biologics and stem cell transplant. Cutaneous lesions in childhood LE can be treated with topical steroid preparations. Less often employed, but also effective, is the intralesional injection of steroids. Complications such as atrophy, telangiectasia, and striae can result from local repetitive use of potent topical steroid therapy to treat cutaneous lupus lesions. Topical tacrolimus ointment, a non-steroid, has been reported to be effective for discoid lupus erythematosus lesions.15 Clofazimine has been employed in adult patients with cutaneous lupus lesions; however, skin pigmentation complications must be considered. Retinoids and tazarotene have been employed with success in adults to control recalcitrant cutaneous lupus lesions. Thalidomide has been effective in treating cutaneous lupus.80 This drug is available in the USA. Imiquimod offlabel is being utilized by some sparked by the observation that thalidomide helps. In addition to topical steroids, oral hydroxychloroquine, an antimalarial, is effective in treating cutaneous lesions of LE. Patients treated with hydroxychloroquine have fewer recurrences of minor flares including cutaneous, as well as joint disease. If antimalarials are used, the patient should have a yearly ophthalmologic examination to assess for possible maculopathy

causing a loss of visual acuity. In addition, care should be observed in prescribing antimalarials to glucose-6-phosphatedehydrogenase deficient (G6PD) patients. Blood counts, liver functions, and electrolytes were previously recommended to be monitored every 2 months but this frequency is no longer recommended by the ACR as alterations of significance are extremely rare.81 Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) may be beneficial in treating myalgias and arthralgias. Care must be taken to avoid excessive gastrointestinal irritation with the potential of a bleeding ulcer. Chronic ibuprofen use is contraindicated in lupus patients because it can rarely cause creatinine elevation in some individuals and is also associated with aseptic meningitis. Normal creatinine concentrations are lower in children than adults so that a mild elevation or apparently normal adult level may be evidence of renal compromise requiring aggressive treatment.4 In the presence of thrombocytopenia, aspirin should not be used but in lupus patients with the lupus anticoagulant (anticardiolipin antibody), 1 mg/kg per day of aspirin may help prevent platelet aggregation. Because of the potential deleterious effects of excessive sunlight exposure, patients and their families should be cautioned about excessive sun exposure. Protective clothing and the judicious use of sunscreens (with a sun protective factor 30 rating or above) should be stressed. Children with SLE should not receive live viral immunizations.

75. Niaudet P. Treatment of lupus nephritis in children. Pediatr Nephrol. 2000; 14(2):158. 76. Lehman TJ, Onel K. Intermittent intravenous cyclophosphamide arrests progression of the renal chronicity index in childhood systemic lupus erythematosus. J Pediatr. 2000;136(2):243–247. 77. Lehman TJ, Sherry DD, Wagner-Weiner L, et al. Intermittent intravenous cyclophosphamide therapy for lupus nephritis. J Pediatr. 1989;114: 1055. 78. Williams M, Haddad E Niaudet P, et al. Rituximab therapy for childhoodonset systemic lupus erythematosus. J Pediatr. 2006;148:623. 79. MacDermott FJ, Lehmen TJ. Prospective, open-label trial of rituximab in childhood systemic lupus erythematosus. Curr Rheumatol Rep. 2006;8:439.

80. Ordi-Ros J, Cortes F, Cucurull F, et al. Thalidomide in the treatment of cutaneous lupus refractory to conventional therapy. J Rheumatol. 2000;27(6):1429. 81. Sontheimer RD. Questions answered and a $1 million question raised concerning lupus erythematosus tumidus. Is routine laboratory surveillance testing during treatment with hydroxychloroquine for skin disease really necessary? Arch Dermatol. 2000;136:1044–1049. 82. McDonagh JE, Isenberg DA. Development of additional autoimmune diseases in a population of patients with systemic lupus erythematosus. Ann Rheum Dis. 2000;59(3):230. 83. Falaschi F, Ravelli A, Martignoni A, et al. Nephrotic-range proteinuria, the major risk factor for early atherosclerosis in juvenile-onset systemic lupus erythematosus. Arthritis Rheum. 2000;43(6):1405.

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Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

PROGNOSIS The prognosis of childhood SLE, like that of adult LE, has markedly improved during the past quarter century. Children with the worst prognosis are those with diffuse proliferative glomerulonephritis in whom hypertension develops within 6 months of diagnosis. The 5-year survival, however, from the time of diagnosis is at least 80%. In all probability, this spectacular improvement in survival is due to earlier diagnosis, aggressive steroid and antibiotic treatment, and the judicious use of pulse cortico­ steroids and IV cyclophosphamide. Infection is the cause of most deaths in children with SLE, especially those on chronic daily steroids, so vigilance for evidence of infection is mandatory in caring for these patients. Children with SLE are at risk of developing additional autoimmune disorders over time.82 Ultrasound has documented carotid wall thickening in severe renal lupus nephritis with nephrotic range proteinuria, suggesting that these patients are also at risk for early atherosclerosis.83 With the improved prognosis, patients with childhood SLE who do not have diffuse proliferative glomerulonephritis have a

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normal life expectancy, but they should be closely monitored. Every means should be employed to minimize the disruption of the normal socialization of the child and adolescent.84 Once the disease is under control, physical activities such as play and physical education should be reinstituted as promptly as possible. Compliance with medication is essential for good control of disease and often becomes difficult to manage in the adolescent years as independence, which must be respected, is asserted by the patient.8 Development of neuropsychiatric lupus confounds the situation beyond the stress of a chronic disease and may impact on cognitive function, school performance and peer and family interaction. Support groups and psychiatric medications help coping mechanisms in some patients. Cutaneous lupus lesions in exposed areas should be treated as aggressively as possible to attempt to minimize their disfiguring nature. To prevent any misunderstanding regarding the possible contagious nature of the patient’s disease, school staff, playmates, and playmates’ parents may be educated as to the nature of the patient’s illness with their consent. The Cushingoid features and growth abnormalities of corticosteroid therapy have an especially detrimental effect on the child’s self-image. Modified disease therapy effects and psychosocial factors have been documented to improve quality of life for SLE patients.85

NEONATAL LUPUS ERYTHEMATOSUS William L. Weston Neonatal lupus erythematous (NLE) is characterized by the development of skin lesions, isolated congenital heart block (CHB), or both.76–78,86–92 It is a distinct syndrome unlike lupus erythematosus in the older child or adult.89–91 The overwhelming majority of NLE infants are born to mothers who have anti-Ro (52 kd and 60 kd/SSA) antibodies.76–78,86,89–92 Approximately 40% of mothers will also have anti-La/SSB antibodies.89,90,92 Rarely, anti-Ro/SSA and anti-La/SSB autoantibodies are absent,

84. White PH. Psychosocial aspects of rheumatic disease in childhood and adolescence. Adolesc Med. 1998;9(1):171. 85. Thumboo J, Fong KY, Chan SP, et al. A prospective study of factors affecting quality of life in systemic lupus erythematosus. J Rheumatol. 2000;27(6):1414. 86. Franco HL, Weston WL, Peebles C, et al. Autoantibodies directed against sicca syndrome antigens in the neonatal lupus syndrome. J Am Acad Dermatol. 1981;4:67. 87. Kephardt D, Hood AF, Provost TT. Neonatal lupus erythematosus: new serologic findings. J Invest Dermatol. 1981;77:331. 88. Weston WL, Harmon C, Peebles C, et al. A serological marker for neonatal lupus. Br J Dermatol. 1982;107:307. 89. Lee, LA. The clinical spectrum of neonatal lupus. Arch Dermatol Res. 2008; 301:107. 90. Lee, LA. Transient autoimmunity related to maternal autoantibodies: neonatal lupus. Autoimmun Rev. 2005;4:207. 91. Lee, LA. Neonatal lupus: clinical features and management. Paediatr Drugs. 2004;6:71. 92. Boh EE. Neonatal lupus erythematosus. Clin Dermatol. 2004;22:125. 93. Neiman AR, Lee LA, Weston WL, et al. Cutaneous manifestations of neonatal lupus without heart block: Characteristics of mothers and children enrolled in a national registry. J Pediatr. 2000;137(5):647. 94. Friedman DM, Rupel A, Buyon JP. Epidemiology, etiology, detection, and treatment of autoantibody-associated congenital heart block in neonatal lupus. Curr Rheumatol Rep. 2007;9:101. 95. Izmirly PM, Rivera TL, Buyon JP. Neonatal lupus syndromes. Rheum Dis Clin North Am. 2007;33(2):267–285. 96. Shanske, AL Bernstein L, Herzog. Chondrodysplasia punctata and maternal autoimmune disease: a new case and review of the literature. Pediatrics. 2007;120:e146.

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and these NLE babies are born to mothers with anti-nRNP (U1 RNP) antibodies.80 About half the newborn infants with NLE demonstrate isolated congenital heart block, 40% have cutaneous lesions and 10% have both.89–94 In addition to these major features, about 10% of NLE infants have jaundice from neonatal cholestatic hepatitis and approximately 4% have hematologic features, such as thrombocytopenia, or aplastic anemia.78,81,89–95 These non-cutaneous features plus the cutaneous LE lesions are transient and resolve as maternal antibodies transferred to the infant wane.76,78,90 In contrast, CHB persists and affected babies require pacemakers.78,91–93,95 Rarely reported associated findings include chondrodysplasia punctata of bone,96 pulmonary necrotizing capillaritis,97 and neurologic symptoms of CNS vasculitis83,98 or macrocephaly and hydrocephaly.99 It is unclear whether these recently described complications persist. Most commonly, babies with NLE have only one organ system involved.78,91 Mothers of NLE infants may or may not show features of connective tissue diseases at the time of birth of the affected infant.76,78,89–94 In at least half of the mothers symptoms are entirely absent or so subtle they are missed on routine maternal history and physical examination. Some 60% of mothers that are symptomatic at delivery will have signs and symptoms of Sjögren’s syndrome,76,78,89,90,93 and about 40% will have rheumatoid arthritis or lupus erythematosus.100–102 It is estimated that a baby born of a mother that is Ro/SSA positive will have a 1 in 20 chance of having NLE.89,92,95,96,103 Kitridou and Mintz detected 21 children with NLE in 292 live births to anti-Ro/SSA positive mothers with symptomatic Sjögren’s syndrome or lupus,101 while Brucato et al. found three NLE babies in 100 women that were anti-Ro/SSA positive when followed prospectively.104 Gerosa et al. found that fetal EKG abnormalities in a prospective controlled study of Anti-Ro/SSA mothers could be detected in one of 61 babies at 18 weeks and another at 30 weeks105 and Sonnesson et al.106 found one-third of fetuses of mothers that specifically had the anti-Ro52 kd autoantibodies developed 1st degree heart block. In a study by Ramsey-Goldman et al.102 of

97. Morton RL, Moore C, Coventry S, et al. Pulmonary capillaritis and hemorrhage in neonatal lupus erythematosus (NLE). J Clin Rheumatol. 2004;10(3):130–133. 98. Prendiville JS, Cabral DA, Poskitt KJ, et al. Central nervous system involvement in neonatal lupus erythematosus. Pediatr Dermatol. 2003;20:60–67. 99. Boros CA, Spence D, Blaser S, et al. Hydrocephalus and macrocephaly: New manifestations of neonatal lupus erythematosus. Arthritis Rheum. 2007;57:261. 100. Askanase AD, Neiman A, Lee LA, et al. Clinical parameters of mothers whose children have permanent and transient manifestations of neonatal lupus and risk of crossover in siblings. Arthritis Rheum. 1999;42:S225. 101. Kitridou R, Mintz G. The neonatal lupus syndrome. In: Wallace DJ, Hahan BH, eds. Dubois lupus erythematosus. Philadelphia: Lea & Febiger; 1992:516. 102. Ramsey-Goldman R, Hom D, Deng J-S, et al. Anti-SSA antibodies and fetal outcome in maternal systemic lupus erythematosus. Arthritis Rheum. 1988;31:697. 103. McCune AB, Weston WL, Lee LA. Maternal and fetal outcome in neonatal lupus erythematosus. Ann Int Med. 1987;106:518. 104. Brucato A, Doria, A Frassi M, et al. Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study. Lupus. 2002;11:716. 105. Gerosa M, Cimaz R, Stramba-Badiale M, et al. Electrocardiographic abnormalities in infants born from mothers with autoimmune diseases – a multicenter prospective study. Rheumatology. 2007;46:1285. 106. Sonnesson SE, Salomonsson S, Jacobsson LA, et al. Signs of first degree heart block occur in one third of fetuses of pregnant women with anti SSA/Ro 52kd antibodies. Arthritis Rheum. 2004;50:1253.

anti-SSA/Ro positive mothers with SLE, six of 79 had congenital heart block, while in a retrospective study from the National Neonatal Lupus Registry that evaluated anti-Ro/SSA and anti-La/ SSB mothers who had one child with CHB, Llanos et al.107 found that 17% had a NLE baby in a subsequent pregnancy. A second affected baby may have the same clinical findings as the first child, or other manifestations of NLE.93,100,102,106 Spence et al. found double the risk of having a NLE baby in Anti-Ro/SSA mothers who had concomitant hypothyroidism.108 Congenital heart block in NLE is complete in 90% of babies.92,94,107 In addition, 2 : 1 atrioventricular block, transient atrioventricular block and sinus bradycardia have been reported. Isolated congenital heart block has been detected as early as 18 weeks’ gestation, with most detected at 20–24 weeks, although there are reports of later onset. A great variety of associated congenital heart abnormalities have been reported in up to 30% of babies with NLE and heart block. These congenital defects include patent ductus arteriosus, ventricular septal defect, transposition of the great vessels, atrial septal defect, patent foramen ovale, coarctation of the aorta, tetralogy of Fallot, hypoplastic right ventricle, dysplastic pulmonary valve, anomalous pulmonary venous return, pulmonary regurgitation, tricuspid valve insufficiency and mitral valve insufficiency. Delayed onset dilated cardiomyopathy has also been reported.90

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Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

A

PRESENTING HISTORY AND PHYSICAL EXAMINATION In babies with isolated congenital heart block, the prenatal care and examination of the mothers before delivery are detailed in a report by Kitridou and Mintz.101 If not routinely done for pregnancy, evaluation of the mother’s thyroid status may have prognostic value.108 The cutaneous lesions of NLE may be present at birth, but most babies have the onset in the first few weeks after birth.78,89–93 The characteristic skin lesions are multiple round, pink to red macules involving the scalp, face and the extremities (Fig. 23.3A). Some skin lesions partially clear in the center giving an annular configuration that mimics tinea. The site most often involved is the periorbital skin, giving rise to what has been termed an ‘owl-eye’ look.78 From multiple reports, it is clear that virtually any area of skin can be involved.78,109 Skin lesions generally clear without scarring, but in dark-skinned infants, a transient hypopigmentation or hyperpigmentation has been reported at the site of lesions (Fig. 23.3B).78,86 Telangiectasia in the sites of previously affected skin may persist until pre-teen years.78 In a few babies, crusted lesions have been reported and correlated with multiorgan involvement.78 There is a report of residual scarring, atrophy and hypopigmentation persisting to teenage years.110 The characteristic skin lesions of NLE may be precipitated or aggravated by ultraviolet light,78 but the presence of lesions at birth and involvement of photoprotected areas of skin

107. Llanos C, Izmirly PM, Katlosh M, et al. Recurrence rates of cardiac manifestations associated with neonatal lupus and maternal/fetal risk factors. Arthritis Rheum. 2009;60:3091–3097. 108. Spence D, Hornberger L, Hamilton R, et al. Increased risk of complete congenital heart block in infants born to women with hypothyroidism and anti-Ro or Anti-La antibodies. J Rheumatol. 2006;33:167. 109. Cimaz R, Biggliogerro, M Catelli L, et al. Ultraviolet light exposure is not a requirement for the development of cutaneous neonatal lupus. Lupus. 2002;11:257.

B

Figure 23.3  (A) Red, annular lesions of neonatal lupus erythematosus on the breast of an infant. (B) Reticulated atrophic macules and periocular erythema of NLE (Both Courtesy Dr A. Torrelo).

indicate that ultraviolet light exposure is not a necessary factor for skin involvement.78,109 Other skin changes reported include petechiae from thrombocytopenia,78,81 jaundice from hepatic disease,78,89–91 lesions compatible with cutis marmorata telangiectasia congenita,111 and widespread hemangiomas.112 The differential diagnosis of the cutaneous findings includes tinea faciei, annular urticaria, infantile dermatitis and psoriasis. The photosensitive genodermatoses, such as Rothmund–Thompson syndrome, Cockayne syndrome, and Bloom syndrome may also be considered.

110. High WA, Costner MI. Persistent scarring, atrophy and dyspigmentation in a preteen girl with neonatal lupus erythematosus. J Am Acad Dermatol. 2003;48:626. 111. Heughan CE, Kanigsberg N. Cutis marmorata telangiectasia congenita and neonatal lupus. Pediatr Dermatol. 2007;24:320. 112. Spalding SJ, Hennon T, Dohar J, et al. Neonatal lupus erythematosus complicated by mucocutaneous and visceral hemangiomas. Lupus. 2007;16:904.

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NLE babies and their mothers have Anti-Ro/SSA autoantibodies in their sera, and this test is crucial for confirming the diagnosis.76,88–92 Laboratories that perform the anti-Ro/SSA test generally also do Anti-La/SSB tests. It may be most practical to examine the blood from the mother rather than the baby in order to have sufficient amounts for testing. Counter-immunoelectrophoresis tests are considered the most reliable for serodiagnosis.113 In the absence of Anti-Ro/SSA and anti-La/SSB antibodies, when the clinical suspicion for NLE is high, anti-U1 RNP antibodies should be sought.80 Autoantibodies clear from the infant’s blood by 7–12 months.80,86 Babies with CHB, crusted skin lesions, jaundice or petechiae, should have a hemogram and liver function tests. Skin biopsies are not usually diagnostic. Mild interface changes are seen, but apoptotic keratinocytes, loss of the basement membrane zone, and skin atrophy seen in established SLE or DLE are often absent.78,86,114 Direct immunofluorescent studies of NLE skin reveal particulate deposits of IgG on epidermal cells like that noted in adult subacute cutaneous lupus erythematosus, but the band of IgG deposits at the basement membrane zone characteristic of SLE or DLE is absent. Autopsies of affected cardiac tissue show widespread cardiocyte apoptosis, cardiac fibrosis with fibrotic replacement of the conduction system and endocardial fibroelastosis.91,92

PATHOGENESIS NLE is unique in that the autoantibodies are produced in the mother, passively transferred to the baby and the tissue injury occurs in the baby.78,89–92,115 From immunogenetic studies, it has been found that mothers of NLE babies have a striking increase in HLA DR3 phenotype.106,115 There appears to be a close relationship between NLE mothers and females with primary Sjögren’s syndrome, females with subacute cutaneous lupus erythematosus and females with the Sjögren’s syndrome/lupus erythematosus overlap syndrome. In all of these anti-Ro/SSA positive subsets, affected females possess an increased frequency of HlA-B8, DR3, DQ2 and DRw52 phenotypes.30,93,100 Not only do the anti-Ro/SSA and anti-La/SSB antibodies serve as disease markers, there is increasing evidence of a specific role for these antibodies in the pathogenesis of both cutaneous and cardiac disease. Deposits of anti-Ro/SSA IgG have been found on keratinocytes and on the cardiocytes of NLE babies. Ultraviolet light is capable of translocation of the Ro/SSA molecule to the plasma membrane of the keratinocyte, making it available to interact with autoantibodies.116 Antibody-mediated cytotoxicity is one possible mechanism of keratinocyte injury,117 and it has also been postulated that Ro-antigen may be specifically

113. Franceschini F, Cavazzana L. Anti-Ro/SSA and La/SSB antibodies. Autoimmunity. 2005;38:55. 114. David-Bajar KM, Bennion SD, DeSpain JD, et al. Clinical, histologic and immunofluorescent distinctions between subacute cutaneous lupus erythematosus and discoid lupus erythematosus. J Invest Dermatol. 1992;99:251. 115. Lee LA, Bias WB, Arnett FC, et al. Immunogenetics of the neonatal lupus syndrome. Ann Intern Med. 1983;99:592. 116. LeFeber WP, Norris DA, Ryan SS. Ultraviolet light induces expression of selected nuclear antigens on cultured human keratinocytes. J Clin Invest. 1984;74:1545. 117. Norris DA, Lee LA. Antibody dependent cellular cytotoxicity and skin disease. J Invest Dermatol. 1985;85:165s.

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recognized by T cells initiating direct injury.92 Similarly in the heart, Reed et al. found that anti-Ro/SSA and anti-La/SSB antibodies opsonize apoptotic cardiocytes.118 Buyon and Clancy119 further hypothesized that the process of cardiocyte apoptosis is accompanied by translocation of the Ro/SSA and La/SSB antigens to the cardiocyte surface. Once opsonized, the dying cardiocytes are scavenged by macrophages, stimulating the release of pro-fibrotic cytokines including TGF-B. Ro/SSA is found in two forms, a 52 kd and 60 kd molecule. The Ro52 kd molecule has been shown to be an E3 ubiquitin ligase120 but has not been shown to participate in cardiocyte injury, which seems to be Ro60 kd-specific.118 Ro60 kd and La translocate to the cardiocyte surface separately in time, with Ro60 kd found on early apoptotic cardiocytes and La on late apoptotic cardiocytes.118

TREATMENT The transient manifestations of NLE clear with time and usually do not require intervention. For the skin lesions, low-potency topical glucocorticosteroid ointments or creams once or twice daily for 2–4 weeks are efficacious, but intervention may not be required as the skin lesions fade within a few weeks to months.78,91 Some authorities treat the residual telangiectasia with pulsed dye lasers, but most recommend waiting until at least 12–24 months of age to determine if they will disappear. Some telangiectasia persist to teenage years. Reversal of congenital heart block in the fetus has been described after the use of intravenous fluorinated steroids administered to the mother.121 Most authors recommend betamethasone over dexamethasone due to less fetal toxicity.121,122 Similarly, steroids administered to the newborn have been therapeutic in cases of hydrops fetalis or poor ventricular function.121,122 With heart block and otherwise normal cardiac function in NLE newborns, use of steroids has not been shown to be effective as the heart block is not reversible. Some authorities122 postulate that intravenous immunoglobulin might substitute for steroids for both the NLE fetus and newborn, but there is insufficient information available regarding efficacy.

PROGNOSIS The presence of CHB at birth adversely affects the prognosis for the NLE baby. Mortality with isolated CHB is 15–20%, and some NLE babies present with severe heart failure or hydrops fetalis.94,107,121 Pacemakers are required in almost all NLE babies with CHB.89,107,121 NLE infants with complete CHB have impaired growth and do not catch up compared with the growth of NLE

118. Reed JH, Neufing PJ, Jackson MW, et al. Different temporal expression of immunodominant Ro60/60 kDa-SSA and La/SSB apotopes. Clin Exp Immunol. 2007;148:153–160. 119. Buyon JP Clancy RM. Neonatal lupus: basic research and clinical perspectives. Rheum Dis Clin North Am. 2005;31:299. 120. Wada K, Kamatani, T. Autoantigen Ro52 is an E3 ubiquitin ligase. Biochem Biophy Res Commun. 2006;339:415. 121. Gordon PA. Congenital heart block: clinical features and therapeutic approaches. Lupus. 2007;16:642. 122. Brucato A. Prevention of congenital heart block in children of SS-A positive mothers. Rheumatology. 2008;47:iii35–iii37.

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JUVENILE SYSTEMIC SCLEROSIS (JSS) (FORMERLY PROGRESSIVE SYSTEMIC SCLEROSIS, PSS; SCLERODERMA) Nancy K. Barnett

JUVENILE SYSTEMIC SCLEROSIS (JSS) (FORMERLY PROGRESSIVE SYSTEMIC SCLEROSIS, PSS; SCLERODERMA)

infants with no heart block.123 NLE babies with 1st degree heart block have delayed growth but catch up.123 The cutaneous, hematologic and hepatitic manifestations are transient and disappear after 2–12 months; they do not reappear during childhood.89–92,103 There are a few reports of NLE babies that developed SLE or rheumatoid arthritis in teenage or adult years after an asymptomatic childhood.89 Long-term follow-up is required to determine the risk for later onset connective tissue diseases. Most mothers of NLE babies who were asymptomatic at the time of delivery will over the next 5 years develop either features of Sjögren’s syndrome or LE.91,102

Figure 23.4  Sclerodactyly, ulceration and dyschromia in progressive systemic sclerosis (Courtesy Dr A. Torrelo).

Progressive systemic sclerosis is rare in childhood.124–126 The first case report of PSS was in a 17-year-old girl in 1753, by Curzio.127 PSS can occur in any race and at any age. The youngest described patient was a 15-month-old female.128 The overwhelming majority of affected patients are female.129 The juvenile disease is clinically quite similar to adult progressive systemic sclerosis but less severe and with less organ system involvement at diagnosis.125 Localized scleroderma (morphea) is the more common subtype of scleroderma in childhood and is described fully in Chapter 18. In a review, Christen-Zaech et al. presented details on patients with morphea who developed evidence of systemic sclerosis and suggest that morphea may be a mosaic cutaneous form of systemic sclerosis.130 Patients with juvenile systemic sclerosis (JSS) generally seek medical attention because of sclerotic changes in the skin or most commonly Raynaud’s phenomenon. Skin complaints are tightening, firmness, and occasional pruritus. Only rarely does an erythematous phase occur; however, edema may precede or coincide with tissue induration before the sclerosis.131 Edema along with arthralgias and myositis are seen in one third of JSS patients and may mimic JIA (formerly juvenile rheumatoid arthritis, JRA) before sclerosis appears. Raynaud phenomenon occurs in 75% of PSS patients124 and may precede other symptoms by months to years.124,131 The acrosclerotic type is the most common type of JSS seen in children. It is characterized by sclerodactyly and Raynaud phenomenon (Fig. 23.4). The ‘diffuse’ scleroderma pattern of PSS is characterized by centrifugal rapidly advancing cutaneous sclero-

sis. Characteristic features include sparing of the fingertips and initial absence of the Raynaud phenomenon.128 The rapid evolution of this latter type over 3–5 years with progressive visceral involvement invariably leads to considerable morbidity.131,132 At present, the strict separation of these two forms of PSS no longer appears clear-cut or especially beneficial prognostically and is not in the provisional classification of JSS.133 It is beneficial to identify scleroderma patients having the CREST syndrome. The name is derived from the initials of the significant clinical features: calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. This entity appears to be more benign, but there is still a 25% mortality over 10 years for CREST syndrome patients; this is still less than for adult patients with PSS.134 The CREST syndrome is not common among children. Cutaneous sclerosis is universally found in PSS and JSS but calcinosis and telangiectatic mats occur in only 10–30% of patients. Other skin findings are fingertip ulcerations secondary to vasospasm overlying calcium deposits especially at pressure points, and pigmentary changes. Cassidy et al.124 reported ulceration in 11 of their 15 patients with PSS and pigmentation abnormalities in three. A common finding in JSS is nail fold capillary abnormalities with fewer more tortuous dilated vessels compared with the normal architecture noted periungually by ophthalmoscopy.131 A patient with Raynaud phenomenon and nail fold capillary abnormalities most likely has early systemic sclerosis. Other organ systems commonly

123. Skog A, Wahren-Herenius N, Sundstrom B, et al. Outcome and growth of infants fetally exposed to heart block-associated maternal anti-Ro52/SSA autoantibodies. Pediatrics. 2008;121:e803. 124. Cassidy JT, Sullivan DB, Dabich L, et al. Scleroderma in children. Arthritis Rheum. 1977;20:31. 125. Martini V, Foeldvari I, Russo R, et al. Systemic sclerosis in childhood: clinical and immunologic features of 153 patients in an international database. Arthritis Rheum. 2006;54:397. 126. Levine BW. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 43-1979. N Engl J Med. 1979;301:929–936. 127. Rodnan GP, Benedek TG. A historical account of the study of progressive systemic sclerosis (diffuse scleroderma). Ann Intern Med. 1962;57:305. 128. Urano J, Kohno H, Watanabe T. Unusual case of progressive systemic sclerosis with onset in early childhood and following infectious mononucleosis. Eur J Pediatr. 1981;136:285.

129. McDonagh JE, Isenberg DA. Development of additional autoimmune diseases in a population of patients with systemic lupus erythematosus. Ann Rheum Dis. 2000;59(3):230. 130. Christen-Zaech S, Halcin MD, Afsar FS, et al. Pediatric morphea (localized scleroderma): review of 136 patients. J Am Acad Dermatol. 2008;59:385. 131. Zulian F. Juvenile systemic sclerosis. UptoDate Online 2008; www. uptodate.com (Accessed 10 September 2008). 132. Doyle JA, Connolly SM, Winkelmann RK. Cutaneous and subcutaneous inflammatory sclerosis syndromes. Arch Dermatol. 1982;118:886. 133. Zulian F, Woo P, Athreya BH, et al. The Pediatric Rheumatology European Society/American College of Rheumatology/European League against Rheumatism Provisional Classification Criteria for juvenile systemic sclerosis. Arthritis Rheum. 2007;57:203. 134. Rodan GP, Jablonska S. Classification of systemic and localized scleroderma. In: Black CM, Myers AR, eds. Systemic sclerosis (scleroderma). New York: Gower Medical; 1985:3.

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involved in JSS include the musculoskeletal, gastrointestinal, pulmonary, cardiac, and renal systems. Arthralgias, arthritis, myalgias, proximal muscle weakness, and muscle atrophy may be seen in children with JSS. Gastroesophageal reflux and dysphagia, symptoms of gastrointestinal sclerosis, have been reported in up to 74% of JSS patients and colonic involvement presents as abdominal pain, constipation, diarrhea and bloating.131 Dyspnea from pulmonary involvement is present at diagnosis in 10% of JSS patients. Cardiac and renal sclerotic changes are usually silent except when far advanced when arrhythmias and organ failure occur. Sclerosis can also cause neuropathy and carpal tunnel syndrome.131

LABORATORY FINDINGS JUVENILE SYSTEMIC SCLEROSIS (JSS) (FORMERLY PROGRESSIVE SYSTEMIC SCLEROSIS, PSS; SCLERODERMA)

The laboratory findings in JSS are non-specific. The complete blood count and ESR are often normal.135,136 Abnormal urinary sediment, albuminuria, blood urea nitrogen (BUN) and creatinine alterations can be detected with renal involvement.131 Pulmonary function testing including carbon monoxide diffusion capacity and vital capacities should be obtained to establish baseline determinations. These tests were abnormal in two-thirds of the patients reported by Cassidy et al.124 and may be abnormal despite normal chest X-rays.131 Spirometry can be an important tool for following lung disease as well as the lung diffusion and capacity measurements and so should also be obtained at baseline. Myocardial sclerosis can produce electrocardiogram (ECG) abnormalities (i.e., conduction defects, ectopic beats, etc.).124 Radiologic examinations are of benefit in evaluating the child with JSS. Chest X-rays may reveal cardiomegaly or congestive heart failure and high resolution CT may reveal pulmonary changes earlier than chest X-ray.137 Barium swallow cine-esophagograms, small bowel series, and barium enemas should be considered in evaluating potential intestinal involvement. Approximately twothirds of patients demonstrate abnormal esophageal motility,124,138 often without symptoms. Rarely, intestinal sclerosis produces duodenal dilatation or colonic sacculations.124 Hand X-rays may demonstrate several soft tissue and bony abnormalities. Soft tissue atrophy and osteopenia of the terminal portion of phalanges are frequently seen. Digital calcification may be prominent, but flexion contractures and erosive arthro­ pathy are rare in children.138 The histologic findings in JSS involve many organs. The skin changes resemble morphea but there is generally less inflammatory infiltrate. Additionally, obliterative vessel changes in the subcutaneous tissue are more prominent; epidermal atrophy is common and calcium deposition is a late finding.139 Other organs may reveal collagen hyalinization and deposition and/or precapillary arteriolitis with subsequent luminal narrowing.

135. Kang B, Veres-Thorner C, Neredia R, et al. Successful treatment of far advanced progressive systemic sclerosis by D-penicillamine. J Allergy Clin Immunol. 1982;69:297. 136. Kornreich H, Koster K, Hanson V. The rheumatic diseases in adolescence. Pediatr Clin North Am. 1973;20:922. 137. Koh DM, Hansell DM. Computed tomography of diffuse interstitial lung disease in children. Clin Radiol. 2000;55:659. 138. Shanks MJ, Blane CE, Adler DD, et al. Radiographic findings of scleroderma in childhood. Am J Radiol. 1983;141:657. 139. Lever WF, Schaumburg-Lever G. Histopathology of the skin, ed 5. Philadelphia: JB Lippincott; 1975. 140. Tan EM. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989;44:93.

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Additional findings include intestinal arteriolitis, smooth muscle fibrosis, and obliterative disease in renal interlobular arteries.139 The pathogenic significance of vascular endothelial proliferation and intimal fibrosis with eventual luminal narrowing or obliteration in various organs in PSS is unclear at present. These findings plus collagen proliferation suggest that endothelial cells and fibroblasts are targets of pathologic significance in scleroderma.

PATHOGENESIS The pathogenesis of scleroderma is unknown. There is an accumulation of evidence to indicate that immunologic activation is involved. Deep biopsies of early sclerodermatous lesions demonstrate that mononuclear cells are prominent in the inflammatory infiltrate. The inflammatory infiltrate may be responsible via cytokine release for induction of new collagen formation and the resultant fibrosis. These cytokines, especially transforming growth factor-β (TGF-β), may also be responsible for the small vessel vasculopathy seen in these lesions. The most compelling evidence suggesting a role for immunologic mechanisms in the pathogenesis of scleroderma has been obtained from ANA studies. With the introduction of tissue culture lines as substrates for ANA (antinuclear antibody) determination, it has been found by numerous investigators that >90% of patients with systemic sclerosis demonstrate ANAs;140 80–90% of children with JSS have high titer ANAs.131,141 These ANAs are directed against various nuclear and nucleolar macromolecules. Approximately 15% of patients with PSS demonstrate antinucleolar antibodies which are directed against U3RNP (fibrillin), RNA polymerase I, and PM/ScL antigens. Approximately 20–30% of JSS patients compared with 30–40% of adults with PSS demonstrate a precipitin antibody against a basic nucleoprotein of approximately 70 kDa molecular weight termed SCL-70 (anti-topoisomerase 1).125,131,141 This antigen has been identified as a breakdown product of topoisomerase I. Also, 5–10% of patients have anti-nRNP (U1RNP) antibodies. ANA studies have determined that patients with the CREST syndrome frequently possess antibodies against the inner and outer plates of the chromosomal centromere (anticentromere antibodies) and anticentromeric antibodies are noted in 7–8% of children with JSS.131,141 Patients with anticentromere antibodies, as compared with patients with other ANAs, have a statistically significant increased duration of their disease, are almost always women and have a statistically significant increased prevalence of calcinosis. They have an absence of diffuse scleroderma, a very low prevalence of renal disease, and a statistically significant lower mortality. A genetic predisposition for PSS is seen in the association with HLA-DR11, DR5*0102, and DRB1*0802 in both Japanese and white patients.142–145 A multifactorial

141. Scalapino K, Arkachaisri T, Lucas M, et al. Childhood onset systemic sclerosis: classification, clinical and serologic features, and survival in comparison with adult onset disease. J Rheumatol. 2006;33:1004–1013. 142. Dunckley H, Jazwoniska EC, Gatenby PA, et al. DNA-DR typing shows HLA-DRw11 RFLPs are increased in frequency in PSS and CREST variants of scleroderma. Tissue Antigens. 1989;33:418. 143. Livingstone JZ, Scott TE, Wigley FM, et al. Systemic sclerosis (scleroderma), clinical genetic, and serologic subsets. J Rheumatol. 1987;14:512. 144. Gladman DD, Keystone EC, Baron M, et al. Increased frequency of HLA-DR5 in scleroderma. Arthritis Rheum. 1981;24:854. 145. Takeuchi F, Nakono K, Yamada H, et al. Association of HLA-DR with PSS in Japanese. J Rheumatol. 1994;21:857.

Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

DIFFERENTIAL DIAGNOSIS The diagnosis of JSS is usually not difficult to make clinically in the child who presents with multiple areas of sclerosis, visceral involvement and typical autoantibodies. Criteria and a classification of JSS have been established by a multinational, multicenter panel of European and American rheumatologists.131,133 The major criteria of proximal sclerosis or skin induration is required along with two of many minor criteria as outlined in the symptoms above and by Zulian131 and it includes systemic sclerosis selective autoantibodies which are anticentromere, antitopoisomerase 1, antifibrillary, anti PM-Scl, antifibrillin and antiRNA polymerase I or III. The differential diagnosis includes scleredema (of Buschke), which in children may follow a streptococcal pharyngitis and can be distinguished histologically from JSS because the thickened collagen is not hyalinized. Eosinophilic fasciitis (see below) may be confused with JSS. The entity most difficult to distinguish from JSS is mixed connective tissue disease (MCTD). This is an overlap syndrome having features of SLE, PSS, and dermatomyositis and the anti-nRNP (U1RNP) antibody. Studies of the original MCTD patients indicate that many have evolved into PSS. A few have developed classic SLE.147 The designation MCTD is employed less and less since it has been realized that the overwhelming majority of anti-nRNP (U1RNP) antibody positive patients satisfy the American College of Rheumatology criteria for the diagnosis of SLE. These patients do, however, have an increased frequency of Raynaud phenomenon, sclerodactyly, esophageal dysmotility, pulmonary disease, and a decreased frequency of renal disease. Chronic graft-versushost disease may have a sclerodermatous component as can Werner’s aging syndrome occurring in adolescence.131 Skin lesions of phenylketonuria and progeria in the young can also be confused with JSS changes.131,148

TREATMENT There is no cure for JSS. It is usually a slowly progressive disorder. General measures to forestall skin breakdown include lubrication with bland emollients, avoidance of temperature extremes to prevent thermal dysregulation, as well as ulceration from vasospasm and xerosis, and range of motion physiotherapy/splinting to prevent debilitating contractures. Arthralgias and arthritis may respond to NSAIDs or aspirin. Elevation of the head of the bed, antacids, and bethanechol

146. Furst DE, Clements PJ. Hypothesis for the pathogenesis of systemic sclerosis. J Rheumatol. 1997;48:53–57. 147. Nimelstein SH, Brody S, McShane D, et al. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine (Balt). 1980;59:239. 148. Al-Mayouf SM, Al-Owain MA. Progressive sclerodermatous skin changes in a child with phenylketonuria. Pediatr Dermatol. 2006;23:136. 149. Dabich L. Scleroderma. In: Cassidy JT, ed. Textbook of pediatric rheumatology. New York: John Wiley and Sons; 1982:433.

are helpful in treating reflux esophagitis. Acute edema, myositis and rapid pulmonary deterioration secondary to fibrosis may respond to systemic corticosteroids. Cyclophosphamide is added to corticosteroids for early-mid-stage fibrosing alveolitis. Care must be taken with dosage as high dose corticosteroids can precipitate renal crisis. Late stage alveolar fibrosis may require oxygen as well as supportive care awaiting lung transplantation. Mycophenolate mofetil can be tried in JSS.131 Renal disease may rarely result in malignant hypertension requiring captopril (angiotensin converting enzyme inhibitor) and/or hemodialysis for control. Oxygen, antibiotics, and diuretics may aid the patient with pulmonary fibrosis and congestive heart failure.149 There is no good evidence to support the effectiveness of any treatment for JSS and agents tried are those used in adults where there is limited data to show benefit.131 D-penicillamine may be effective in treating some PSS patients. Use of this drug has been rarely associated with the development of pancytopenia, glomerulonephritis, myasthenia gravis, SLE, and pemphigus. This mildly immunosuppressive antifibrotic drug, which inhibits collagen synthesis in vitro, may be tried in PSS to forestall internal involvement, lengthen survival, and decrease sclerosis. Kang et al.135 refer to two successful reports of the use of D-penicillamine in children with JSS. There is good evidence to support the use of methotrexate for the treatment of PSS in adults: it is widely used for JIA, so it can be and has been tried as an immunomodulator for JSS. It seems particularly effective with prednisone for skin induration as in localized scleroderma (morphea). Calcium channel blockers, CCBS (e.g., nifedipine and nicardipine) are effective in controlling Raynaud phenomenon associated with JSS. Prostaglandin analogs such as Iloprost can be added for disease refractory to CCBS. Autologous hematopoietic stem cell transplant to theoretically ablate self-reactive lymphocyte clones has been tried for adult disease as a treatment of last resort with a 10% mortality rate.131 It has been shown to improve skin thickening and to stabilize organ function150 and it may have a role as a treatment for JSS.151 Antifibrotic UVA-1 phototherapy may help sclerotic skin but puts children at risk of excessive UVA radiation.

JUVENILE SYSTEMIC SCLEROSIS (JSS) (FORMERLY PROGRESSIVE SYSTEMIC SCLEROSIS, PSS; SCLERODERMA)

hypothesis for the pathogenesis of PSS has been proposed.146 This hypothesis suggests that in the correct genetic background, a cycle of immune activation, endothelial cell damage with subsequent fibroblast proliferation and collagen synthesis can result in PSS.

23

PROGNOSIS Some 95% of children with scleroderma have a better prognosis than adults.152 JSS patients generally survive for years with slow progression of their visceral disease after stabilization of skin sclerosis by about 5 years.131 Young males have the worst prognosis,124 as do patients with significant cardiac, pulmonary, or renal disease. Cardiopulmonary complications such as arrhythmias from conduction fibrosis, decreased ventricular function, pulmonary fibrotic hypertension and right heart failure are the main causes of mortality in JSS.133

150. Vonk MC, Marjovic Z, van den Hoogen FH, et al. Long term follow-up results of autologous hematopoietic stem cell transplantation for severe systemic sclerosis. Ann Rheum Dis. 2008;67:98. 151. Rosenkranz MF, Agle LM, Efthimiou P, et al. Systemic and localized scleroderma in children: current and future treatment options. Pediatr Drugs. 2006;8:270. 152. Foeldivar I. Systemic sclerosis in childhood. Rheumatology. 2008; 45:iii28.

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Figure 23.6  The back of a teenage boy with eosinophilic fasciitis (Courtesy Dr A Lucky).

EOSINOPHILIC FASCIITIS

Figure 23.5  The abdomen of a teenage boy with eosinophilic fasciitis (Courtesy Dr A Lucky).

EOSINOPHILIC FASCIITIS In 1975, Shulman described a scleroderma-like syndrome characterized by diffuse fasciitis with eosinophilia: this has since been designated eosinophilic fasciitis (EF).153 This entity, although rare, has been reported in children. There is a female predisposition to the disease in childhood, as up to 75% of cases have been reported in girls.154 EF is characterized by the acute onset of swelling and induration particularly of the arms and legs associated with skin thickening.155 These cutaneous changes have rarely been associated with polyarthritis156 and can progress to significant flexion contractures. The skin lesions typically begin on the extremities with relative sparing of the face, trunk, fingers, and toes. The skin thickening (Fig. 23.5) can occasionally be distinguished by an irregular puckered pattern, often described as peau d’orange (Fig. 23.6). This can be especially prominent on the inner aspect of the upper arms. In contradistinction to PSS, the normal skin lines are preserved and Raynaud phenomenon is rare but has been described in children with EF.154 Periungual telangiectasias and digital ulcers are unusual.156 Generally, systemic manifestations are unusual. A significant number of EF patients have subsequently developed aplastic anemia. The sera of some of these patients have demonstrated the presence of humoral factors (probably antibodies) capable (in vitro) of inhibiting hemato- and myelopoiesis.157

PATHOGENESIS The etiology and exact pathogenesis of EF are unknown. Possible triggers for EF include: a history of vigorous exercise or trauma (up to 50% of adult cases), inconsistent reports of Borrelia burgdorferi positive serology, toxic exposure to aniline-denatured rapeseed oil and L-tryptophan, and other autoimmune manifestations.158

DIFFERENTIAL DIAGNOSIS

The laboratory findings typical of EF are transient peripheral eosinophilia, elevated ESR with disease activity, and hypergammaglobulinemia. Bone marrow biopsy may reveal plasmacytosis and eosinophilia.156 Recent studies have demonstrated value

The differential diagnosis of EF includes systemic sclerosis and localized scleroderma (morphea). Other scleroderma-like fibrosing skin disorders should be considered. These include graftversus-host disease (GVHD), nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), scleromyxedema, hypothyroidism (myxedema), phenylketonuria, porphyria cutanea tarda, progeroid disorders, and toxic ingestions. Toxic oil syndrome (aniline denatured grapeseed oil) occurred in epidemic proportions in Spain.159 In addition to patchy areas of cutaneous sclerosis, many of these patients developed severe muscle weakness especially of the pulmonary accessory muscles. Prolonged muscle weakness secondary to a neuropathy was associated with

153. Shulman LE. Diffuse fasciitis with eosinophilia: a new syndrome? Trans Assoc Am Physicians. 1975;88:70–86. 154. Quintero-Del-Rio AI, Punaro M, Pascual V. Faces of eosinophilic fasciitis in childhood. J Clin Rheumatol. 2002;8:99–103. 155. Bischoff L, Derk C, Eosinophilic fasciitis: demographics, disease pattern and response to treatment: report of 12 cases and review of the literature. Int J Derm. 2008;47:29–35.

156. Shulman LE. Eosinophilic fasciitis. Johns Hopkins Med J. 1981;148:81. 157. Michaels RM. Eosinophilic fasciitis complicated by Hodgkin’s disease. J Rheumatol. 1982;9:3. 158. Boin F, Hummers LK. Scleroderma-like fibrosing disorders. Rheum Dis Clin North Am. 2008;34:199–220. 159. Tabuenca JM. Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet. 1981;2:567–568.

LABORATORY FINDINGS

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with MRI detecting fascial thickening, and signal abnormalities in patients with EF.155 Skin biopsy must be full thickness to include the muscular fascia, which is characteristically thickened due to collagenous hypertrophy it contains a lymphocytic and plasmacytic infiltrate. Scattered or perivascular eosinophils may be seen in the thickened fascia. A similar, but less intense process may be seen in the subcutaneous tissue but the dermis may only exhibit a minimal cellular infiltrate. Occasionally, dermal edema is prominent when skin swelling is initially noted. The early lack of new collagen deposition in the dermis and subcutaneous tissue distinguishes EF from scleroderma histologically but late EF biopsies may be indistinguishable.

Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

BOX 23.2 CLINICAL FEATURES OF PATIENTS WITH JUVENILE DERMATOMYOSITIS

Systemic features

>> Fever: 16–65% >> Adenopathy: 20% >> Lethargy: 10%

TREATMENT

Pulmonary

In general, corticosteroids (prednisone 1–2 mg/kg per day) are commonly used as first-line treatment for EF in both adults and children, and are reportedly effective in up to 70% of adult cases. Other agents used include D-penicillamine, antihistamines (cimetidine), hydroxychloroquine, methotrexate, and mycophenolate mofetil. Physical and occupational therapy can be used to mobilize joint contractures.158 Poor prognostic signs include pediatric onset, trunk involvement, and the presence of morphea lesions.162

Gastrointestinal

JUVENILE DERMATOMYOSITIS Alfons Krol Juvenile dermatomyositis (JDM) is a rare, multisystem idiopathic inflammatory vasculopathy primarily affecting muscle and skin. The changes in small blood vessels include necrotizing vasculitis with intimal proliferation, thrombosis, and infarction. This microvascular angiopathy is the primary clinical and pathologic feature of JDM. The clinical presentation involves symmetric proximal muscle weakness, raised serum concentrations of muscle enzymes and a pathognomonic rash; a heliotrope eruption over the eyelids and Gottron’s papules over the extensor joint surfaces. The disorder is chronic, with occasional involvement of the myocardium and the gastrointestinal tract, and late emergence of calcinosis in severe cases.

INCIDENCE The incidence of JDM in North America is 3.2/million children per year, with a similar incidence in the UK.163,164 The average age of onset is 7 years but 25% of patients are younger than 4 years of age at presentation.165 The ratio of females to males is 2.3 : 1 in the USA compared with 5 : 1 in the UK.164

PRESENTING COMPLAINT The clinical features of JDM are summarized in Box 23.2.

160. Iglesias JL, DeMorazes JM. The cutaneous lesions of the Spanish toxic oil syndrome. J Am Acad Dermatol. 1983;9:159. 161. Silver RM, Heyes HP, Maize JC, et al. Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med. 1990;322:874. 162. Endo Y, Tamura A, Matsushima Y, et al. Eosinophilic fasciitis: report of two cases and a systemic review of the literature dealing with clinical variables that predict outcome. Clin Rheumatol. 2007;26:1445–1451. 163. Mendez EP, Lipton R, Ramsey-Goldman R, et al. US incidence of juvenile dermatomyositis 1995–2003;1998: results from the National Institutes of Arthritis and Musculoskeletal and Skin Diseases Registry. Arthritis Rheum 2003:49:300–305. 164. Symmons DP, Sills JA, Davis SM. The incidence of juvenile dermatomyositis: results from a nation wide study. Br J Rheumatol. 1995;34:732–736.

>> Dyspnea: 7–43% >> Dysphonia or dysphagia: 18–44% >> Gastrointestinal symptoms: 22–37% Musculoskeletal

>> Weakness: 95% >> Myalgia or arthralgias: 25–73% >> Arthritis: 25–58% >> Contractures: 26–27% >> Raynaud’s disease: 9–14%

JUVENILE DERMATOMYOSITIS

a significant mortality.160 A similar condition termed the eosinophilia myalgia syndrome occurred in the USA secondary to ingestion of adulterated L-tryptophan obtained from a single manufacturer. The manifestations of this syndrome (patches of cutaneous sclerosis, myopathy, and pulmonary insufficiency associated with a significant mortality) were reminiscent of the toxic syndrome reported from Spain.161

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Cutaneous

>> Gottron’s papules: 57–100% >> Heliotrope rash: 66–100% >> Nail fold capillary changes: 91% >> Malar or facial rash: 42–73% >> Mouth ulcers: 35% >> Skin ulceration: 23–30% >> Limb edema: 11–32% >> Calcinosis: 6–30% >> Lipodystrophy: 10–14% Modified from Feldman BM, Rider LG, Pachman LM. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet 2008;371:2201–2212.166

The characteristic eruption is usually the first sign to appear in 50% of patients, while weakness is the presenting symptom in 25%.167 Less common initial presentations include fever, dysphagia, hoarseness, dyspnea or abdominal pain. Rapid simultaneous onset of both the eruption and weakness occurs less frequently as does the amyopathic form where the eruption is not followed by any clinical or laboratory signs of muscle involvement for at least 6 months.168 Medical attention is sought for a variety of reasons. Easy fatigue, fever or weakness may prompt the initial visit but as the most common presenting complaint is rash, approximately 40% of patients present initially to a

165. Pachman LM, Lipton R, Ramsey-Goldman R et al. History of infection before the onset of juvenile dermatomyositis: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Registry. Arthritis Rheum. 2005;53:166–172. 166. Feldman BM, Rider LG, Pachman LM. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet. 2008;371:2201–2212. 167. Pachman LM, Hayford JR, Chung A, et al. Juvenile dermatomyositis at diagnosis: clinical characteristics of 79 children. J Rheumatol. 1998;25:1198–1204. 168. Gerami P, Walling HW, Lewis J. eta al. A systematic review of juvenileonset clinically amyopathic dermatomyositis. Br J Dermatol. 2007;157:637–644.

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JUVENILE DERMATOMYOSITIS

Figure 23.7  Heliotrope and facial photodermatitis of juvenile dermatomyositis (Courtesy Dr A. Torrelo).

dermatologist.169 Signs of muscle involvement include difficulty in climbing or descending stairs and inclines, rising from a chair, bed, or the floor, brushing the hair and/or raising the upper extremities and reaching. Toddlers may ask to be carried more often by parents and increased clumsiness may be noted. Muscle pain or tenderness, although a common component of the syndrome, is usually not a cause of complaint early in its course. Similarly, although dysphagia and/or nasal speech due to palatal weakness with or without esophageal dysfunction occurs fairly often, this is rarely an initial presenting complaint. Dyspnea, due to either myocarditis (with heart block) or to involvement of respiratory muscles, is often seen in the chronic stages but rarely, at the onset of the disease. When the eruption is the chief complaint, there is often a history of worsening noted after sun exposure. A recurrent, photosensitive, diffuse, itchy widespread dermatitis can often precede the myopathy by months.170 Pachman et al. summarized the clinical characteristics of 79 children with JDM. At diagnosis, all the children had rash (100%), and proximal muscle weakness (100%); 73% had muscle pain; 65% fever; 44% dysphagia; 43% hoarseness; 37% abdominal pain; 35% arthritis; 23% calcinosis; and 13% melena.167

PHYSICAL FINDINGS Skin In the majority of children, the rash is pathognomonic. It presents with findings as variable as minimal erythema over the eyelids (Fig. 23.7) and extensor surfaces of the joints to severe desquamating and ulcerating lesions over the entire body. Initially, there is edema and indurations on the face, especially the eyelids, with pink to violet (heliotrope) discoloration of the upper eyelids which is often associated with a malar rash.

169. Peloro TM, Miller FO, Hahn TF, et al. Juvenile dermatomyositis: a retrospective review of a 30-year experience. J Am Acad Dermtol. 2001;45:28–34. 170. Woo TR, Rasmussen J, Callen JP. Recurrent photosensitive dermatitis preceding juvenile dermatomyositis. Pediatr Dermatol. 1985;2:207. 171. Crowe WE, Bove KE, Levinson JE, et al. Clinical and pathogenetic implications of histopathology in childhood polydermatomyositis. Arthritis Rheum. 1982;25:126.

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Figure 23.8  Gottron’s papules and nail bed capillary telangiectasias of juvenile dermatomyositis.

Gottron’s papules appear symmetrically over the extensor surfaces of joints, especially the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) and less over distal interphalangeal (DIP) and finger joints (Fig. 23.8). The lesions are erythematous and at times scaly, atrophic and shiny, well-circumscribed papules and plaques. Violaceous scaling plaques may involve the extensor surfaces of the knees and elbows, and the trunk. Areas with extensive involvement may have subcutaneous and intradermal edema. Edema and ulceration may affect the periorbital areas and the corners of the eyes as well as the digits, and the skin folds of the axillary and inguinal regions. Extensive cutaneous ulceration is associated with a poor outcome.171 The vascular changes include telangiectasia of the upper eyelids and the cuticles of the nail beds. The periungual areas usually become erythematous. Nail fold capillaroscopy reveals capillary dilation with dropout of capillary loops (Fig. 23.9). These capillary findings are best seen with a dermatoscope, but can frequently be identified with the unaided eye or hand magnifier. The severity of nail changes correlates with chronicity of the disease. In the chronic stages, poikiloderma characterized by atrophy, telangiectasia, and hypo- and hyperpigmentation occurs (Fig. 23.10). Multifocal lipodystrophy, often preceded by panniculitis, may be seen.172,173 Mucosal ulcerations can occur throughout the gastrointestinal tract. As many as 40% of children get oral lesions that can cause dysphagia.174 Scalp involvement may be present and both scarring and non-scarring alopecia may be seen in

172. Pope E, Janson A, Khambalia A., et al. Childhood acquired lipodystrophy: A retrospective study. J Am Acad Dermatol. 2006;55:947–950. 173. Bingham A, Mammyrova G, Rother KI, et al. Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity. Medicine. 2008;87(2):70–86. 174. Hamlin C, Shelton JE. Management of oral findings in a child with an advanced case of dermatomyositis. Pediatr Dent. 1984;6:46.

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JUVENILE DERMATOMYOSITIS

Figure 23.11  Nodular calcinosis in juvenile dermatomyositis (Courtesy Dr A. Torrelo).

Figure 23.9  Nail fold dermoscopy showing telangiectasia and capillary dropout.

Figure 23.10  Poikiloderma in dermatomyositis (Courtesy Dr A. Torrelo).

Figure 23.12  Extensive exoskeleton like calcinosis in juvenile

JDM. Widespread edema and anasarca are rare presentations. Dystrophic calcification occurs in up to 30% of patients (Figs 23.11, 23.12). This finding in children is clinically different from adult onset dermatomyositis, where calcinosis occurs in fewer than 5%.175 There are rare instances of initial presentation of JDM with calcinosis, but it usually appears late in the course, typically 1–3 years and rarely up to 20 years after the onset.176 Speculation on the etiology of the calcinosis has included a provocative longterm study of 15 children with JDM, nine of whom developed calcinosis. Granulocyte chemotaxis to Staphylococcus aureus was

severely depressed in those who developed calcinosis, whereas those without calcinosis did not differ from controls. The nine children with calcinosis had higher IgE concentrations than nonatopic controls. These IgE findings antedated the calcinosis as did the occurrence of staphylococcal infections. Those without calcinosis had findings similar to controls.177 This suggests preceding immunologic differences in patients with dermatomyositis who do, compared with those who do not, develop calcinosis. Calcinosis is associated with delayed diagnosis, length of duration of untreated disease, chronicity of treated disease, and inadequate corticosteroid therapy.178,179 The sites most frequently

175. Ramanan AV, Feldman BM. Clinical features and outcomes of juvenile dermatomyositis and other childhood onset myositis syndromes. Rheum Dis Clin North Am. 2002;28:833–857. 176. Rider LG. Calcinosis in JDM: pathogenesis and current therapies. Pediatr Rheumatol Online J. 2003;1:119–133. 177. Moore EC, Cohen F. Staphylococcal infections in childhood dermatomyositis. Ann Rheum Dis. 1992;51:378.

178. Bowyer SL, Blane CE, Sullivan DB, et al. Childhood dermatomyositis: factors predicting functional outcome and development of dystrophic calcification. J Pediatr. 1983;103:882. 179. Fisler RE, Liang MG, Fuhlbrigge RC, et al. Aggressive management of juvenile dermatomyositis results in improved outcome and decreased incidence of calcinosis. J Am Acad Dermatol. 2002;47:505–511.

dermatomyositis.

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JDM is diagnosed clinically by the pathognomonic eruption and proximal muscle findings. Bohan and Peter182 described diagnostic criteria that are helpful in establishing a correct diagnosis. These include characteristic rash, symmetric weakness of proximal muscles and anterior neck flexors, elevated muscle

enzymes, and confirmation with either characteristic muscle biopsy findings and/or characteristic electromyography (EMG). Those with characteristic rash and two other criteria are considered to have probable JDM and those with rash and three others have definite JDM. EMG and muscle biopsy are not used as frequently at this time for diagnosis in the classic onset of JDM; 56% of pediatric rheumatologists surveyed used EMG, and 61% used muscle biopsy to diagnose JDM; this suggests that the accepted criteria may need to be revised.183 When a muscle biopsy is performed, it should be guided by MRI findings of inflammation: muscle involvement is often spotty and unguided biopsies may miss the sites of active inflammation. Measurement of serum muscle enzymes helps with both initial diagnosis and monitoring of therapeutic intervention. The four most useful measurements are aspartate aminotransferase (AST), creatine phosphokinase (CPK), lactic dehydrogenase (LDH), and serum aldolase. There is individual variation in the elevation of the enzymes and it is useful to monitor all four. Any or all of the enzymes may be normal early in the course of the disease or in patients with chronic disease who are being treated. Elevated neopterin and von Willebrand factor may also be markers of disease activity.184,185 EMG shows the characteristic findings of myopathy and denervation. Evidence of membrane instability and random fiber destruction is often found. Because of the invasive nature of EMG and muscle biopsy, MRI is used as an alternative sensitive method of assessing muscle inflammation. In a prevalence sample of 102 patients who had myositis (all stages of the disease) 76% had an abnormal MRI.186 The authors demonstrated similar usefulness of the technique in assessing the upper legs and lower pelvis of four other children.187 They noted that the T2-weighted images are related to accumulated extracellular water and that the abnormalities would exist in any inflammatory or infectious myopathy and in rhabdomyolysis. This differs from the fatty replacement of muscles seen in toxic myopathies and muscular dystrophies. MRI may also be employed to choose the site for muscle biopsy and used to follow the course of JDM from the onset of the disease through resolution of a primary relapse. The signal intensity of the T2-weighted image of involved muscles is elevated during periods of disease activity and returns to normal levels with effective suppression of the disease. T1-weighted images remain normal, despite disease activity.188 Muscle biopsy is useful if the skin changes are absent or atypical and muscle enzyme levels are not clearly abnormal. It provides histologic reassurance that another type of myopathy is not the cause of the problem. Standard scoring systems for muscle biopsy have

180. Pachman LM, Liotta-Davis MR, Hong DK, et al. TNFα-308A allele in juvenile dermatomyositis: association with an increased production of tumor necrosis factor α, disease duration, and pathologic calcifications. Arthritis Rheum. 2000;43:2368–2377. 181. Pachman LM, Veis A, Stock S, et al. Composition of calcifications in children with juvenile dermatomyositis: association with chronic cutaneous inflammation. Arthritis Rheum. 2006;54:3345–3350. 182. Bohan A, Peter JB. Polymyositis and dermatomyositis. N Engl J Med. 1975;292:344. 183. Brown VE, Pilkington CA, Feldman BM, et al. Network for juvenile dermatomyositis PRES. An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM). Rheumatology. 2006;45:990–993.

184. Bloom BJ, Tucker LBL, Miller LC, et al. von Willebrand factor in juvenile dermatomyositis. J Rheumatol. 1995;22:230. 185. Pachman LM. An update on juvenile dermatomyositis. Curr Opin Rheumatol. 1995;7:437. 186. McCann LJ, Juggins AD, Maillard SM, et al. The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland): clinical characteristics of children recruited within the first 5 years. Rheumatology. 2006; 1255–1260. 187. Hernandez RJ, Keim DR, Sullivan DB, et al. Magnetic resonance imaging appearance of muscles in childhood dermatomyositis. J Pediatr. 1990; 117:546. 188. Keim DR, Hernandez RJ, Sullivan DB. Serial magnetic resonance imaging in juvenile dermatomyositis. Arthritis Rheum. 1991;34:1580.

affected are pressure points on elbows, knees, digits, and buttocks. Four subtypes have been described: cutaneous or subcutaneous plaques or nodules, deposits that extend into muscles, calcinosis along fascial planes that may lead to contractures, and a widespread calcium exoskeleton. Calcinosis may eventually lead to skin ulceration with erythema, tenderness and drainage that must be distinguished from cellulitis and functional disability from joint contractures and pain due to nerve entrapment. Patients with calcinosis have increased local production of tumor necrosis factor alpha (TNFα) and there is an increased association with the TNFα-308 polymorphism, resulting in increased intensity of inflammation.180 The calcified areas contain hydroxyapatite but true bone does not occur.181 JUVENILE DERMATOMYOSITIS

Muscles and arteries There is early muscle involvement of the proximal limb groups and anterior neck flexors with weakness of limb girdle function and impaired walking, rising, squatting, and reaching. Gower’s sign may be present in severe cases, where on rising from the floor, the child rolls to the prone position, kneels, then pushes the hands against the shins, knees, and then the thighs to assist achievement of a standing position. Neck, trunk, paraspinal, and abdominal muscles are also involved but do not impinge on functional disability except in advanced cases. Pain is moderate and is usually described as stiffness or tenderness. Other sites of involvement of striated muscle include palatal, pharyngeal, or hypopharyngeal groups that can cause nasal speech, dysphonia, choking, aspiration, dysphagia, and drooling. Dysphagia can also be a sign of upper esophageal involvement. Distal extremity weakness is a late phenomenon and may be very severe. Respiratory muscle involvement can cause restrictive pulmonary disease in the more severe chronic cases. Arteritis can involve the myocardium with heart block, the pericardium with pericarditis and the gastrointestinal tract with mucosal ulceration. The retina with small vessel occlusion causing cytoid bodies can also be involved, and, rarely, the kidneys with glomerular cellular proliferation and microscopic hematuria that does not progress to insufficiency.

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ETIOLOGY AND PATHOGENESIS Various infectious agents have been proposed as the etiological agent in JDM. In a review, most children with JDM had antecedent upper respiratory or gastrointestinal illnesses in the 3 months prior to onset.193 Group A beta hemolytic streptococcus (GABHS) has been implicated due to molecular mimicry between GABHS and the myosin heavy chain.194 Other agents that have been inconsistently associated with disease onset include toxoplasmosis, coxsackie B, enterovirus and parvovirus B19; however examination with case control studies and PCR testing of blood or diseased muscle failed to show any differences from controls.195–198 Specific HLA alleles including B8, DRB1*0301,DQA1*0501 and DQA1*0301 are more common in JDM.199 Polymorphisms of cytokines including TNFα-308A and the IL-1 receptor antagonist are also increased risk factors in Caucasian patients. In Hispanic patients the HLA-DRB1*0301, as well as those with anti-p155 (myositis associated autoantibody) have seasonal

189. Wedderburn LR, Varsani H, Li CKC, et al. International consensus on a proposed score system for muscle biopsy evaluation in patients with JDM, for potential use in clinical trials. Arthritis Rheum. 2007;57:1192–1201. 190. Banker BQ, Victor M. Dermatomyositis (systemic angiopathy) of childhood. Medicine. 1966;45:261. 191. Smith RL, Sundberg J, Shamiyah E, et al. Skin involvement in juvenile dermatomyositis is associated with loss of end row nail fold capillary loops. J Rheumatol. 2004;31:1644–1649. 192. Ingegnoli F, Zeni S, Gerloni V, et al. Capillaroscopic observations in childhood rheumatic diseases and healthy controls. Clin Exp Rheumatol. 2005;23:905–911. 193. Pachman LM, Lipton R, Ramsey-Goldman R, et al. History of infection before the onset of juvenile dermatomyositis: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Research registry. Arthritis Rheum. 2005;53:166–172. 194. Massa M, Costouros N, Mazzoli F, et al. Self epitopes shared between human skeletal myosin and Streptococcus pyogenes M5 protein are targets of immune responses in active juvenile dermatomyositis. Arthritis Rheum. 2002;46:3015–3025. 195. Christensen ML, Pachman LM, Schneiderman R, et al. Prevalence of Coxsackie B virus antibodies in patients with dermatomyositis. Arthritis Rheum. 1986;29:1265. 196. Magid SK, Kagen LJ. Serologic evidence for acute toxoplasmosis in polymyositis-dermatomyositis. Am J Med. 1983;75:313. 197. Mamyrova G, Rider LG, Haagenson L, et al. Parvovirus B19 and onset of juvenile dermatomyositis. JAMA. 2005;294:2170–2171. 198. Pachman LM, Litt DL, Rowley AH, et al. Lack of detection of enteroviral RNA or bacterial DNA in MRI imaging directed muscle biopsies from twenty children with active untreated juvenile dermatomyositis. Arthritis Rheum. 1995;38:1513–1518. 199. Mamyrova G, O’Hanlon TP, Monroe JB, et al. Immunogenetic risk and protective factors for juvenile dermatomyositis in Caucasians. Arthritis Rheum. 2006;54:3979–3987.

birth distributions suggesting exposures early in life may contribute to onset of the illness.200 JDM is a vasculopathy.190 Muscle changes include capillary endothelial swelling resulting in obliteration of the lumen, perifascicular atrophy, perivascular inflammation and various degrees of muscle degeneration and regeneration.189 Humoral, cellular and innate immunity contribute to the pathogenesis of JDM. Perivascular and perifascicular inflammatory cells accumulate including CD4+ T cells and B lymphocytes which produce immunoglobin. Complement is deposited in the vessels of the muscle and areas of the affected skin.201–203 Myocytes increase expression of MHC (major histocompatibility) Class I and II molecules. The role of type 1 interferons in JDM has been emphasized.204 Genes regulated by type 1 interferons mediate immunoregulation, and expression profiles from untreated patients have shown that many of the upregulated genes are associated with immune responses; most of these genes were inducible by type 1 interferons.205 The effects of type 1 interferon upregulation include upregulation of MHC class I, activating cytotoxic effects of natural killer cells, thus promoting activated T-cell survival and supporting dendritic cell maturation. Chemokine interferon-inducible protein 10 (IP-10 or CXCL10) and monocyte chemoattractant protein (MCP-1 or CCL2, MCP-2 or CCl8) correlate with disease activity.204 MxA (myxovirus resistance protein) is a muscle associated type-1 interferon inducible protein which may be a biomarker for myositis.206 It is speculated that type 1 interferons induce inappropriate expression of MHC class I molecules in affected myofibers that leads to direct injury of myocytes through hypoxic stress to the endoplasmic reticulum.207 Additional effects of cytokines and interleukins, including IL-15, and effects of upregulating cellular and vascular adhesion molecules ICAM-1 and VCAM-1 contribute to the ongoing inflammatory process in vessels and myocytes.208,209

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been shown to be reliable.189 A biopsy can provide useful prognostic information.171,190 It is customary to perform open biopsies but needle biopsy may be useful in attempts at sequential monitoring. The typical findings show evidence of vasculitis, inflammatory cell infiltrates, and focal necrosis and phagocytosis of muscle fibers, as well as evidence of regeneration with basophilia, endomysial proliferation, random fiber atrophy, and perifascicular atrophy. Nail fold capillaroscopy is highly sensitive in the diagnosis of JDM. Patients show abnormally dilated loops with reduced capillary density (dropout).191,192 The histology of the skin lesions is non-diagnostic. The pathologic features are similar to the findings in lupus erythematosus.

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200. Vegosen LJ, Weinberg CR, O’Hanlon TP, et al. Seasonal birth patterns in myositis subgroups suggest an etiologic role of early environmental exposures. Arthritis Rheum. 2007;56:2719–2728. 201. Scott JP, Arroyave C. Activation of complement and coagulation in juvenile dermatomyositis. Arthritis Rheum. 1986;30:572. 202. Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med. 1986;314:329. 203. Kissel JT, Halterman RK, Rammohan KW, et al. Relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis. Arch Neurol. 1991; 48:26. 204. Baechler EC, Bauer JW, Slattery CA, et al. An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity. Mol Med. 2007;13:59–68. 205. Tezak Z, Hoffman EP, Lutz Jl, et al. Gene expression profiling in DQA1*0501 children with untreated dermatomyositis: a novel model of pathogenesis. J Immunol. 2002;168:4154–4163. 206. O’Connor KA, Abbott KA, Sabin B, et al. MxA gene expression in juvenile dermatomyositis peripheral blood mononuclear cells: association with muscle involvement. Clin Immunol. 2006;120:319–325. 207. Nagaraju K, Casciola-Rosen L, Lundberg I, et al. Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fibre damage and dysfunction. Arthritis Rheum. 2005;52: 1824–1835. 208. Sallum AME, Kiss MHB, Silva CAA, et al. Difference in adhesion molecule expression (ICAM-1 and VCAM-1) in juvenile and adult dermatomyositis, polymyositis and inclusion body myositis. Autoimmun Rev. 2006;5: 93–100. 209. Caproni M, Torchia D, Cardinali C, et al. Infiltrating cells, related cytokines and chemokine receptors in lesional skin of patients with dermatomyositis. Br J Dermatol. 2004;151:784–791.

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Maternal microchimerism may contribute to autoimmunity and has been reported in 80–100% of muscle tissue samples from patients with JDM.210 Despite many advances, the initiating event as well as the role of dendritic cells and of the interferon-α response in JDM has not yet been completely elucidated.166 Specific autoantibodies have been commonly detected in adult patients with polymyositis/dermatomyositis.211,212 The myositis-specific antibodies define homogeneous subsets of adult patients.213 The most common of these antibodies are directed against aminoacyl-tRNA synthetases. Anti-Jo-1 (antihistidyl-tRNA synthetase) is the most common antisynthetase antibody, occurring in 15–20% of adult polymyositis/dermatomyositis patients (see below). The clinical picture associated with antisynthetase antibodies is characterized by a myositis more resistant to therapy, a high frequency of interstitial lung disease (50–70%), arthritis (>90%), and Raynaud phenomenon (approximately 60%). Skin lesions in these patients may have a striking eruption on the hands, ‘mechanic’s hand,’ characterized by hyperkeratosis with hyperpigmentation and fissuring along the sides of the fingers appearing as dirty horizontal lines.214 Another antibody commonly detected in myositis patients, anti-PM/Scl, is directed against non-RNA containing proteins (predominantly 100 kD and 75 kD) residing in the nucleolus. Most of the patients in whom this antibody has been described have been adults with HLA–DB1*0301, and associated scleroderma-myositis overlap syndrome with a high frequency of interstitial lung disease; this antibody has also been detected in children.215 Anti-Mi-2 antibodies have been detected in dermatomyositis patients, including JDM. The antibody is directed against a complex of non-nucleic acid containing five nuclear proteins.211,216 Children with anti-Mi-2 have mild disease, which is readily controlled by corticosteroids. This antibody is seen in 5% of JDM. A new myositis associated autoantibody (MAA anti-p155) is seen in up to 30% of JDM patients, 20% of adult dermatomyositis patients, and as an anti-p155 and p-140 heterodimer in most patients studied with cancer associated dermatomyositis.217 Malignancies, including lymphoma, solid tumors and leukemia, have been reported in association with JDM with atypical features.218,219 These instances are so infrequent in children

210. Reed AM, McNallan K, Wettstein P, et al. Does HLA dependent chimerism underlie the pathogenesis of juvenile dermatomyositis? J Immunol. 2004;172:5041–5046. 211. Targoff I. Humoral immunity in polymyositis/dermatomyositis. J Invest Dermatol. 1993;100:116S. 212. Reichlin M, Arnett FC. Multiplicity of antibodies in myositis sera. Arthritis. Rheum. 1984;27:1150. 213. Love LA. A new approach to the classification of idiopathic inflammatory myopathy: myositis specific autoantibodies define useful homogeneous patient groups. Medicine. 1991;70:360. 214. Stahl NI. A cutaneous lesion associated with myositis. Ann Intern Med. 1979;91:577. 215. Blaszczyk M. Childhood scleromyositis: an overlap syndrome associated with PM/Scl antibodies. Pediatr Dermatol. 1991;8:1. 216. Targoff I, Reichlin M. The association between Mi-2 antibodies and dermatomyositis. Arthritis Rheum. 1985;28:796. 217. Kaji K, Fujimoto M, Hasegawa M, et al. Identification of a novel autoantibody reactive with 155 and 140 kDa nuclear proteins in patients with dermatomyositis: an association with malignancy. Rheumatology. 2007;46:25–28. 218. Falcini F, Taccetti G, Trapani S, et al. Acute lymphocytic leukemia with dermatomyositis-like onset in childhood. J Rheumatol. 1993;20(7):1260.

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that an assessment for occult malignancy is not routinely performed.

PROGNOSIS The combination of the characteristic skin rash, proximal muscle weakness and elevated muscle enzymes usually poses no diagnostic problem. Other diagnoses include post-infectious myositis (e.g., influenza A and B, coxsackievirus B, enterovirus, parvovirus, hepatitis B, HTLV-1, trichinosis, Lyme borreliosis and toxoplasmosis), inflammatory myopathy associated with other collagen vascular disorder, and the large group of congenital myopathies.220,221 The post-viral myositis disorders usually persist for 3–5 days and do not have the accompanying characteristic rash.193 The myopathy associated with Trichinella spiralis infestation is related to the presence of the larval cysts of the nematode in the affected muscle. It involves muscles of the face, neck, and chest and is usually accompanied by significant peripheral blood eosinophilia.222 The malar rash of dermatomyositis often resembles the SLE ‘butterfly rash’ but lacks the well-defined borders and extension to the forehead. Children with scleroderma do not have the typical Gottron’s patches over extensor surfaces of elbows, knees, and knuckles. Children with myositis associated SLE rarely have the significant elevation of muscle enzymes seen in dermatomyositis. When there is no rash, severe hypothyroidism, drug induced myositis, and a broad variety of neuromuscular diseases require consideration. Family history, age at onset, site of muscle involvement, and type of onset should aid in differentiating these diseases.223

TREATMENT JDM remains a serious disease despite many therapeutic advances. Prior to the widespread use of corticosteroids, approximately one-third of the children died, usually of a perforated viscus or aspiration pneumonia;224 one-third had a progressive course, marked by contractures, calcinosis and persistent weakness225 and many had chronic active disease which continued into adulthood.226 The disease has two identifiable clinical courses: unicyclic (with permanent remission in 2–3 years) and

219. Rider LG, Miller FW. Classification and treatment of the juvenile idiopathic inflammatory myopathies. Rheum Dis Clin North Am. 1997;23: 619–655. 220. Nirmalananthan N, Holton JL Hanna MG, et al. Is it really myositis? A consideration of the differential diagnosis. Curr Opin Rheumatol. 2004;16:684–691. 221. Compeyrot-Lacassangne S, Feldman BM. Inflammatory myopathies in children. Pediatr Clin North Am. 2005;52:493–520. 222. Baker JP, Goldstein M. Myositis (post-influenza, Coxsackie virus, Trichinella spiralis). In: Feigin RD, Cherry JD, eds. Textbook of pediatric infectious diseases, ed 2. Philadelphia: WB Saunders; 1987:783. 223. Dubowitz V. Muscle disorders in childhood. Philadelphia: WB Saunders; 1978. 224. Bitnum S, Daeschner CW Jr, Travis LB, et al. Dermatomyositis. J Pediatr. 1964;64:101. 225. Sullivan DB, Cassidy JT, Petty RE. Dermatomyositis in the pediatric patient. Arthritis and Rheum. 1977;20:S327–S331. 226. Chalmers A, Sayson R, Walters K. Juvenile dermatomyositis: medical, social and economic status in adulthood. Can Med Assoc J. 1982;126: 31–33.

non-unicyclic/polycyclic (periods of remission followed by relapses or chronic continuous disease).227 Delayed or inadequate treatment with corticosteroids is the most important predictor of poor outcome and a chronic course. The standard treatment for JDM has been high dose daily oral corticosteroids usually beginning at 2 mg/kg per day of prednisone in divided doses. This dose is continued until clinical and laboratory improvement occurs and is then slowly reduced over a 2-year period. The rationale for this approach is based on lessening the incidence or severity of calcinosis in treated patients. In order to reduce the incidence of steroid side-effects many patients are now treated by alternate routes including pulse steroids or with the early addition of immunosuppressive medications as steroid sparing agents.228–230 The rationale for pulse steroid therapy is that some patients with JDM absorb oral steroids poorly, possibly secondary to gut vasculopathy.231 Methotrexate improves strength and reduces signs of disease activity in steroid resistant patients and has a steroid sparing effect.232–235 The usual dose age of methotrexate is 15 mg/m2 once weekly orally or subcutaneously. Patients given methotrexate at disease onset had half the cumulative steroid dose, less steroid induced side-effects and achieved the same disease control compared to a group receiving steroids alone.236 Metho­ trexate is now widely used by pediatric rheumatologists at the start of treatment as a steroid sparing agent.166 Cyclosporin A may be used as a steroid sparing agent and has been reported to be effective at doses of 5–8 mg/kg per day but

no comparative trials have been published.237–240 Significant sideeffects of cyclosporin in children are hypertension and hirsutism. Intravenous immunoglobulin was initially shown to be efficacious in adult dermatomyositis and is now widely used in JDM particularly for steroid resistant or steroid dependent disease, especially persistent skin disease.241–243 IVIG is administered at a dose of 2 g/kg usually at monthly intervals. Other medications used for refractory disease include hydroxychloroquine, azathioprine, oral tacrolimus, mycophenolate mofetil, and cyclophosphamide. All these drugs may show benefit in individual patients.244–249 Although anti-TNF blocking biologic agents are commonly used to treat other rheumatic diseases in children, there are no reports of their use in JDM but use in adult dermatomyositis has shown mixed results.250,251 The B-cell depleting biologic agent rituximab has been associated with remissions in a small case series,252 and randomized trials of this agent in JDM are underway. Treatment of calcinosis is challenging. Spontaneous regression either through resorption or extrusion may occur. Excision or incision and drainage may be used for localized lesions.253 For larger areas of involvement or diffuse lesions along fascial planes particularly when associated with contraction or ulceration, drugs that include diltiazem,254 probenecid,255 aluminum hydroxide,256 coumadin,257 alendronate,258 and colchicine259 have been reported in single case reports or small series. Sodium thiosulfate given intravenously has had good success in treating

227. Constantin T, Ponyi A, Orban I, et al. National registry of patients with juvenile idiopathic inflammatory myopathies in Hungary: clinical characteristics and disease course of 44 patients with juvenile dermatomyositis. Autoimmunity. 2006;39:223–232. 228. Miller JJ III. Prolonged use of large intravenous steroid pulses in the rheumatic diseases of children. Pediatrics. 1980;65:989. 229. Laxer RM, Stein LD, Petty RE. Intravenous pulse methylprednisolone treatment of juvenile dermatomyositis. Arthritis Rheum. 1987;30:328. 230. Pachman LM, Callen AM, Hayford J, et al. Juvenile dermatomyositis: Decreased calcinosis with intermittent high-dose intravenous methylprednisolone therapy. Arthritis Rheum. 1994;37:S429. 231. Rouster-Stevens KA, Gursahaney A, Ngai K-L, et al. Pharmacokinetic study of oral prednisolone compared with intravenous methyl prednisolone in patients with juvenile dermatomyositis. Arthritis Rheum. 2008;58:222–226. 232. Malyaviya AN. Treatment of dermatomyositis with methotrexate. Lancet. 1968;2:485. 233. Fischer TJ. Childhood dermatomyositis and polymyositis: treatment with methotrexate and prednisone. Am J Dis Child. 1979;133:386. 234. Miller LC. Methotrexate treatment of recalcitrant childhood dermatomyositis. Arthritis Rheum. 1992;35:1143. 235. Al Mayouf S, Al-Mazyed A, Bahabri S. Efficacy of early treatment of severe juvenile dermatomyositis with intravenous methylprednisone and methotrexate. Clin Rheumatol. 2000;19:138–141. 236. Ramanan AV, Campbell-Webster N, Ota S, et al. The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. Arthritis Rheum. 2005;52:3570–3578. 237. Heckmatt J. Effectiveness of cyclosporin for dermatomyositis. Lancet. 1989;1:1063. 238. Dantzig P. Juvenile dermatomyositis treated with cyclosporine. J Am Acad Dermatol. 1990;22:310. 239. Giardin E. Cyclosporine for juvenile dermatomyositis. J Pediatr. 1988;112:165. 240. Reiff A, Rawlings DJ, Shaham B, et al. Preliminary evidence for cyclosporine A as an alternative in the treatment of recalcitrant juvenile rheumatoid arthritis and juvenile dermatomyositis. J Rheumatol. 1997;24(12):2436. 241. Lang BA, Laxer RM. Treatment of dermatomyositis with intravenous gamma globulin. Am J Med. 1991;91:189. 242. Dalakas MC, Illa I, Dambrosia JM, et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment of dermatomyositis. N Engl J Med. 1993;329:1993. 243. Roifman CM. Use of intravenous immune globulin in the therapy of children with rheumatological diseases. J Clin Immunol. 1995;15(6):42S.

244. Woo TY, Callen JP, Voorhees JJ, et al. Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine. J Am Acad Dermatol. 1984;10:592. 245. Olson NY, Lindsley CB. Adjunctive use of hydroxychloroquine in childhood dermatomyositis. J Rheumatol. 1988;16:1545. 246. Jacobs JC. Methotrexate and azathioprine treatment of childhood dermatomyositis. Pediatrics. 1977;59:212. 247. Nalda AM, Caballero CM, Guimeral CA, et al. Efficacy of tacrolimus (FK-506) in the treatment of recalcitrant juvenile dermatomyositis: study of six cases. Med Clin. 2006;126:697–701. 248. Edge JC, Outland JD, Dempsey JR, et al. Mycophenolate mofetil as an effective corticosteroid-sparing therapy for recalcitrant dermatomyositis. Arch Dermatol. 2006;142:65–69. 249. Riley P, Maillard SM, Wedderburn LR, et al. Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety. Rheumatology. 2004;43:491–496. 250. Efthimiou P Schwartzman S, Kagen LJ. Possible role for tumor necrosis factor inhibitors in the treatment of resistant dermatomyositis and polymyositis: a retrospective study of eight patients. Ann Rheum Dis. 2006;65:1223–1226. 251. Iannone F, Scioscia C, Falappone PC, et al. Use of etanercept in the treatment of dermatomyositis: a case series. J Rheumatol. 2006;33:1802–1904. 252. Cooper MA, Willingham DI, Brown DE, et al. Rituximab for the treatment of juvenile dermatomyositis: a report of four pediatric patients. Arthritis Rheum. 2007;56:3107–3111. 253. Wu JJ, Metz BJ. Calcinosis cutis of juvenile dermatomyositis treated with incision and drainage. Dermatol Surg. 2008;34:575–577. 254. Ichiki Y, Akiyama T, Shimozawa N, et al. An extremely severe case of cutaneous calcinosis with juvenile dermatomyositis, and sucessful treatment with diltiazem. Br J Dermatol. 2001;144:894–897. 255. Nakamura H, Kawakami A, Ida H, et al. Efficacy of probenecid for a patient with juvenile dermatomyositis complicated with calcinosis. J Rheumatol. 2006;33:1691–1693. 256. Nakagawa T, Takaiwa T. Calcinosis cutis in juveile dermatomyositis responsive to aluminum hydroxide treatment. J Dermatol. 1993;20:558–560. 257. Matsuoka Y, Miyajima S, Okada N. A case of calcinosis universalis successfully treated with low dose warfarin. J Dermatol. 1998;25:716–720. 258. Ambler GR, Chaitow J, Rogers M, et al. Rapid improvement of calcinosis in juvenile dermatomyositis with alendronate therapy. J Rheumatol. 2005;32:1837–1839. 259. Fuchs D, Fruchter L, Fishel B, et al. Colchicine suppression of local inflammation due to calcinosis in dermatomyositis and progressive systemic sclerosis. Clin Rheumatol. 1986;5:527–530.

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calciphylaxis260 associated with renal disease; a report showed efficacy of topical sodium thiosulfate in treating leg ulcers with associated dystrophic calcification.261 Although there are no reports of its use in calcinosis associated with JDM this agent may become a useful option in treating severe calcinosis. Cutaneous lesions usually improve once oral steroid/ immunosuppressive therapy has been started. Topical steroids and topical immunomodulators such as tacrolimus may offer some benefit for the cutaneous changes but used alone their effect is inconsistent. Parents and the patient should be made aware of the importance of photoprotection: wearing appro­ priate photoprotective clothing and use of broad spectrum sunscreens. Physiotherapy and exercise during rehabilitation are important to prevent contractures and improve muscle function. Calcium and vitamin D supplements may be given to improve bone density. The mortality of JDM has been reduced to > Photosensitivity >> Periungual telangiectasia >> Hypo- and/or hyperpigmentation >> Heliotrope eyelid rash >> Sclerodactyly/sclerosis >> Alopecia Musculoskeletal

>> Arthralgia/arthritis >> Proximal muscle weakness >> Raynaud phenomenon Gastrointestinal

>> Abnormal esophageal motility Pulmonary

>> Abnormal pulmonary function tests >> Pulmonary fibrosis Cardiac

>> Pericarditis/myocarditis >> Aortic insufficiency >> Congestive heart failure

The majority of patients are females over 50 years of age. Females also outnumber males 3 to 1 in reported childhood cases.268,269 The mean age at diagnosis in the pediatric population is 11 years.268,269 Symptoms have occurred in patients as young as 30 months.269 The usual complaints are of excessive water ingestion, lack of saliva, decreased tearing and irritated eyes. Occasionally, recurrent parotid swelling is a feature and is more characteristic of the disorder in childhood than in adults.270,271 This may be due to the fact that salivary glands are less damaged in children with SS than in adults who have it.270 Physical examination reveals a relatively dry oral mucosa with minimal saliva production, conjunctival injection, decreased tearing, and perhaps, parotid enlargement. The spectrum of physical findings in patients with SS can expand to numerous extraglandular inflammatory manifestations; in the kidneys, lungs, pancreas, central nervous system, joints and skin,271 such as arthritis and cutaneous vasculitis. Cutaneous vasculitis manifestations such as palpable purpura of the lower extremities and urticarial vasculitis are found in 25% of adult primary SS patients. Whether or not such a strong relationship exists in primary SS and cutaneous vasculitis in childhood is unknown. In a large study including children a subset of patients with adverse predictors for mortality emerged with purpuric findings. These are decreased C4 complement levels and mixed cryoglobulinemia at initial presentation.272 Without these adverse prognostic factors the overall prognosis is same as that of the general population.

SJÖGREN SYNDROME

BOX 23.4 FINDINGS IN MIXED CONNECTIVE TISSUE DISEASE (MCTD)

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Renal

>> Glomerulonephritis

LABORATORY FINDINGS

Neurologic

Sjögren syndrome (SS) is a symptom complex of dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca) resulting from a chronic lymphocytic and plasma cell infiltration of the salivary and lacrimal glands. It may be a primary process or secondary, as found in association with such autoimmune diseases as lupus erythematosus, progressive systemic sclerosis, and rheumatoid arthritis.

Minor salivary gland biopsy from the lip demonstrates a lymphocytic and plasma cell infiltrate. Parotid gland biopsy may be more sensitive273 but is more risky due to possible facial nerve injury. Eye findings can be evaluated by tear break-up time, the Schirmer’s test, and Rose Bengal dye staining of the cornea and conjunctiva.269 Chudwin et  al. reported a positive ANA in six of eight children with SS,269 whereas Bernstein et  al. noted a negative ANA in all four of their patients with SS268 but according to Singer et  al.273 80% of reported cases of childhood SS since 1988 are ANA positive. Rheumatoid factor (RF) is found in approximately 90% of adult SS patients.274 Chudwin et  al.269 found a significant RF titer in five of eight SS patients but Bernstein et  al.268 failed to demonstrate RF activity in their four SS patients. Five of the seven patients reported by Singer et  al. had elevated RF levels and these authors propose that this finding be considered as a scoring factor in the diagnosis of SS.275 Unfortunately, criteria such as the American-European criteria for adults273 have not been agreed upon for children with SS who may fulfill as many as three of the six, which

268. Berstein B, Koster-King K, Singsen B, et al. Sjögren’s syndrome in childhood. Arthritis Rheum. 1977;20:361. 269. Chudwin DS, Daniels TE, Wara DW, et al. Spectrum of Sjögren’s syndrome in children. J Pediatr. 1981;98:213. 270. Cimaz R, Casadei A, Rose C etal. Primary Sjögren syndrome in the pediatric age: a multicentre survey. Eur J Pediatr. 2003;162(10):661. 271. Civilibal M, Canpolat N, Yurt A, et al. A child with primary Sjögren’s syndrome and a review of the literature. Clin Pediatr Oct. 2007;46(8): 738.

272. Skopouli FN, Dafni U, Ioannidis JP, et al. Clinical evolution and morbidity and mortality of primary Sjögren’s syndrome. Semin Arthritis Rheum. 2000;29(5):296. 273. Singer NG, Tomonova-Soltys J, Lowe R. Sjögren’s syndrome in childhood. Curr Rheumatol Rep. 2008;10(2):147. 274. Bloch KJ, Buchanan WW, Wohl MJ, et al. Sjögren’s syndrome. A clinical, pathological and serological study of sixty-two cases. Medicine. 1965;44:187. 275. Pessler F, Emery H, Dai L, et al. The spectrum of renal tubular acidosis in paediatric Sjögren syndrome. Rheumatology. 2006;45(1):85.

>> Seizures >> Headache >> Peripheral neuropathy to treat Raynaud’s phenomenon. Hydroxychloroquine is commonly used to treat the cutaneous manifestations.

SJÖGREN SYNDROME Nancy K. Barnett

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JUVENILE IDIOPATHIC ARTHRITIS (JIA)

are: (1) one of three ocular symptoms; (2) one of three oral symptoms; (3) ocular signs; (4) one of three oral signs (abnormal salivary scintigraphy, abnormal parotid scintigraphy or abnormal sialometry); (5) positive lip biopsy; and (6) positive SS A (Ro) or SS B (La) antibody. The disease is rare and case series are just beginning to accumulate to give data on childhood Sjögren’s patient manifestations, treatment and follow-up.270,273 The ESR may be elevated. Hypergammaglobulinemia, leukopenia, thrombocytopenia, and anemia have all been found in patients. Hypokalemia may indicate renal tubular acidosis due to renal SS.275 Serum should be examined for the presence of Ro(Sjögren syndrome-A or SSA) antibody, which is found in approximately 45% of adult Sjögren syndrome patients.276 La antibody, which is identical to SS-B (Sjögren syndrome-B) antibody, should also be sought. The La(SS-B) antibody is found in a variable number of SS patients. Approximately 50–60% of those with Ro antibody276 also have La(SS-B) antibodies; 80% of childhood SS patients have Ro or La antibody.273 Ro-positive SS patients may be at risk of developing more extraglandular features than Ronegative patients. Anti-fodrin antibodies to cytoskeletal protein, a potential pathogenic target in adult SS, has been detected in 15 of 15 children with primary or secondary SS and may be a diagnostic marker of the disease.273,277 Analysis of sera of patients with primary SS, including adolescents, revealed 12.6% with anti-CD4 antibodies.278 The significance of this finding is unknown and did not correlate with CD4 and T lymphocyte depletion but the authors suggest that as in HIV, these anti-CD4 antibodies lend support to a possible viral role in SS. Magnetic resonance imaging (MRI) of enlarged parotid glands has been reported as characteristic in patients with the sicca syndrome and hyperlipidemia.279 MR sialography can also be used in children and Tomiita et al.280 advocate it over traditional X-ray sialography as a primary tool, since it is less painful; it may be less sensitive for early gland changes. In experienced hands, salivary gland ultrasonography and scintigraphy can also be useful diagnostic tools.

TREATMENT Treatment for SS is presently symptomatic. Numerous water rinses alleviate xerostomia and the use of sour, sugarless hard candies induces saliva formation.269 The frequent application of artificial tears prevents ulcerations and scarring seen in keratoconjunctivitis sicca. A persistent conjunctivitis should suggest secondary infection in these individuals and requires a culture with subsequent use of topical or systemic antibiotics. Dental cavities are frequent and are caused by the decrease in salivation. This, as well as early tooth decay, was recently confirmed in a large study of SS in childhood.281 Dental health must be monitored regularly. MR sialography should be considered for monitoring the status of parotid gland changes.280 Topical fluoride treatments may help to prevent cavities. Systemic steroids should be considered to treat extraglandular manifestations of SS, such as vasculitis, arthritis, or associated autoimmune diseases. Methotrexate, hydroxychloroquine, IVIG and non-steroidal antiinflammatory drugs, cyclosporin, cyclophosphamide and anti-TNF agents have all been tried for control of symptoms with or without steroids but there is no single agreed upon treatment regimen for childhood SS with extraglandular manifestations.270,271,273

JUVENILE IDIOPATHIC ARTHRITIS (JIA)

SS has been reported in children with hypergammaglobulinemia, autoimmune hematologic abnormalities, juvenile rheumatoid arthritis (JRA), scleroderma, MCTD, lupus erythematosus, and dermatomyositis.268,269 It needs to be distinguished from juvenile recurrent parotitis, HIV-associated diffuse infiltrative lymphocytosis, other bacterial and viral infectious parotitis immunodeficiencies with parotitis, sialadenosis and infiltrative sarcoid or lymphoma,271 as well as idiopathic xerostomia and salivary gland disorders, which also produce dry mouth (i.e.,

Juvenile arthritis is one of the most frequent chronic illnesses of children. The majority of children with JIA have syndromes that are unique to childhood. Even in those types of JIA which have an adult equivalent, such as ankylosing spondylitis and psoriatic arthritis, children often have a different pattern of onset and course than adults. There have been two major sets of criteria for the diagnosis and classification for juvenile arthritis. The diagnostic criteria for juvenile chronic arthritis (JCA) were defined by the European League Against Rheumatism (EULAR).283 In North America, the most frequently used criteria have been those of the American College of Rheumatology (ACR) for juvenile

276. Alexander EL, Arnett FC, Provost TT, et al. Sjögren’s syndrome: association of anti-Ro(SSA) antibodies with vasculitis, hematologic abnormalities and serologic hyperreactivity. Ann Intern Med. 1983;98:155. 277. Maeno N, Takei S, Imanaka H, et al. Anti-alpha-fodrin antibodies in Sjögren’s syndrome in children. J Rheumatol. 2001;28:860. 278. Henriksson G, Manthorpe R, Bredberg A. Antibodies to CD4 in primary Sjögren’s syndrome. Rheum. 2000;39:142. 279. Izumi M, Hida A, Takagi Y, et al. MR imaging of the salivary glands in sicca syndrome: comparison of lipid profiles and imaging in patients with hyperlipidemia and patients with Sjögren’s syndrome. Am J Roentgenol. 2000;175(3):829.

280. Tomiita M, Ueda T, Nagata H, et al. Usefulness of magnetic resonance sialography in patients with juvenile Sjögren’s syndrome. Clin Exp Rheumatol. 2005;23(4):540. 281. Foeldvari I, Bidde M. Validation of the proposed ILAR classification criteria for juvenile idiopathic arthritis. International League of Associations for Rheumatology, Edmonton. Rheumatol. 2000;27(4):1069–1072. 282. Ohlsson V, Strike H, James-Ellison M, et al. Renal tubular acidosis, arthritis and autoantibodies: primary Sjögren’s syndrome in childhood. Rheumatology. 2006;45(2):238–240. 283. Nomenclature and classification of arthritis in children. European League Against Rheumatism (EULAR), Bulletin 4. Basel: National Zeitung AG; 1997.

DIFFERENTIAL DIAGNOSIS

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vitamin C deficiency and drug therapy). The sicca syndrome must be differentiated from eyelid, lacrimal gland, or duct abnormalities that cause keratoconjunctivitis sicca symptoms. A study of 23 children recommends that SS be assumed or confirmed when oral and ocular symptoms are present with recurrent salivary gland enlargement even in the absence of diagnostic criteria, which are less reliable.281 Likewise, just as renal tubular acidosis (RTA) is a known extraglandular complication in adults with SS, SS must be considered in a child with unexplained RTA.282

Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

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BOX 23.5  ILAR CLASSIFICATION OF JUVENILE IDIOPATHIC ARTHRITIS: EDMONTON, 2001

Arthritis of unknown etiology that begins before the 16th birthday and persists at least 6 weeks; other known conditions excluded.

Exclusions All categories of JIA are mutually excluded. a. Psoriasis or a history of psoriasis in the patient or 1st-degree relative. b. Arthritis in an HLA-B27 positive male beginning after the 6th birthday. c. Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis, or a history of one of these disorders in a 1st-degree relative.

2. Extended oligoarthritis: affects a total of more than four joints after the first 6 months of the disease Exclusions: a, b, c, d, e.

>> Polyarthritis (rheumatoid factor negative): arthritis affecting five or more joints during the first 6 months of disease; tests for RF are negative Exclusions: a, b, c, d, e.

>> Polyarthritis (rheumatoid factor positive): arthritis affecting five or more joints during the first 6 months of disease; tests for RF are positive Exclusions: a, b, c, e.

>> Psoriatic arthritis: arthritis and psoriasis, or arthritis and at least two of the following:

d. The presence of IgM RF on at least two occasions at least 3 months apart.

1. Dactylitis

e. The presence of systemic JIA in the patient.

3. Psoriasis in a 1st-degree relative

Categories:

>> Systemic arthritis: arthritis in one or more joints with or preceded by fever of at least 2 weeks’ duration that is documented to be daily for at least 3 days, accompanied by one or more of the following:

2. Nail pitting or onycholysis Exclusions: b, c, d, e.

>> Enthesitis related arthritis: arthritis and enthesitis, or arthritis or enthesitis with at least two of the following:

1. Sacroiliac joint tenderness and/or inflammatory lumbosacral pain

1. Evanescent (nonfixed) erythematous rash

2. Presence of HLA B27

2. Generalized lymph node enlargement

3. Onset of arthritis in a male after age 6 years

3. Hepatomegaly and/or splenomegaly

4. Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome or acute anterior uveitis in a 1st-degree relative.

4. Serositis Exclusions: a, b, c, d.

>> Oligoarthritis: arthritis affecting one to four joints during the first 6 months of disease. Two subcategories are recognized:

1. Persistent oligoarthritis: affects no more than four joints throughout the disease course.

JUVENILE IDIOPATHIC ARTHRITIS (JIA)

General definition of JIA

Exclusions: a, d, e.

>> Undifferentiated arthritis: arthritis that does not fulfill inclusion criteria for any category, or is excluded by fulfilling criteria for more than one category.

From Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton 2001. J Rheumatol 2004;31:309–392.

rheumatoid arthritis (JRA).284 These criteria, although similar, do not identify identical populations or spectra of disease, but have often been used interchangeably. This has led to confusion in interpretation of studies of the epidemiology, treatment and outcome of juvenile arthritis. The International League of Associations of Rheumatologists (ILAR) initially proposed,285 revised,286 and then re-revised287 criteria for the diagnosis and classification of juvenile arthritis as the ‘Edmonton Criteria’ (Box 23.5). The term JIA has been proposed to replace both JRA and JCA and encompasses all juvenile (8 years) who are HLA-DR4 positive, and is indistinguishable from adult rheumatoid arthritis. These children are more likely to have a symmetric small joint arthritis, rheumatoid nodules, and early erosive synovitis with a chronic course. They rarely develop chronic uveitis. Most patients with active polyarthritis have an elevated ESR, typically 20–80 mm/h. The ESR is often a useful measure of disease activity in children.304,340 Children with significant joint

328. Schneider R, Lang BA, Reilly BJ. Prognostic indicators of joint destruction in systemic-onset juvenile rheumatoid arthritis. J Pediatr. 1992;120: 200–205. 329. Lomater C, Gerloni V, Gattinara M, et al. Systemic onset juvenile idiopathic arthritis: a retrospective study of 80 consecutive patients followed for 10 years. J Rheumatol. 2000;27(2):491–496. 330. Prieur AM, Stephan JL. Macrophage activation syndrome in children with joint diseases. Rev Rheum Engl Ed. 1994;61:385–388. 331. Ravelli A, De Benedetti F, Viola S, et al. Macrophage activation syndrome in systemic juvenile rheumatoid arthritis successfully treated with cyclosporine. J Pediatr. 1996;128(2):275–278. 332. Mouy R, Stephan JL, Pillet P, et al. Efficacy of cyclosporine A in the treatment of macrophage activation syndrome in juvenile arthritis: report of five cases. J Pediatr. 1996;129(5):750–754. 333. Sailer M, Cabral D, Petty RE, et al. Rheumatoid factor positive, oligoarticular onset juvenile rheumatoid arthritis. J Rheumatol. 1997;24(3): 586–588.

334. Bunger C, Bulow J, Tondebold E. Microcirculation of the juvenile knee in chronic arthritis. Clin Orthop. 1986;204:294–299. 335. Vostrejs M, Hollister JR. Muscle atrophy and leg length discrepancies in pauciarticular juvenile rheumatoid arthritis. Am J Dis Child. 1988;142: 343–349. 336. Kanski JJ. Uveitis in juvenile chronic arthritis. Eye. 1988;2:641–645. 337. Sherry DD, Mellins ED, Wedgewood RJ. Decreasing severity of chronic uveitis in children with pauciarticular arthritis. Am J Dis Child. 1991;145:1026–1028. 338. Chalom EC, Goldsmith DP, Koehler MA, et al. Prevalence and outcome of uveitis in a regional cohort of patients with juvenile rheumatoid arthritis. J Rheumatol. 1997;24(10):2031–2034. 339. Nguyen QD, Foster S. Saving the vision of children with juvenile rheumatoid arthritis-associated uveitis. JAMA. 1998;280(13): 1132–1133. 340. Olshaker JS, Jerrard DA. The erythrocyte sedimentation rate. J Emerg Med. 1997;15(6):869–874.

Oligoarthritis

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Clinical course

disease often develop anemia of chronic disease with a hemoglobin in the range of 7–10 g/dL: the anemia is more marked in systemic arthritis.321,322

heralded by the involvement of a small number of fingers or toes, which are relatively asymptomatic but result in marked overgrowth of the digit(s).

Clinical course

Clinical course

Children with RF-positive polyarthritis are at risk for a prolonged and destructive course. The children are typically older girls with multiple joints involved (≥20), including the small joints of the hands and feet, early erosions, and rheumatoid nodules. The presence of hip arthritis has been shown to be a poor prognostic sign and may lead to destruction of the femoral heads.341 The onset of puberty seems to have no relation to disease activity or remission.342 Severe polyarticular (polyarticular and systemic JIA) disease with involvement of the temporomandibular joints prior to 5 years of age can result in micrognathia.343

Children with psoriatic arthritis may have a chronic lifelong problem that may follow a relapsing and remitting course. Arthritis mutilans and predominant DIP joint disease are unusual in childhood but many of the children have prolonged polyarthritis that may result in irreversible joint damage.344 Chronic anterior uveitis has been observed in up to 17% of children,345,346 is associated with a positive ANA titer, and is clinically indistinguishable from the uveitis in oligo- and polyarthritis. The uveitis associated with psoriatic arthritis may be more resistant to treatment than the other forms of chronic uveitis associated with childhood arthritis.342

Psoriatic arthritis The diagnosis of juvenile psoriatic arthritis was considered to be rare in children. Prior to 1982, there were fewer than 80 cases described in the English literature, when Shore and Ansell344 published the first large collection of 60 children with psoriatic arthritis. The rarity of juvenile psoriatic arthritis was unusual due to the relatively large number of children with psoriasis and the fact that 7% of adults with psoriasis have arthritis.345 Juvenile psoriatic arthritis was historically considered a juvenile spondyloarthropathy. However, studies have shown the juvenile psoriatic arthritis is a distinct entity, which has been underdiagnosed, often due to the long period from onset of arthritis to onset of psoriasis.345,346 Psoriatic arthritis accounts for up to 7% of JIA. There is a slight female predominance (1.6–2.3 girls to 1 boy) and it often affects young children with a median onset age of 5.9–10.1 years. The arthritis is often an asymmetric oligo- or polyarthritis affecting both large and small joints. At onset, the majority have nail pitting (67%), a family history of psoriasis (69%), or dactylitis (39%), and less than half of the children have the rash of psoriasis (13–43%).319,345,346 Current criteria do not require the development of psoriasis to confirm a diagnosis of psoriatic arthritis.286 Children with psoriatic arthritis do not usually develop a positive RF, but a positive ANA can be seen in 50% and is a risk factor for uveitis. HLA-DR1 and HLA-DR6 are statistically significant risk factors for development of juvenile psoriatic arthritis.346 There is a mild but not statistically significant increase in the presence of HLA-B27 in children with psoriatic arthritis and these children are more likely to have axial arthritis.344–346 The presentation of arthritis in children under 5 years of age is often

341. Blane CE, Ragsdale CG, Hensinger RN. Late effects of JRA on the hip. J Pediatr Orthop. 1987;7:677–701. 342. Cassidy JT, Petty RE. Textbook of pediatric rheumatology, ed 3. Philadelphia: WB Saunders; 1995. 343. Olson L, Echerdal O, Hallonsten AL. Craniomandibular function in juvenile chronic arthritis. A clinical and radiographic study. Swed Dent J. 1991;15:71–76. 344. Shore A, Ansell BM. Juvenile psoriatic arthritis-an analysis of 60 cases. J Pediatr. 1982;100(4):529–535. 345. Southwood TR, Petty RE, Malleson PN, et al. Psoriatic arthritis in children. Arthritis Rheum. 1989;32(8):1007–1013.

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JUVENILE IDIOPATHIC ARTHRITIS (JIA)

Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

Enthesitis-related arthritis The criteria for classification of enthesitis-related arthritis (ERA) describes a group of arthritides, which includes undifferentiated spondyloarthritis, ankylosing spondylitis, and inflammatory bowel disease associated arthritis. At the onset, juvenile spondyloarthropathies are often undifferentiated, preventing the application of adult-onset criteria for diagnosis. The addition of criteria for the presence of HLA-B27, a family history of HLA-B27 associated disease, and the onset of arthritis in a boy after the age of 8 will increase the number of children included in this category.286 ERA is often associated with enthesitis and arthralgias or arthritis, long before any axial skeletal involvement is identified.347 Enthesitis is identified when marked tenderness is noted at the 10, 2, and 6 o’clock positions on the patella, at the tibial tuberosity, iliac crest, or the attachments of the Achilles tendon or plantar fascia.342 In some children, the only manifestation of ERA may be severe enthesopathy of the heel(s).348 Laboratory evaluation of children with ERA is relatively unremarkable. There is often systemic inflammation with thrombocytosis and an elevated ESR. A highly elevated ESR (100) is more likely to be associated with inflammatory bowel disease in a child who meets criteria for ERA. The RF is uniformly negative, but ANAs can be present in the same proportion as in the normal childhood population.306,307 The primary extra-articular manifestation of ERA is an acute anterior uveitis (AAU), which can occur in up to 27% of children with ankylosing spondylitis.349 AAU is highly associated with the presence of HLA-B27 (50%).350 It typically presents with an acute, painful, red, photophobic eye. Although AAU may resolve with no ocular residua, some

346. Roberton DM, Cabral DA, Malleson PN, et al. Juvenile psoriatic arthritis: followup and evaluation of diagnostic criteria. J Rheumatol. 1996;23(1): 166–170. 347. Cabral DA, Oen KG, Petty RE. SEA syndrome revisited: a long-term follow-up of children with a syndrome of seronegative enthesopathy and arthropathy. J Rheumatol. 1992;19:1282–1285. 348. Gerster JC, Piccinin P. Enthesopathy of the heels in juvenile onset seronegative B-27 positive spondyloarthropathy. J Rheumatol. 1984;12:310–314. 349. Ansell BM Ankylosing spondylitis. In: Moll JMH, ed. Juvenile spondylitis and related disorders. Edinburgh: Churchill Livingstone; 1980:120–125. 350. Derhaag PJFM, Feltkamp TEW. Acute anterior uveitis and HLA-B27. Int Opthalmol. 1990;14:19–23.

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children will have a persistent uveitis that is relatively resistant to therapy and can result in blindness.351,352

Juvenile ankylosing spondylitis

JUVENILE IDIOPATHIC ARTHRITIS (JIA)

Children with juvenile ankylosing spondylitis (JAS) have often been diagnosed based on adult criteria that require radiographic evidence of sacroiliitis. JAS most often presents in late childhood or adolescence. Children with JAS and sacroiliac involvement are often HLA-B27 positive (82–95%) and the male-to-female ratio is 6 : 1.293 Most children ultimately diagnosed with JAS will initially have an episodic arthritis of large joints of the lower extremities and the tarsal bones. Regardless of axial disease, the most reliable predictors to differentiate JAS from oligo- or poly­ articular JIA are the presence of enthesitis and tarsal disease in children who have arthritis of the lower but not of the upper extremities.353 The presentation of JAS is most remarkable for the absence of axial involvement. Only 12.8–24% of children with JAS have pain, stiffness or limitation of motion of the sacroiliac or lumbosacral spine at onset. A peripheral arthropathy or enthesopathy affecting predominantly the lower limb joints and entheses is seen in 79–89.4%. These children tend to have fewer than five joints involved and rarely more than 10. At presentation, the joint involvement is usually asymmetric or even unilateral.354

Clinical course The initial course of JAS is characterized by remitting and relapsing symptoms, which are frequently mild. This cannot be differentiated from the child who seems to have recurrent bouts of reactive arthritis. However, the pattern of joint disease often progresses to become polyarticular and axial disease is usually evident after the 3rd year of illness.354 Children with longstanding JAS have been shown to develop tarsal bone coalition, which has been termed ankylosing tarsitis.355 Outcome data for JAS are incomplete and at times contradictory. The prognosis of JAS has been reported as both worse and better than adult-onset ankylosing spondylitis.356,357 Peripheral joint arthritis tends to be more common than that seen in adults.342 Hip disease has been associated with a poor functional outcome,356,358 and may require total hip arthroplasty.

351. Rosenbaum JT. Acute anterior uveitis and spondyloarthropathies. Rheum Dis Clin North Am. 1992;18:143–151. 352. Power WJ, Rodriguez A, Pedroza-Seres M, et al. Outcomes in anterior uveitis associated with the HLA-B27 haplotype. Ophthalmology. 1998;105(9):1646–1651. 353. Burgos-Vargas R, Vazquez-Mellado J. The early clinical recognition of juvenile-onset ankylosing spondylitis and its differentiation from juvenile rheumatoid arthritis. Arthritis Rheum. 1995;38(6):835–844. 354. Burgos-Vargas R, Petty RE. Juvenile ankylosing spondylitis. Rheum Dis Clin North Am. 1992;18:123–142. 355. Burgos-Vargas R. Spondyloarthropathies and psoriatic arthritis in children. Curr Opin Rheumatol. 1993;5(5):634–643. 356. Garcia-Morteo O, Maldonado-Cocco JA, Suarez-Almazor ME, et al. Ankylosing spondylitis of juvenile onset: comparison with adult onset disease. Scand J Rheumatol. 1983;12:246–248. 357. Calin A, Elswood J. The natural history of juvenile-onset ankylosing spondylitis: a 24-year retrospective case–control study. Br J Rheumatol. 1988;27:91–93.

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Inflammatory bowel disease-associated arthritis The prevalence of arthritis in children with inflammatory bowel disease (IBD) has been reported to be 7–21%, and usually occurs after the diagnosis of the bowel disease.359–361 There are two different patterns of arthritis seen.342 The most common type is an oligo- or polyarticular arthritis of the lower limbs. This group is less likely to meet the criteria for ERA. This arthritis is often episodic with exacerbations lasting 4–6 weeks and rarely for months. The activity of the peripheral arthritis often reflects the underlying activity of the IBD. The less common type of IBDassociated arthritis is a HLA-B27 associated oligoarticular arthritis of the lower limbs, with sacroiliitis and enthesitis, and no relationship to bowel inflammation.342 This form is more likely to persist and progress despite control of the bowel disease and seems identical to other ERA.

TREATMENT OF JIA The fundamental purpose of pharmacologic therapy is to achieve pain control, decrease inflammation, preserve function, and promote normal growth and overall development. The medications used are individualized for each patient, depending on their subtype of arthritis, degree of inflammation, and previous response to medications.

Non-steroidal anti-inflammatory drugs (NSAIDs) The mechanism of action of NSAIDs is by inhibition of the biosynthesis of prostaglandins by direct action on the enzyme cyclo-oxygenase (COX).362 The discovery of a second COX enzyme (COX-2), which is induced in the proinflammatory cascade, and the differential inhibition of the two COX isoforms (COX-1 and COX-2) by individual NSAIDs, has provided the basis for the development of safer NSAIDs.363 At this time, no COX-2-specific NSAID is approved for use in children. However, this exciting scientific advance will likely change NSAID use in children in the near future. NSAIDs are the initial therapeutic intervention in most children with JIA. They provide both analgesia and an antiinflammatory effect. The average time course for response to NSAIDs is 4–12 weeks.364 An NSAID is usually given for 4–8 weeks before substituting another if there has not been sufficient improvement. NSAIDs are generally safe and well tolerated in

358. Marks SH, Barnett M, Calin A. A case–control study of juvenile- and adult-onset ankylosing spondylitis. J Rheumatol. 1982;9:739–747. 359. Farmer RG, Michener WM. Prognosis of Crohn’s disease with onset in childhood and adolescence. Dig Dis Sci. 1979;24:752–757. 360. Lindsley C, Schaller J. Arthritis associated with inflammatory bowel disease in children. J Pediatr. 1974;84:16–20. 361. Hamilton JR, Bruce MD, Abdourhamam M. Inflammatory bowel disease in children and adolescents. Adv Pediatr. 1979;26:311–322. 362. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–235. 363. Vane J. Towards a better aspirin. Nature. 1994;367:215–216. 364. Lovell D, Giannini E, Brewer E. Time course of response to nonsteroidal anti-inflammatory drugs in patients with juvenile rheumatoid arthritis. Arthritis Rheum. 1984;27:1433–1437.

Rheumatic diseases in children, autoinflammatory syndromes in children, and selected systemic diseases with skin manifestations

Corticosteroids Intra-articular corticosteroid injections are safe and effective in controlling the synovitis in JIA.368,369 Triamcinolone hexacetonide (1 mg/kg for large joints, 0.5 mg/kg medium joints, 0.2– 0.4 mg total dose per small joint, 0.25/mg per kg per joint for temporomandibular joint) is the most commonly used agent and often provides long-term control of inflammation. The most frequent adverse consequence of intra-articular corticosteroids is development of subcutaneous atrophy at the site of injection. Systemic corticosteroids (1–2 mg/kg per day or up to 30 mg/kg per day for pulse dosing with maximum 1 g/day) can be used for rapid control of severe arthritis. However, long-term use should be restricted to those children with severe arthritis or systemic features that do not respond to other interventions.

has been shown to decrease the severity of uveitis in children with JIA who were dependent on topical corticosteroids.373 The major side-effects with methotrexate use are nausea, diarrhea and oral ulcers. Hair loss, headaches, and mood changes are also reported occasionally. Supplementation with folic acid (1 mg/day) or folinic acid (5–10 mg/week) can usually prevent gastrointestinal complications. Pneumonitis has been rarely reported in children taking methotrexate for rheumatic disease, and it usually responds to discontinuation of treatment and administration of corticosteroids. Hepatoxicity, mainly in the form of elevated transaminase levels, is a potential concern with the long-term use of methotrexate. Cirrhosis has not been reported in children on methotrexate for JIA, and several small studies have shown no significant liver biopsy abnormalities in JIA patients on methotrexate for 2.3–6.0 years of treatment.374,375 Laboratory monitoring (including a complete blood count, liver transaminases, plasma creatinine, and urinalysis) should be initiated monthly, and then reduced to every 6–8 weeks when the dose of methotrexate is stable.376

JUVENILE IDIOPATHIC ARTHRITIS (JIA)

most children. Abdominal pain, nausea and vomiting are common side-effects, but gastrointestinal hemorrhage is rare.365 Gastroduodenal injury is more frequent in children receiving high doses or more than one NSAID.366 The use of aspirin for JIA is no longer recommended, due to the risk of Reye syndrome, increased hepatotoxicity, bleeding, and four times per day dosing. In the USA, the most commonly used NSAID for JIA is naproxen (10–20 mg/kg per day divided, bid). In children with fevers and serositis associated with systemic arthritis and with JAS, indomethacin is often the most effective NSAID.342 Nearly two-thirds of children with juvenile arthritis are inadequately treated with NSAIDs alone.367 These children require additional pharmacologic interventions.

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Sulfasalazine Sulfasalazine has been used extensively in Europe, and increasingly in North America, for treatment of both spondyloarthropathies and JRA/JCA.377,378 It is typically given in the enteric-coated form at a dose of 50 mg/kg per day in two divided doses. A randomized, double-blind, placebo-controlled trial showed that sulfasalazine is both safe and effective for the treatment of oligoand polyarticular JCA.379 Serious side-effects have been noted in children with systemic arthritis and the routine use of sulfasalazine is not recommended for this subgroup.380,381

Methotrexate

Biologic agents

Methotrexate is the most commonly used second-line agent for treatment of juvenile arthritis. It is typically given at 0.3–1 mg/ kg (with a maximum of 25 mg orally or 15 mg/m2 subcutaneously) once weekly by mouth or subcutaneous injection. It has been shown to be superior to placebo in polyarticular and extended oligoarticular, but not systemic arthritis370,371 and can produce radiologic improvement of erosions.372 Methotrexate

A new category of therapeutic agents, biologic response modifiers, are now available for the treatment of juvenile arthritis. This group of medications includes the tumor necrosis factor-α (TNFα) inhibitors, costimulation modulators, interleukin-1 (IL-1) inhibitors, B-cell depleters, and IL-6 inhibitors. These medications are specifically designed to target various mediators involved in the immune response in arthritis.

365. Lindsley C. Uses of nonsteroidal anti-inflammatory drugs in pediatrics. Am J Dis Child. 1993;147:229–236. 366. Mulberg AE, Linz C, Bern E, et al. Identification of nonsteroidal antiinflammatory drug-induced gastroduodenal injury in children with juvenile rheumatoid arthritis. J Pediatr. 1993;122:647–649. 367. Giannini EH, Cawkwell GD. Drug treatment in children with juvenile rheumatoid arthritis. Past, present, and future. Pediatr Clin North Am. 1995;42(5):1099–1125. 368. Huppertz HI, Tschammler A, Horwitz AE, et al. Intraarticular corticosteroids for chronic arthritis in children: efficacy and effects on cartilage and growth. J Pediatr. 1995;127(2):317–321. 369. Padeh S, Passwell JH. Intraarticular corticosteroid injection in the management of children with chronic arthritis. Arthritis Rheum. 1998; 41(7):1210–1214. 370. Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis. Results of the USA–USSR double-blind, placebo-controlled trial. N Engl J Med. 1992;326:1043–1049. 371. Woo P, Wilkes H, Southwood T, et al. Low dose methotrexate is effective in extended oligoarticular arthritis but not in systemic arthritis of children. Arthritis Rheum. 1997;40:S47. 372. Ravelli A, Viola S, Ramenghi B, et al. Radiologic progression in patients with juvenile chronic arthritis treated with methotrexate. J Pediatr. 1998;133(2):262–265.

373. Weiss AH, Wallace CA, Sherry DD. Methotrexate for resistant chronic uveitis in children with juvenile rheumatoid arthritis. J Pediatr. 1998; 133(2):266–268. 374. Kugaathasan S, Newman AJ, Dahms BB, et al. Liver biopsy findings in patients with juvenile rheumatoid arthritis receiving long-term, weekly methotrexate therapy. J Pediatr. 1996;128:149–151. 375. Hashkes PJ, Balistreri WF, Bove KE, et al. The relationship of hepatotoxic risk factors and liver histology in methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr. 1999;134:47–52. 376. Szer IS, Kimura Y, Malleson PN, et al. Arthritis in children and adolescents: juvenile idiopathic arthritis, ed 1. New York: Oxford University Press; 2006. 377. Huang JL, Chen LC. Sulphasalazine in the treatment of children with chronic arthritis. Clin Rheumatol. 1998;17(5):359–363. 378. Imundo LF, Jacobs JC. Sulfasalazine therapy for juvenile rheumatoid arthritis. J Rheum. 1996;23(2):360–366. 379. van Rossum MA, Fiselier TJ, Franssen MJ, et al. Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group. Arthritis Rheum. 1998;41(5):808–816. 380. Ansell BM, Hall MA, Loftus JK, et al. A multicenter pilot study of sulphasalazine in juvenile chronic arthritis. Clin Exp Rheumatol. 1991;9: 201–203. 381. Hertzberger-ten Cate R, Cats A. Toxicity of sulfasalazine in systemic juvenile chronic arthritis. Clin Exp Rheumatol. 1991;9:85–88.

1301

v

FAMILIAL MEDITERRANEAN FEVER

1302

Neoplasms and Systemic Diseases

tor and the IL-1 accessor protein. A phase II trial of rilonacept in systemic JIA patients showed marked clinical improvements.391 Rilonacept is being used in doses of 2.2–4.4 mg/kg via a weekly subcutaneous injection. It should be noted that neither anakinra nor rilonacept is currently FDA approved for treatment of JIA. Rituximab is a chimeric anti-CD20 monoclonal antibody that targets pre-B, naïve, memory and mature B-cells. Rituximab was FDA approved in 2005 to treat adult rheumatoid arthritis refractory to the TNF-α inhibitors. There have been several case reports of the successful use of rituximab in adult patients with polyarticular and systemic JIA.392–394 Rituximab is given as a 500–1000 mg/dose intravenous infusion at week zero and then 2 weeks later. It is currently not FDA approved to treat JIA. The cytokine IL-6 has also been studied in the pathogenesis of systemic JIA. Tocilizumab is a humanized anti-IL-6 monoclonal receptor antibody available in Japan for the treatment of systemic JIA. A recent withdrawal phase III trial showed efficacy and an acceptable safety profile for the use of tocilizumab in systemic JIA patients.395 Tocilizumab is administered as an intravenous infusion dosed at 8 mg/kg every 2 weeks. It is not currently FDA approved to treat JIA.

TNF-α is a key cytokine in the inflammatory cascade of arthritis patients, and soluble TNF receptor serum levels correlate with other inflammatory parameters such as C-reactive protein in active JIA. The TNF-α inhibitors include etanercept (a soluble TNF receptor), infliximab (a chimeric monoclonal anti-TNF-α antibody), and adalimumab (a fully humanized anti-TNF-α antibody). Etanercept, 0.4 mg/kg (maximum 25 mg) given subcutaneously twice weekly, is safe, effective and FDA approved to treat moderate to severe polyarticular JIA in children aged 2 and above.382 Adalimumab, 20 mg for those 3.0 mg/ dL is suggestive of KD.503 Supplemental laboratory criteria included in this algorithm include: albumin ≤3.0 g/dL; anemia for age; elevation of serum ALT; platelets ≥450 000 after illness

In addition to the clinical criteria for KD, patients may present with other organ system involvement presumed to result from the systemic vasculitis. Right upper quadrant pain, nausea, and vomiting may be associated with tenderness and fullness in the right upper quadrant, suggesting hydrops of the gallbladder which can be confirmed by abdominal ultrasonography and resolves without surgical intervention. Other gastrointestinal manifestations include diarrhea, small bowel obstruction, ileus, hepatitis, and pancreatitis. Arthralgia and/or arthritis is seen in up to 30% of patients. Arthritis can occur in the first week of illness and is usually polyarticular, involving the knees, ankles and hands, persisting for about three weeks. More common is late-onset arthritis in the 2nd to 3rd week of illness, which is usually pauciarticular, involving knees, ankles, and hips. The mean duration is approximately 2–3 weeks. The arthritis and arthralgias are self-limited, rarely persisting beyond the fourth week of illness. Patients may complain of photophobia during the acute illness. Mild anterior uveitis is common in acute KD and has been reported in approximately 70% of patients examined with a slit-lamp during the first 10 days of illness. Sterile pyuria in acute KD is common. Dysuria may be associated with urethral meatitis during acute KD. Evidence of aseptic meningitis is seen in about one-half of patients who undergo lumbar puncture, with mild pleocytosis but normal glucose and protein values in the cerebrospinal fluid. Hepatic dysfunction with mild obstructive jaundice and mildly to moderately elevated levels of serum transaminases occurs. Localized erythema at the site of previous bacille Calmette–Guérin (BCG) inoculation is common in Japanese patients and those from other areas where BCG is used widely. Takayama et al.504 reported erythema at the BCG inoculation site in 88% of patients who develop KD within 4–6 months following BCG vaccination, but this was not seen in patients who developed KD later than 3